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Diehl, Anna Mae

Overview:

Our lab has a long standing interest in liver injury and repair. To learn more about the mechanisms that regulate this process, we study cultured cells, animal models of acute and chronic liver damage and samples from patients with various types of liver disease. Our group also conducts clinical trials in patients with chronic liver disease. We are particularly interested in fatty liver diseases, such as alcoholic fatty liver disease and nonalcoholic fatty liver disease (NAFLD).

Research by our group has advanced understanding in two main areas: 1) immune system regulation of liver injury and regeneration and 2)the role of fetal morphogens, such as the hedgehog pathway, in regulating fibrotic responses to liver damage. Our basic research programs have been enjoyed continuous NIH support since 1989. We welcome students, post-doctoral fellows and visiting scientists who have interests in this research area to contact us about training opportunities and potential collaborations.

Since 2001 we have also been an active participant in the NIDDK-funded Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN), a national consortium comprised of 8 university medical centers selected to generate a national registry for patients with NAFLD and to conduct multicenter treatment trials for this disorder. We are actively recruiting patients for this program, as well as a number of other industry-supported NAFLD studies.

Positions:

Florence McAlister Professor of Medicine, in the School of Medicine

Medicine, Gastroenterology
School of Medicine

Professor of Medicine

Medicine, Gastroenterology
School of Medicine

Professor in Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Regeneration Next Initiative

Regeneration Next Initiative
School of Medicine

Education:

M.D. 1978

M.D. — Georgetown University

Medical Resident, Medicine

Johns Hopkins University

Fellow In Gastroenterology, Medicine

Johns Hopkins University

Grants:

Building Interdisciplinary Research Careers in Women's Health

Administered By
Obstetrics and Gynecology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 26, 2002
End Date
July 31, 2022

Postdoctoral training in genomic medicine research

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
June 14, 2017
End Date
May 31, 2022

Hedgehog Signaling and Adult Liver Regeneration

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 15, 2016
End Date
August 31, 2021

Duke Training Grant in Digestive Diseases and Nutrition

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1988
End Date
June 30, 2021

TNF Alpha and Recovery from Alchoholic Liver Injury

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2014
End Date
July 31, 2019

Endocrinology and Metabolism Training Program

Administered By
Medicine, Endocrinology, Metabolism, and Nutrition
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2014
End Date
June 30, 2019

NASH Clinical Research Network

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2004
End Date
June 30, 2019

Epigenetics and the Development of Nonalcoholic Fatty Liver Disease

Administered By
Medicine, Gastroenterology
AwardedBy
American College of Gastroenterology
Role
Mentor
Start Date
July 01, 2015
End Date
June 30, 2018

Serial Block Face Scanning Electron Microscope

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Major User
Start Date
June 01, 2016
End Date
May 31, 2018

Trabecular Meshwork Cytoskeletal Signaling-Regulation of Aqueous Humor Outflow

Administered By
Ophthalmology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
January 01, 2008
End Date
April 30, 2018

TAIWANJ JKB 121-001

Administered By
Medicine, Gastroenterology
AwardedBy
TaiwanJ Pharmaceuticals Co. Ltd
Role
Principal Investigator
Start Date
April 01, 2015
End Date
March 31, 2018

An integrated and diverse genomic medicine program for undiagnosed diseases

Administered By
Pediatrics, Medical Genetics
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
July 01, 2014
End Date
March 31, 2018

Submucosal esophageal structures as a progenitor niche for esophageal repair

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
April 01, 2013
End Date
March 31, 2018

Impact of IMM-124E on Innate Immune and Fibrogenic Responses in Preclinical Mouse Model of NASH

Administered By
Medicine, Gastroenterology
AwardedBy
Immuron, Ltd
Role
Principal Investigator
Start Date
December 22, 2016
End Date
December 21, 2017

Role of the Stroma in Fibrolamellar Hepatocellular Carcinoma

Administered By
Medicine, Gastroenterology
AwardedBy
Fibrolamellar Cancer Foundation
Role
Principal Investigator
Start Date
December 08, 2016
End Date
December 07, 2017

Impact of Fructose on Metabolism, Energy Homeostasis and MR biomarkers in NAFLD

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
January 01, 2012
End Date
September 30, 2016

Pathogenesis of NASH Cirrhosis

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 15, 2015
End Date
August 31, 2016

Cancer Biology Training Grant

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Cancer Institute
Role
Mentor
Start Date
July 01, 1993
End Date
March 31, 2016

Liver Disease in Obesity

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 1999
End Date
March 31, 2015

TNF Alpha and Recovery from Alchoholic Liver Injury

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 1994
End Date
July 31, 2014

Rac1 Promotes Hepatic Stellate Accumulation/Activation in Liver Injury

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 22, 2009
End Date
June 30, 2014

Characterizing Alcohol's Effects on Repair of Liver Injury

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2009
End Date
August 31, 2012

Hyperinsulimia and Insulin Resistance in Nonalcoholic Fatty Liver Disease

Administered By
Duke Clinical Research Institute
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
April 01, 2006
End Date
December 31, 2010

Cholesterol, Hedgehog Signaling & Fetal Alcohol Syndrome

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 28, 2007
End Date
August 31, 2010

Drug Abuse: Discovering Ligands for Pertinent GPCRs

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 30, 2006
End Date
June 30, 2010

Innovative Assays for Oncogenic Hedgehog Signaling

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
April 21, 2006
End Date
February 28, 2010

Liver Derived Microparticles In Cirrhosis Pathogenesis

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 06, 2008
End Date
August 31, 2009

Metabolic Profiling to Identify Alcohol Biomarker Signature

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
June 01, 2006
End Date
May 31, 2009

Bioenergetics and Alcoholic Liver Disease Pathogenesis

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 2000
End Date
April 30, 2006
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Awards:

AASLD Distinguished Achievement Award. American Association for the Study of Liver Diseases.

Type
National
Awarded By
American Association for the Study of Liver Diseases
Date
January 01, 2012

Publications:

HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease.

Recent clinical studies found a strong association of colonic inflammation and Inflammatory bowel disease (IBD)-like phenotype with NonAlcoholic Fatty liver Disease (NAFLD) yet the mechanisms remain unknown. The present study identifies high mobility group box 1 (HMGB1) as a key mediator of intestinal inflammation in NAFLD and outlines a detailed redox signaling mechanism for such a pathway. NAFLD mice showed liver damage and release of elevated HMGB1 in systemic circulation and increased intestinal tyrosine nitration that was dependent on NADPH oxidase. Intestines from NAFLD mice showed higher Toll like receptor 4 (TLR4) activation and proinflammatory cytokine release, an outcome strongly dependent on the existence of NAFLD pathology and NADPH oxidase. Mechanistically intestinal epithelial cells showed the HMGB1 activation of TLR-4 was both NADPH oxidase and peroxynitrite dependent with the latter being formed by the activation of NADPH oxidase. Proinflammatory cytokine production was significantly blocked by the specific peroxynitrite scavenger phenyl boronic acid (FBA), AKT inhibition and NADPH oxidase inhibitor Apocynin suggesting NADPH oxidase-dependent peroxynitrite is a key mediator in TLR-4 activation and cytokine release via an AKT dependent pathway. Studies to ascertain the mechanism of HMGB1-mediated NADPH oxidase activation showed a distinct role of Receptor for advanced glycation end products (RAGE) as the use of inhibitors targeted against RAGE or use of deformed HMGB1 protein prevented NADPH oxidase activation, peroxynitrite formation, TLR4 activation and finally cytokine release. Thus, in conclusion the present study identifies a novel role of HMGB1 mediated inflammatory pathway that is RAGE and redox signaling dependent and helps promote ectopic intestinal inflammation in NAFLD.

Authors
Chandrashekaran, V; Seth, RK; Dattaroy, D; Alhasson, F; Ziolenka, J; Carson, J; Berger, FG; Kalyanaraman, B; Diehl, AM; Chatterjee, S
MLA Citation
Chandrashekaran, V, Seth, RK, Dattaroy, D, Alhasson, F, Ziolenka, J, Carson, J, Berger, FG, Kalyanaraman, B, Diehl, AM, and Chatterjee, S. "HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease." Redox biology 13 (October 2017): 8-19.
PMID
28551086
Source
epmc
Published In
Redox Biology
Volume
13
Publish Date
2017
Start Page
8
End Page
19
DOI
10.1016/j.redox.2017.05.005

The diversity and plasticity of adult hepatic progenitor cells and their niche.

The liver is a unique organ for homoeostasis with regenerative capacities. Hepatocytes possess a remarkable capacity to proliferate upon injury; however, in more severe scenarios liver regeneration is believed to arise from at least one, if not several facultative hepatic progenitor cell compartments. Newly identified pericentral stem/progenitor cells residing around the central vein is responsible for maintaining hepatocyte homoeostasis in the uninjured liver. In addition, hepatic progenitor cells have been reported to contribute to liver fibrosis and cancers. What drives liver homoeostasis, regeneration and diseases is determined by the physiological and pathological conditions, and especially the hepatic progenitor cell niches which influence the fate of hepatic progenitor cells. The hepatic progenitor cell niches are special microenvironments consisting of different cell types, releasing growth factors and cytokines and receiving signals, as well as the extracellular matrix (ECM) scaffold. The hepatic progenitor cell niches maintain and regulate stem cells to ensure organ homoeostasis and regeneration. In recent studies, more evidence has been shown that hepatic cells such as hepatocytes, cholangiocytes or myofibroblasts can be induced to be oval cell-like state through transitions under some circumstance, those transitional cell types as potential liver-resident progenitor cells play important roles in liver pathophysiology. In this review, we describe and update recent advances in the diversity and plasticity of hepatic progenitor cell and their niches and discuss evidence supporting their roles in liver homoeostasis, regeneration, fibrosis and cancers.

Authors
Chen, J; Chen, L; Zern, MA; Theise, ND; Diehl, AM; Liu, P; Duan, Y
MLA Citation
Chen, J, Chen, L, Zern, MA, Theise, ND, Diehl, AM, Liu, P, and Duan, Y. "The diversity and plasticity of adult hepatic progenitor cells and their niche." Liver international : official journal of the International Association for the Study of the Liver 37.9 (September 2017): 1260-1271. (Review)
Website
http://hdl.handle.net/10161/14630
PMID
28135758
Source
epmc
Published In
Liver International
Volume
37
Issue
9
Publish Date
2017
Start Page
1260
End Page
1271
DOI
10.1111/liv.13377

Low and High Birth Weights Are Risk Factors for Nonalcoholic Fatty Liver Disease in Children.

To examine the distribution of birth weight in children with nonalcoholic fatty liver disease (NAFLD) compared with the general US population, and to investigate the relationship between birth weight and severity of NAFLD.A multicenter, cross-sectional study of children with biopsy-proven NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network Database. Birth weight was categorized as low birth weight (LBW), normal birth weight (NBW), or high birth weight (HBW) and compared with the birth weight distribution in the general US population. The severity of liver histology was assessed by birth weight category.Children with NAFLD (n = 538) had overrepresentation of both LBW and HBW compared with the general US population (LBW, 9.3%; NBW, 75.8%; HBW, 14.9% vs LBW, 6.1%; NBW, 83.5%; HBW 10.5%; P < .0001). Children with HBW had significantly greater odds of having more severe steatosis (OR, 1.82, 95% CI. 1.15-2.88) and nonalcoholic steatohepatitis (OR, 2.03; 95% CI, 1.21-3.40) compared with children with NBW. In addition, children with NAFLD and LBW had significantly greater odds of having advanced fibrosis (OR, 2.23; 95% CI, 1.08-4.62).Birth weight involves maternal and in utero factors that may have long-lasting consequences. Children with both LBW and HBW may be at increased risk for developing NAFLD. Among children with NAFLD, those with LBW or HBW appear to be at increased risk for more severe disease.

Authors
Newton, KP; Feldman, HS; Chambers, CD; Wilson, L; Behling, C; Clark, JM; Molleston, JP; Chalasani, N; Sanyal, AJ; Fishbein, MH; Lavine, JE; Schwimmer, JB; Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN),
MLA Citation
Newton, KP, Feldman, HS, Chambers, CD, Wilson, L, Behling, C, Clark, JM, Molleston, JP, Chalasani, N, Sanyal, AJ, Fishbein, MH, Lavine, JE, Schwimmer, JB, and Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN), . "Low and High Birth Weights Are Risk Factors for Nonalcoholic Fatty Liver Disease in Children." The Journal of pediatrics 187 (August 2017): 141-146.e1.
PMID
28366357
Source
epmc
Published In
The Journal of Pediatrics
Volume
187
Publish Date
2017
Start Page
141
End Page
146.e1
DOI
10.1016/j.jpeds.2017.03.007

Thymosin beta-4 regulates activation of hepatic stellate cells via hedgehog signaling.

The molecular mechanisms of thymosin beta-4 (TB4) involved in regulating hepatic stellate cell (HSC) functions remain unclear. Therefore, we hypothesize that TB4 influences HSC activation through hedgehog (Hh) pathway. HSC functions declined in a TB4 siRNA-treated LX-2. TB4 suppression down-regulated both integrin linked kinase (ILK), an activator of smoothened, and phosphorylated glycogen synthase kinase 3 beta (pGSK-3B), an inactive form of GSK-3B degrading glioblastoma 2 (GLI2), followed by the decreased expression of both smoothened and GLI2. A TB4 CRISPR also blocked the activation of primary HSCs, with decreased expression of smoothened, GLI2 and ILK compared with cells transfected with nontargeting control CRISPR. Double immunostaining and an immunoprecipitation assay revealed that TB4 interacted with either smoothened at the cytoplasm or GLI2 at the nucleus in LX-2. Smoothened suppression in primary HSCs using a Hh antagonist or adenovirus transduction decreased TB4 expression with the reduced activation of HSCs. Tb4-overexpressing transgenic mice treated with CCl4 were susceptible to the development hepatic fibrosis with higher levels of ILK, pGSK3b, and Hh activity, as compared with wild-type mice. These findings demonstrate that TB4 regulates HSC activation by influencing the activity of Smoothened and GLI2, suggesting TB4 as a novel therapeutic target in liver disease.

Authors
Kim, J; Hyun, J; Wang, S; Lee, C; Lee, J-W; Moon, E-Y; Cha, H; Diehl, AM; Jung, Y
MLA Citation
Kim, J, Hyun, J, Wang, S, Lee, C, Lee, J-W, Moon, E-Y, Cha, H, Diehl, AM, and Jung, Y. "Thymosin beta-4 regulates activation of hepatic stellate cells via hedgehog signaling." Scientific Reports 7.1 (June 19, 2017): 3815-.
PMID
28630423
Source
epmc
Published In
Scientific Reports
Volume
7
Issue
1
Publish Date
2017
Start Page
3815
DOI
10.1038/s41598-017-03782-x

Reply.

Authors
Yang, JD; AbdelmaleK, MF; Guy, CD; Diehl, AM; Suzuki, A
MLA Citation
Yang, JD, AbdelmaleK, MF, Guy, CD, Diehl, AM, and Suzuki, A. "Reply." Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association (May 11, 2017). (Letter)
Website
http://hdl.handle.net/10161/14628
PMID
28502788
Source
epmc
Published In
Clinical Gastroenterology and Hepatology
Publish Date
2017
DOI
10.1016/j.cgh.2017.05.003

Reply to Kim et al.

Authors
Patel, YA; Henao, R; Moylan, CA; Guy, CD; Piercy, DL; Diehl, AM; Abdelmalek, MF
MLA Citation
Patel, YA, Henao, R, Moylan, CA, Guy, CD, Piercy, DL, Diehl, AM, and Abdelmalek, MF. "Reply to Kim et al." The American journal of gastroenterology 112.5 (May 2017): 807-808.
PMID
28469220
Source
epmc
Published In
The American Journal of Gastroenterology (Elsevier)
Volume
112
Issue
5
Publish Date
2017
Start Page
807
End Page
808
DOI
10.1038/ajg.2017.45

Loss of pericyte smoothened activity in mice with genetic deficiency of leptin.

Obesity is associated with multiple diseases, but it is unclear how obesity promotes progressive tissue damage. Recovery from injury requires repair, an energy-expensive process that is coupled to energy availability at the cellular level. The satiety factor, leptin, is a key component of the sensor that matches cellular energy utilization to available energy supplies. Leptin deficiency signals energy depletion, whereas activating the Hedgehog pathway drives energy-consuming activities. Tissue repair is impaired in mice that are obese due to genetic leptin deficiency. Tissue repair is also blocked and obesity enhanced by inhibiting Hedgehog activity. We evaluated the hypothesis that loss of leptin silences Hedgehog signaling in pericytes, multipotent leptin-target cells that regulate a variety of responses that are often defective in obesity, including tissue repair and adipocyte differentiation.We found that pericytes from liver and white adipose tissue require leptin to maintain expression of the Hedgehog co-receptor, Smoothened, which controls the activities of Hedgehog-regulated Gli transcription factors that orchestrate gene expression programs that dictate pericyte fate. Smoothened suppression prevents liver pericytes from being reprogrammed into myofibroblasts, but stimulates adipose-derived pericytes to become white adipocytes. Progressive Hedgehog pathway decay promotes senescence in leptin-deficient liver pericytes, which, in turn, generate paracrine signals that cause neighboring hepatocytes to become fatty and less proliferative, enhancing vulnerability to liver damage.Leptin-responsive pericytes evaluate energy availability to inform tissue construction by modulating Hedgehog pathway activity and thus, are at the root of progressive obesity-related tissue pathology. Leptin deficiency inhibits Hedgehog signaling in pericytes to trigger a pericytopathy that promotes both adiposity and obesity-related tissue damage.

Authors
Xie, G; Swiderska-Syn, M; Jewell, ML; Machado, MV; Michelotti, GA; Premont, RT; Diehl, AM
MLA Citation
Xie, G, Swiderska-Syn, M, Jewell, ML, Machado, MV, Michelotti, GA, Premont, RT, and Diehl, AM. "Loss of pericyte smoothened activity in mice with genetic deficiency of leptin." BMC cell biology 18.1 (April 20, 2017): 20-.
Website
http://hdl.handle.net/10161/15150
PMID
28427343
Source
epmc
Published In
BMC Cell Biology
Volume
18
Issue
1
Publish Date
2017
Start Page
20
DOI
10.1186/s12860-017-0135-y

Id2 Collaborates with Id3 To Suppress Invariant NKT and Innate-like Tumors.

Inhibitor of DNA binding (Id) proteins, including Id1-4, are transcriptional regulators involved in promoting cell proliferation and survival in various cell types. Although upregulation of Id proteins is associated with a broad spectrum of tumors, recent studies have identified that Id3 plays a tumor-suppressor role in the development of Burkitt's lymphoma in humans and hepatosplenic T cell lymphomas in mice. In this article, we report rapid lymphoma development in Id2/Id3 double-knockout mice that is caused by unchecked expansion of invariant NKT (iNKT) cells or a unique subset of innate-like CD1d-independent T cells. These populations began to expand in neonatal mice and, upon malignant transformation, resulted in mortality between 3 and 11 mo of age. The malignant cells also gave rise to lymphomas upon transfer to Rag-deficient and wild-type hosts, reaffirming their inherent tumorigenic potential. Microarray analysis revealed a significantly modified program in these neonatal iNKT cells that ultimately led to their malignant transformation. The lymphoma cells demonstrated chromosome instability along with upregulation of several signaling pathways, including the cytokine-cytokine receptor interaction pathway, which can promote their expansion and migration. Dysregulation of genes with reported driver mutations and the NF-κB pathway were found to be shared between Id2/Id3 double-knockout lymphomas and human NKT tumors. Our work identifies a distinct premalignant state and multiple tumorigenic pathways caused by loss of function of Id2 and Id3. Thus, conditional deletion of Id2 and Id3 in developing T cells establishes a unique animal model for iNKT and relevant innate-like lymphomas.

Authors
Li, J; Roy, S; Kim, Y-M; Li, S; Zhang, B; Love, C; Reddy, A; Rajagopalan, D; Dave, S; Diehl, AM; Zhuang, Y
MLA Citation
Li, J, Roy, S, Kim, Y-M, Li, S, Zhang, B, Love, C, Reddy, A, Rajagopalan, D, Dave, S, Diehl, AM, and Zhuang, Y. "Id2 Collaborates with Id3 To Suppress Invariant NKT and Innate-like Tumors." Journal of immunology (Baltimore, Md. : 1950) 198.8 (April 2017): 3136-3148.
PMID
28258199
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
198
Issue
8
Publish Date
2017
Start Page
3136
End Page
3148
DOI
10.4049/jimmunol.1601935

Hypoxia of the growing liver accelerates regeneration.

After portal vein ligation of 1 side of the liver, the other side regenerates at a slow rate. This slow growth may be accelerated to rapid growth by adding a transection between the 2 sides, i.e., performing portal vein ligation and parenchymal transection. We found that in patients undergoing portal vein ligation and parenchymal transection, portal vein hyperflow in the regenerating liver causes a significant reduction of arterial flow due to the hepatic arterial buffer response. We postulated that the reduction of arterial flow induces hypoxia in the regenerating liver and used a rat model to assess hypoxia and its impact on kinetic growth.A rat model of rapid (portal vein ligation and parenchymal transection) and slow regeneration (portal vein ligation) was established. Portal vein flow and pressure data were collected. Liver regeneration was assessed in rats using computed tomography, proliferation with Ki-67, and hypoxia with pimonidazole and HIF-1α staining.The rat model confirmed acceleration of regeneration in portal vein ligation and parenchymal transection as well as the portal vein hyperflow seen in patients. Additionally, tissue hypoxia was observed after portal vein ligation and parenchymal transection, while little hypoxia staining was detected after portal vein ligation. To determine if hypoxia is a consequence or an inciting stimulus of rapid liver regeneration, we used a prolyl-hydroxylase blocker to activate hypoxia signaling pathways in the slow model. This clearly accelerated slow to rapid liver regeneration. Inversely, abrogation of hypoxia led to a blunting of rapid growth to slow growth. The topical application of prolyl-hydroxylase inhibitors on livers in rats induced spontaneous areas of regeneration.This study shows that pharmacologically induced hypoxic signaling accelerates liver regeneration similar to portal vein ligation and parenchymal transection. Hypoxia is likely an accelerator of liver regeneration. Also, prolyl-hydroxylase inhibitors may be used to enhance liver regeneration pharmaceutically.

Authors
Schadde, E; Tsatsaris, C; Swiderska-Syn, M; Breitenstein, S; Urner, M; Schimmer, R; Booy, C; Z'graggen, BR; Wenger, RH; Spahn, DR; Hertl, M; Knechtle, S; Diehl, AM; Schläpfer, M; Beck-Schimmer, B
MLA Citation
Schadde, E, Tsatsaris, C, Swiderska-Syn, M, Breitenstein, S, Urner, M, Schimmer, R, Booy, C, Z'graggen, BR, Wenger, RH, Spahn, DR, Hertl, M, Knechtle, S, Diehl, AM, Schläpfer, M, and Beck-Schimmer, B. "Hypoxia of the growing liver accelerates regeneration." Surgery 161.3 (March 2017): 666-679.
PMID
27436690
Source
epmc
Published In
Surgery
Volume
161
Issue
3
Publish Date
2017
Start Page
666
End Page
679
DOI
10.1016/j.surg.2016.05.018

Novel plasma biomarkers associated with liver disease severity in adults with nonalcoholic fatty liver disease.

Despite the high prevalence of nonalcoholic fatty liver disease (NAFLD), therapeutic options and noninvasive markers of disease activity and severity remain limited. We investigated the association between plasma biomarkers and liver histology in order to identify markers of disease activity and severity in patients with biopsy-proven NAFLD. Thirty-two plasma biomarkers chosen a priori as possible discriminators of NAFLD were measured in participants enrolled in the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network. Dichotomized histologic outcomes were evaluated using centrally read biopsies. Biomarkers with statistically significant associations with NAFLD histology were evaluated in multivariable models adjusted for clinical factors. Of 648 participants (74.4% white, 61.7% female, mean age 47.7 years), 58.0% had definite NASH, 55.5% had mild/no fibrosis (stage 0-1), and 44.4% had significant fibrosis (stage 2-4). Increased activated plasminogen activator inhibitor 1 had a strong association with definite NASH compared to not NASH or borderline NASH in multivariable analysis (odds ratio = 1.20, 95% confidence interval 1.08-1.34, P < 0.001). Biomarkers associated with significant fibrosis (versus mild/no fibrosis) in multivariable analysis included higher levels of interleukin-8, monocyte chemoattractant protein-1, resistin, soluble interleukin-1 receptor I, soluble interleukin-2 receptor alpha, and tumor necrosis factor alpha and lower levels of insulin-like growth factor 2.Specific plasma biomarkers are significantly associated with disease activity and severity of fibrosis in NAFLD and are potentially valuable tools for noninvasive stratification of patients with NAFLD and identification of targets for therapeutic intervention. (Hepatology 2017;65:65-77).

Authors
Ajmera, V; Perito, ER; Bass, NM; Terrault, NA; Yates, KP; Gill, R; Loomba, R; Diehl, AM; Aouizerat, BE; NASH Clinical Research Network,
MLA Citation
Ajmera, V, Perito, ER, Bass, NM, Terrault, NA, Yates, KP, Gill, R, Loomba, R, Diehl, AM, Aouizerat, BE, and NASH Clinical Research Network, . "Novel plasma biomarkers associated with liver disease severity in adults with nonalcoholic fatty liver disease." Hepatology (Baltimore, Md.) 65.1 (January 2017): 65-77.
PMID
27532276
Source
epmc
Published In
Hepatology
Volume
65
Issue
1
Publish Date
2017
Start Page
65
End Page
77
DOI
10.1002/hep.28776

Patient Sex, Reproductive Status, and Synthetic Hormone Use Associate With Histologic Severity of Nonalcoholic Steatohepatitis.

Sex and sex hormones can affect responses of patients with nonalcoholic fatty liver disease (NAFLD) to metabolic stress and development of hepatocyte injury and inflammation.We collected data from 3 large U.S. studies of patients with NAFLD (between October 2004 and June 2013) to assess the association between histologic severity and sex, menopause status, synthetic hormone use, and menstrual abnormalities in 1112 patients with a histologic diagnosis of NAFLD. We performed logistic or ordinal logistic regression models, adjusting for covariates relevant to an increase of hepatic metabolic stress.Premenopausal women were at an increased risk of lobular inflammation, hepatocyte ballooning, and Mallory-Denk bodies than men and also at an increased risk of lobular inflammation and Mallory-Denk bodies than postmenopausal women (P < .01). Use of oral contraceptives was associated with an increased risk of lobular inflammation and Mallory-Denk bodies in premenopausal women, whereas hormone replacement therapy was associated with an increased risk of lobular inflammation in postmenopausal women (P < .05).Being a premenopausal woman or a female user of synthetic hormones is associated with increased histologic severity of hepatocyte injury and inflammation among patients with NAFLD at given levels of hepatic metabolic stress.

Authors
Yang, JD; Abdelmalek, MF; Guy, CD; Gill, RM; Lavine, JE; Yates, K; Klair, J; Terrault, NA; Clark, JM; Unalp-Arida, A; Diehl, AM; Suzuki, A; Nonalcoholic Steatohepatitis Clinical Research Network,
MLA Citation
Yang, JD, Abdelmalek, MF, Guy, CD, Gill, RM, Lavine, JE, Yates, K, Klair, J, Terrault, NA, Clark, JM, Unalp-Arida, A, Diehl, AM, Suzuki, A, and Nonalcoholic Steatohepatitis Clinical Research Network, . "Patient Sex, Reproductive Status, and Synthetic Hormone Use Associate With Histologic Severity of Nonalcoholic Steatohepatitis." Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 15.1 (January 2017): 127-131.e2.
PMID
27523635
Source
epmc
Published In
Clinical Gastroenterology and Hepatology
Volume
15
Issue
1
Publish Date
2017
Start Page
127
End Page
131.e2
DOI
10.1016/j.cgh.2016.07.034

TRPV4 activation of endothelial nitric oxide synthase resists nonalcoholic fatty liver disease by blocking CYP2E1-mediated redox toxicity.

NAFLD is a clinically progressive disease with steatosis, inflammation, endothelial dysfunction and fibrosis being the stages where clinical intervention becomes necessary. Lack of early biomarkers and absence of a FDA approved drug obstructs efforts for effective treatment. NAFLD progression is strongly linked to a balance between liver injury, tissue regeneration and the functioning of endogenous defense mechanisms. The failure of the defense pathways to resist the tissue damage arising from redox stress, one of the "multiple hits" in disease progression, give rise to heightened inflammation and occasional fibrosis. We introduce an endogenous defense mechanism in the liver that is mediated by TRPV4, a transient receptor potential calcium-permeable ion channel that responds to the cytotoxic liver environment and negatively regulates CYP2E1, a cytochrome p450 enzyme. Using Trpv4-/- mice and cultured primary cells, we show that TRPV4 is activated both by damage associated molecular pattern HMGB1 and collagen in diseased Kupffer cells that in turn activate the endothelial NOS (NOS3) to release nitric oxide (NO). The diffusible NO acts in a paracrine fashion in neighboring hepatocytes to deactivate the redox toxicity induced by CYP2E1. We also find that CYP2E1-mediated TRPV4 repression in late stages causes an unrestricted progression of disease. Thus, TRPV4 functions as a sensor of cell stress in the diseased fatty liver and constitutes an endogenous defense molecule, a novel concept with potential for therapeutic approaches against NAFLD, perhaps also against hepatic drug toxicity in general.

Authors
Seth, RK; Das, S; Dattaroy, D; Chandrashekaran, V; Alhasson, F; Michelotti, G; Nagarkatti, M; Nagarkatti, P; Diehl, AM; Bell, PD; Liedtke, W; Chatterjee, S
MLA Citation
Seth, RK, Das, S, Dattaroy, D, Chandrashekaran, V, Alhasson, F, Michelotti, G, Nagarkatti, M, Nagarkatti, P, Diehl, AM, Bell, PD, Liedtke, W, and Chatterjee, S. "TRPV4 activation of endothelial nitric oxide synthase resists nonalcoholic fatty liver disease by blocking CYP2E1-mediated redox toxicity." Free radical biology & medicine 102 (January 2017): 260-273.
PMID
27913210
Source
epmc
Published In
Free Radical Biology & Medicine
Volume
102
Publish Date
2017
Start Page
260
End Page
273
DOI
10.1016/j.freeradbiomed.2016.11.047

Timing Is Everything.

In a recent issue of Cancer Cell, Kettner and colleagues (2016) link disruption of normal circadian rhythms to NASH and associated liver cancer, suggesting that molecular clocks, as well as their regulators and target genes, might provide novel therapeutic targets in these diseases.

Authors
Diehl, AM
MLA Citation
Diehl, AM. "Timing Is Everything." Cell metabolism 25.1 (January 2017): 2-4.
PMID
28076761
Source
epmc
Published In
Cell Metabolism
Volume
25
Issue
1
Publish Date
2017
Start Page
2
End Page
4
DOI
10.1016/j.cmet.2016.12.015

Serum osteopontin is a biomarker of severe fibrosis and portal hypertension in human and murine schistosomiasis mansoni.

Schistosomiasis is a major cause of fibrosis and portal hypertension. The reason 4-10% of infected subjects develops hepatosplenic schistosomiasis remains unclear. Chronically infected male CBA/J mice reproduce the dichotomic forms of human schistosomiasis. Most mice (80%) develop moderate splenomegaly syndrome (similar to hepatointestinal disease in humans) and 20% present severe hypersplenomegaly syndrome (analogous to human hepatosplenic disease). We demonstrated that the profibrogenic molecule osteopontin discriminates between mice with severe and mild disease and could be a novel morbidity biomarker in murine and human schistosomiasis. Failure to downregulate osteopontin during the chronic phase may explain why hepatosplenic subjects develop severe fibrosis.

Authors
Pereira, TA; Syn, W-K; Pereira, FEL; Lambertucci, JR; Secor, WE; Diehl, AM
MLA Citation
Pereira, TA, Syn, W-K, Pereira, FEL, Lambertucci, JR, Secor, WE, and Diehl, AM. "Serum osteopontin is a biomarker of severe fibrosis and portal hypertension in human and murine schistosomiasis mansoni." International journal for parasitology 46.13-14 (December 2016): 829-832.
PMID
27729270
Source
epmc
Published In
International Journal for Parasitology
Volume
46
Issue
13-14
Publish Date
2016
Start Page
829
End Page
832
DOI
10.1016/j.ijpara.2016.08.004

Increased parenchymal damage and steatohepatitis in Caucasian non-alcoholic fatty liver disease patients with common IL1B and IL6 polymorphisms.

Non-alcoholic fatty liver disease (NAFLD) is a complex, multifactorial disease affected by diet, lifestyle and genetics. Proinflammatory cytokines like IL-1β and IL-6 have been shown to be elevated in non-alcoholic steatohepatitis (NASH).To investigate the relationship between IL1B and IL6 gene polymorphisms and histological features of NAFLD in the NASH CRN cohort.A total of 604 adult (≥18 years) non-Hispanic Caucasians with biopsy-proven NAFLD were genotyped for the following SNPs: IL1B, rs16944, rs1143634; IL6, rs1800795, rs10499563. Logistic regression was used to examine the relationship between genotype and a definitive diagnosis and advanced histological features of NASH after controlling for the following variables selected a priori: age, sex, diabetes, obesity and HOMA-IR level.The IL6 rs10499563 C allele was independently associated with the presence of definitive NASH, and increased ballooning and Mallory bodies. The IL1B rs1143634 TT genotype was associated with advanced fibrosis and increased Mallory bodies. The IL6 rs1800795 C allele was associated with not only increased risk for severe steatosis, >66% but also decreased risk for advanced fibrosis and lobular inflammation and Mallory body formation.These results suggest that common variants in the IL6 and IL1B genes may increase susceptibility for NASH and confer a higher risk of hepatic parenchymal damage including increased ballooning, increased Mallory bodies, and bridging fibrosis or cirrhosis. In contrast, the IL6 rs1800795 C allele may confer a higher risk for steatosis, but less parenchymal damage. Our findings support the development of therapeutics aimed at IL-1β and IL-6 suppression.

Authors
Nelson, JE; Handa, P; Aouizerat, B; Wilson, L; Vemulakonda, LA; Yeh, MM; Kowdley, KV; NASH Clinical Research Network,
MLA Citation
Nelson, JE, Handa, P, Aouizerat, B, Wilson, L, Vemulakonda, LA, Yeh, MM, Kowdley, KV, and NASH Clinical Research Network, . "Increased parenchymal damage and steatohepatitis in Caucasian non-alcoholic fatty liver disease patients with common IL1B and IL6 polymorphisms." Alimentary pharmacology & therapeutics 44.11-12 (December 2016): 1253-1264.
PMID
27730688
Source
epmc
Published In
Alimentary Pharmacology & Therapeutics
Volume
44
Issue
11-12
Publish Date
2016
Start Page
1253
End Page
1264
DOI
10.1111/apt.13824

GS-4997, an Inhibitor of Apoptosis Signal-Regulating Kinase (ASK1), Alone or in Combination with Simtuzumab for the Treatment of Nonalcoholic Steatohepatitis (NASH): A Randomized, Phase 2 Trial

Authors
Loomba, R; Lawitz, E; Mantry, PS; Jaya-kumar, S; Caldwell, SH; Arnold, H; Diehl, AM; Djedjos, CS; Jia, C; Myers, RP; Subramanian, M; McHutchison, JG; Goodman, ZD; Afdhal, NH; Charlton, MR
MLA Citation
Loomba, R, Lawitz, E, Mantry, PS, Jaya-kumar, S, Caldwell, SH, Arnold, H, Diehl, AM, Djedjos, CS, Jia, C, Myers, RP, Subramanian, M, McHutchison, JG, Goodman, ZD, Afdhal, NH, and Charlton, MR. "GS-4997, an Inhibitor of Apoptosis Signal-Regulating Kinase (ASK1), Alone or in Combination with Simtuzumab for the Treatment of Nonalcoholic Steatohepatitis (NASH): A Randomized, Phase 2 Trial." December 2016.
Source
wos-lite
Published In
Hepatology
Volume
64
Issue
6
Publish Date
2016
Start Page
1119A
End Page
1120A

Vitamin D is Not Associated With Severity in NAFLD: Results of a Paired Clinical and Gene Expression Profile Analysis.

The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is complex. Vitamin D (VitD) has been implicated in NAFLD pathogenesis because it has roles in immune modulation, cell differentiation and proliferation, and regulation of inflammation. We evaluated the association of VitD levels, hepatic gene expression for VitD metabolizing genes, and NAFLD histological severity.Two adult cohorts, controls (n=39) and NAFLD (n=244), who underwent liver biopsy were compared. Two-sided t-tests or Wilcoxon's rank-sum tests for continuous predictors and chi-squared tests or Fisher's exact tests for categorical variables were used to analyze the association of VitD and NAFLD. Generalized linear models were used to analyze the association of VitD levels and VitD metabolizing genes with histological severity of NAFLD while adjusting for potential confounders and correcting for multiple comparisons.NAFLD patients were more likely than controls to have higher HbA1c (6.5±1.2 vs 5.9±1.0; P=0.009), a risk factor for VitD deficiency. However, no difference in VitD levels was observed between groups. VitD levels did not correlate with the severity of hepatic steatosis, lobular or portal inflammation, or ballooned hepatocytes after adjusting for confounding factors. Furthermore, no association was noted between VitD deficiency or differential expression of genes involved in VitD metabolism and severity of hepatic fibrosis or any other histologic feature of NAFLD.Neither VitD deficiency, nor hepatic expression of VitD-related genes, associate with the presence or histologic severity of NAFLD in patients. Hence, despite preclinical evidence implicating VitD in NAFLD pathogenesis, VitD deficiency does not appear to be associated with NAFLD severity in humans.

Authors
Patel, YA; Henao, R; Moylan, CA; Guy, CD; Piercy, DL; Diehl, AM; Abdelmalek, MF
MLA Citation
Patel, YA, Henao, R, Moylan, CA, Guy, CD, Piercy, DL, Diehl, AM, and Abdelmalek, MF. "Vitamin D is Not Associated With Severity in NAFLD: Results of a Paired Clinical and Gene Expression Profile Analysis." The American journal of gastroenterology 111.11 (November 2016): 1591-1598.
PMID
27644736
Source
epmc
Published In
The American Journal of Gastroenterology (Elsevier)
Volume
111
Issue
11
Publish Date
2016
Start Page
1591
End Page
1598
DOI
10.1038/ajg.2016.406

Osteopontin Is Upregulated in Human and Murine Acute Schistosomiasis Mansoni.

Symptomatic acute schistosomiasis mansoni is a systemic hypersensitivity reaction against the migrating schistosomula and mature eggs after a primary infection. The mechanisms involved in the pathogenesis of acute schistosomiasis are not fully elucidated. Osteopontin has been implicated in granulomatous reactions and in acute hepatic injury. Our aims were to evaluate if osteopontin plays a role in acute Schistosoma mansoni infection in both human and experimentally infected mice and if circulating OPN levels could be a novel biomarker of this infection.Serum/plasma osteopontin levels were measured by ELISA in patients with acute (n = 28), hepatointestinal (n = 26), hepatosplenic (n = 39) schistosomiasis and in uninfected controls (n = 21). Liver osteopontin was assessed by immunohistochemistry in needle biopsies of 5 patients. Sera and hepatic osteopontin were quantified in the murine model of schistosomiasis mansoni during acute (7 and 8 weeks post infection, n = 10) and chronic (30 weeks post infection, n = 8) phase. Circulating osteopontin levels are increased in patients with acute schistosomiasis (p = 0.0001). The highest levels of OPN were observed during the peak of clinical symptoms (7-11 weeks post infection), returning to baseline level once the granulomas were modulated (>12 weeks post infection). The plasma levels in acute schistosomiasis were even higher than in hepatosplenic patients. The murine model mirrored the human disease. Macrophages were the major source of OPN in human and murine acute schistosomiasis, while the ductular reaction maintains OPN production in hepatosplenic disease. Soluble egg antigens from S. mansoni induced OPN expression in primary human kupffer cells.S. mansoni egg antigens induce the production of OPN by macrophages in the necrotic-exudative granulomas characteristic of acute schistosomiasis mansoni. Circulating OPN levels are upregulated in human and murine acute schistosomiasis and could be a non-invasive biomarker of this form of disease.

Authors
Pereira, TA; Syn, W-K; Amâncio, FF; Cunha, PHD; Caporali, JFM; Trindade, GVDM; Santos, ET; Souza, MM; Andrade, ZA; Witek, RP; Secor, WE; Pereira, FEL; Lambertucci, JR; Diehl, AM
MLA Citation
Pereira, TA, Syn, W-K, Amâncio, FF, Cunha, PHD, Caporali, JFM, Trindade, GVDM, Santos, ET, Souza, MM, Andrade, ZA, Witek, RP, Secor, WE, Pereira, FEL, Lambertucci, JR, and Diehl, AM. "Osteopontin Is Upregulated in Human and Murine Acute Schistosomiasis Mansoni." PLoS neglected tropical diseases 10.10 (October 18, 2016): e0005057-.
PMID
27755536
Source
epmc
Published In
PLoS neglected tropical diseases
Volume
10
Issue
10
Publish Date
2016
Start Page
e0005057
DOI
10.1371/journal.pntd.0005057

Hepatic estrogen transcriptional activity and estrogen receptor a gene expression are negatively correlated with fibrosis stage in patients with nonalcoholic fatty liver disease (NAFLD)

Authors
Suzuki, A; Spencer, HJ; Moylan, CA; Dranoff, JA; Abdelmalek, MF; Guy, CD; Diehl, AM
MLA Citation
Suzuki, A, Spencer, HJ, Moylan, CA, Dranoff, JA, Abdelmalek, MF, Guy, CD, and Diehl, AM. "Hepatic estrogen transcriptional activity and estrogen receptor a gene expression are negatively correlated with fibrosis stage in patients with nonalcoholic fatty liver disease (NAFLD)." October 2016.
Source
wos-lite
Published In
Hepatology
Volume
64
Publish Date
2016
Start Page
105A
End Page
105A

BCAT1 is Associated with Clinical Decompensation in NAFLD: A Pilot Study

Authors
Wegermann, K; Henao, R; Pan, Y; Diehl, AM; Abdelmalek, MF; Moylan, CA
MLA Citation
Wegermann, K, Henao, R, Pan, Y, Diehl, AM, Abdelmalek, MF, and Moylan, CA. "BCAT1 is Associated with Clinical Decompensation in NAFLD: A Pilot Study." October 2016.
Source
wos-lite
Published In
Hepatology
Volume
64
Publish Date
2016
Start Page
577A
End Page
577A

Vitamin D is Not Associated with Histologic Severity in NAFLD: Results of a Paired Clinical and Hepatic Gene Expression Profile Analysis

Authors
Patel, YA; Henao, R; Moylan, CA; Guy, CD; Piercy, DL; Diehl, AM; Abdelmalek, MF
MLA Citation
Patel, YA, Henao, R, Moylan, CA, Guy, CD, Piercy, DL, Diehl, AM, and Abdelmalek, MF. "Vitamin D is Not Associated with Histologic Severity in NAFLD: Results of a Paired Clinical and Hepatic Gene Expression Profile Analysis." October 2016.
Source
wos-lite
Published In
Hepatology
Volume
64
Publish Date
2016
Start Page
577A
End Page
577A

TRPV4 prevents tissue injury in diseased fatty liver by blocking CYP2E1-mediated redox-toxicity via Kupffer cell-induced nitric oxide production

Authors
Seth, RK; Dattaroy, D; Chandrashekaran, V; Das, S; Alhasson, F; Bonini, MG; Michelotti, GA; Nagarkatti, M; Nagarkatti, P; Diehl, AM; Bell, PD; Liedtke, WB; Chatterjee, S
MLA Citation
Seth, RK, Dattaroy, D, Chandrashekaran, V, Das, S, Alhasson, F, Bonini, MG, Michelotti, GA, Nagarkatti, M, Nagarkatti, P, Diehl, AM, Bell, PD, Liedtke, WB, and Chatterjee, S. "TRPV4 prevents tissue injury in diseased fatty liver by blocking CYP2E1-mediated redox-toxicity via Kupffer cell-induced nitric oxide production." October 2016.
Source
wos-lite
Published In
Hepatology
Volume
64
Publish Date
2016
Start Page
793A
End Page
794A

Cholangiocyte chemokine secretion and macrophage accumulation is mediated by osteopontin in murine liver models

Authors
Coombes, JD; Manka, PP; Swiderska-Syn, M; Reid, D; Riva, A; Claridge, LC; Dolle, L; Younis, R; Briones, MA; Kitamura, N; Mehta, K; Mi, Z; Kuo, PC; Williams, R; Diehl, AM; van Grunsven, LA; Chokshi, S; Canbay, A; Flamant, F; Gauthier, K; Eksteen, B; Syn, W-K
MLA Citation
Coombes, JD, Manka, PP, Swiderska-Syn, M, Reid, D, Riva, A, Claridge, LC, Dolle, L, Younis, R, Briones, MA, Kitamura, N, Mehta, K, Mi, Z, Kuo, PC, Williams, R, Diehl, AM, van Grunsven, LA, Chokshi, S, Canbay, A, Flamant, F, Gauthier, K, Eksteen, B, and Syn, W-K. "Cholangiocyte chemokine secretion and macrophage accumulation is mediated by osteopontin in murine liver models." October 2016.
Source
wos-lite
Published In
Hepatology
Volume
64
Publish Date
2016
Start Page
89A
End Page
90A

Hedgehog-responsive Myofibroblasts activate Yes-associated Protein (Yap) 1 and Promote TGFb-Signaling to Induce Epithelial-Mesenchymal Transitions in Hepatocytes during Murine Liver Regeneration

Authors
Swiderska-Syn, M; Xie, G; Diehl, AM
MLA Citation
Swiderska-Syn, M, Xie, G, and Diehl, AM. "Hedgehog-responsive Myofibroblasts activate Yes-associated Protein (Yap) 1 and Promote TGFb-Signaling to Induce Epithelial-Mesenchymal Transitions in Hepatocytes during Murine Liver Regeneration." October 2016.
Source
wos-lite
Published In
Hepatology
Volume
64
Publish Date
2016
Start Page
835A
End Page
836A

Hepatic stellate cell Yes-associated protein 1 (Yap1) is necessary for liver regeneration

Authors
Premont, RT; Swiderska-Syn, M; Jewell, M; Diehl, AM
MLA Citation
Premont, RT, Swiderska-Syn, M, Jewell, M, and Diehl, AM. "Hepatic stellate cell Yes-associated protein 1 (Yap1) is necessary for liver regeneration." October 2016.
Source
wos-lite
Published In
Hepatology
Volume
64
Publish Date
2016
Start Page
837A
End Page
837A

MMP9 is a potential mediator of TWEAK-Fn14 signaling in a rodent model of acute alcoholic steatohepatitis

Authors
Jewell, M; Swiderska-Syn, M; Xie, G; Karaca, G; Premont, RT; Diehl, AM
MLA Citation
Jewell, M, Swiderska-Syn, M, Xie, G, Karaca, G, Premont, RT, and Diehl, AM. "MMP9 is a potential mediator of TWEAK-Fn14 signaling in a rodent model of acute alcoholic steatohepatitis." October 2016.
Source
wos-lite
Published In
Hepatology
Volume
64
Publish Date
2016
Start Page
836A
End Page
836A

BCAT1 Is Associated with Clinical Decompensation in Nonalcoholic Fatty Liver Disease: a Pilot Study

Authors
Moylan, CA; Wegermann, KJ; Henao, RG; Murphy, SK; Diehl, AM; Abdelmalek, MF
MLA Citation
Moylan, CA, Wegermann, KJ, Henao, RG, Murphy, SK, Diehl, AM, and Abdelmalek, MF. "BCAT1 Is Associated with Clinical Decompensation in Nonalcoholic Fatty Liver Disease: a Pilot Study." October 2016.
Source
wos-lite
Published In
The American Journal of Gastroenterology (Elsevier)
Volume
111
Publish Date
2016
Start Page
S381
End Page
S381

Reply.

Authors
Boursier, J; Barret, M; Diehl, AM
MLA Citation
Boursier, J, Barret, M, and Diehl, AM. "Reply." Hepatology (Baltimore, Md.) 64.3 (September 2016): 994-995. (Letter)
PMID
26998974
Source
epmc
Published In
Hepatology
Volume
64
Issue
3
Publish Date
2016
Start Page
994
End Page
995
DOI
10.1002/hep.28562

Hedgehog regulates yes-associated protein 1 in regenerating mouse liver.

Adult liver regeneration requires induction and suppression of proliferative activity in multiple types of liver cells. The mechanisms that orchestrate the global changes in gene expression that are required for proliferative activity to change within individual liver cells, and that coordinate proliferative activity among different types of liver cells, are not well understood. Morphogenic signaling pathways that are active during fetal development, including Hedgehog and Hippo/Yes-associated protein 1 (Yap1), regulate liver regeneration in adulthood. Cirrhosis and liver cancer result when these pathways become dysregulated, but relatively little is known about the mechanisms that coordinate and control morphogenic signaling during effective liver regeneration. We evaluated the hypothesis that the Hedgehog pathway controls Yap1 activation during liver regeneration by studying intact mice and cultured liver cells. In cultured hepatic stellate cells (HSCs), disrupting Hedgehog signaling blocked activation of Yap1, and knocking down Yap1 inhibited induction of both Yap1- and Hedgehog-regulated genes that enable HSC to become myofibroblasts (MFs). In mice, disrupting Hedgehog signaling in MFs inhibited liver regeneration after partial hepactectomy (PH). Reduced proliferative activity in the liver epithelial compartment resulted from loss of stroma-derived paracrine signals that activate Yap1 and the Hedgehog pathway in hepatocytes. This prevented hepatocytes from up-regulating Yap1- and Hedgehog-regulated transcription factors that normally promote their proliferation.Morphogenic signaling in HSCs is necessary to reprogram hepatocytes to regenerate the liver epithelial compartment post-PH. This discovery identifies novel molecules that might be targeted to correct defective repair during cirrhosis and liver cancer. (Hepatology 2016;64:232-244).

Authors
Swiderska-Syn, M; Xie, G; Michelotti, GA; Jewell, ML; Premont, RT; Syn, W-K; Diehl, AM
MLA Citation
Swiderska-Syn, M, Xie, G, Michelotti, GA, Jewell, ML, Premont, RT, Syn, W-K, and Diehl, AM. "Hedgehog regulates yes-associated protein 1 in regenerating mouse liver." July 2016.
PMID
26970079
Source
epmc
Published In
Hepatology
Volume
64
Issue
1
Publish Date
2016
Start Page
232
End Page
244
DOI
10.1002/hep.28542

A longer duration of estrogen deficiency increases fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease.

Postmenopausal women with nonalcoholic steatohepatitis are at an increased risk of hepatic fibrosis compared with premenopausal women. Whether duration of estrogen deficiency in postmenopausal state dictates an individual's fibrosis risk remains uninvestigated. We assessed the associations of age at menopause and time from menopause with fibrosis severity in postmenopausal women with nonalcoholic fatty liver disease. Data from 488 postmenopausal women with (1) histologic diagnosis of nonalcoholic fatty liver disease and (2) self-reported information on age at menopause were analyzed. The associations of premature menopause (age at menopause of <40 years) and time from menopause (age at study enrollment - age at menopause, years) with fibrosis severity (stage 0-4) were assessed using multiple ordinal logistic regression models with and without adjusting for clinical confounders. Among the participants (age at menopause 43.7 ± 8.6 years), women with premature menopause (29.3%) were younger at enrollment (P < 0.001) and used hormone replacement therapy more often (P < 0.003). After adjusting for age at enrollment, race, waist circumference standardized by body mass index, current smoking, current alcohol use, hypertension, diabetes/impaired fasting glucose, homeostatic model assessment of insulin resistance, and hormone replacement therapy, premature menopause was associated with an increased likelihood of having more severe fibrosis (adjusted cumulative odds ratio = 1.9, 95% confidence interval 1.3-2.7, P = 0.001), while time from menopause was directly associated with an increased likelihood of having more severe fibrosis (adjusted cumulative odds ratio for 5-year unit = 1.2, 95% confidence interval 1.1-1.3, P = 0.002).Duration of estrogen deficiency in postmenopausal state confers fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease. (Hepatology 2016;64:85-91).

Authors
Klair, JS; Yang, JD; Abdelmalek, MF; Guy, CD; Gill, RM; Yates, K; Unalp-Arida, A; Lavine, JE; Clark, JM; Diehl, AM; Suzuki, A; Nonalcoholic Steatohepatitis Clinical Research Network,
MLA Citation
Klair, JS, Yang, JD, Abdelmalek, MF, Guy, CD, Gill, RM, Yates, K, Unalp-Arida, A, Lavine, JE, Clark, JM, Diehl, AM, Suzuki, A, and Nonalcoholic Steatohepatitis Clinical Research Network, . "A longer duration of estrogen deficiency increases fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease." Hepatology (Baltimore, Md.) 64.1 (July 2016): 85-91.
PMID
26919573
Source
epmc
Published In
Hepatology
Volume
64
Issue
1
Publish Date
2016
Start Page
85
End Page
91
DOI
10.1002/hep.28514

Hedgehog Regulates Yes-Associated Protein 1 in Regenerating Mouse Liver

Authors
Swiderska-Syn, M; Xie, G; Michelotti, GA; Jewell, ML; Premont, RT; Syn, W-K; Diehl, AM
MLA Citation
Swiderska-Syn, M, Xie, G, Michelotti, GA, Jewell, ML, Premont, RT, Syn, W-K, and Diehl, AM. "Hedgehog Regulates Yes-Associated Protein 1 in Regenerating Mouse Liver." HEPATOLOGY 64.1 (July 2016): 232-244.
Source
wos-lite
Published In
Hepatology
Volume
64
Issue
1
Publish Date
2016
Start Page
232
End Page
244
DOI
10.1002/hep.28542

Pathogenesis of Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a necro-inflammatory response that ensues when hepatocytes are injured by lipids (lipotoxicity). NASH is a potential outcome of nonalcoholic fatty liver (NAFL), a condition that occurs when lipids accumulate in hepatocytes. NASH may be reversible, but it can also result in cirrhosis and primary liver cancer. We are beginning to learn about the mechanisms of progression of NAFL and NASH. NAFL does not inevitably lead to NASH because NAFL is a heterogeneous condition. This heterogeneity exists because different types of lipids with different cytotoxic potential accumulate in the NAFL, and individuals with NAFL differ in their ability to defend against lipotoxicity. There are no tests that reliably predict which patients with NAFL will develop lipotoxicity. However, NASH encompasses the spectrum of wound-healing responses induced by lipotoxic hepatocytes. Differences in these wound-healing responses among individuals determine whether lipotoxic livers regenerate, leading to stabilization or resolution of NASH, or develop progressive scarring, cirrhosis, and possibly liver cancer. We review concepts that are central to the pathogenesis of NASH.

Authors
Machado, MV; Diehl, AM
MLA Citation
Machado, MV, and Diehl, AM. "Pathogenesis of Nonalcoholic Steatohepatitis." Gastroenterology 150.8 (June 2016): 1769-1777. (Review)
PMID
26928243
Source
epmc
Published In
Gastroenterology
Volume
150
Issue
8
Publish Date
2016
Start Page
1769
End Page
1777
DOI
10.1053/j.gastro.2016.02.066

Role of Hedgehog Signaling Pathway in NASH.

Non-alcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease in the Western world. Although only a minority of patients will ultimately develop end-stage liver disease, it is not yet possible to efficiently predict who will progress and, most importantly, effective treatments are still unavailable. Better understanding of the pathophysiology of this disease is necessary to improve the clinical management of NAFLD patients. Epidemiological data indicate that NAFLD prognosis is determined by an individual's response to lipotoxic injury, rather than either the severity of exposure to lipotoxins, or the intensity of liver injury. The liver responds to injury with a synchronized wound-healing response. When this response is abnormal, it leads to pathological scarring, resulting in progressive fibrosis and cirrhosis, rather than repair. The hedgehog pathway is a crucial player in the wound-healing response. In this review, we summarize the pre-clinical and clinical evidence, which demonstrate the role of hedgehog pathway dysregulation in NAFLD pathogenesis, and the preliminary data that place the hedgehog pathway as a potential target for the treatment of this disease.

Authors
Verdelho Machado, M; Diehl, AM
MLA Citation
Verdelho Machado, M, and Diehl, AM. "Role of Hedgehog Signaling Pathway in NASH." International journal of molecular sciences 17.6 (June 2016). (Review)
PMID
27258259
Source
epmc
Published In
International journal of molecular sciences
Volume
17
Issue
6
Publish Date
2016
DOI
10.3390/ijms17060857

Nonalcoholic Fatty Liver Disease and the Gut Microbiome.

Recent progress has allowed a more comprehensive study of the gut microbiota. Gut microbiota helps in health maintenance and gut dysbiosis associates with chronic metabolic diseases. Modulation of short-chain fatty acids and choline bioavailability, lipoprotein lipase induction, alteration of bile acid profile, endogenous alcohol production, or liver inflammation secondary to endotoxemia result from gut dysbiosis. Modulation of the gut microbiota by pre/probiotics gives promising results in animal, but needs to be evaluated in human before use in clinical practice. Gut microbiota adds complexity to the pathophysiology of nonalcoholic fatty liver disease but represents an opportunity to discover new therapeutic targets.

Authors
Boursier, J; Diehl, AM
MLA Citation
Boursier, J, and Diehl, AM. "Nonalcoholic Fatty Liver Disease and the Gut Microbiome." Clinics in liver disease 20.2 (May 2016): 263-275. (Review)
PMID
27063268
Source
epmc
Published In
Clinics in Liver Disease
Volume
20
Issue
2
Publish Date
2016
Start Page
263
End Page
275
DOI
10.1016/j.cld.2015.10.012

Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches.

The ductular reaction (DR) involves mobilisation of reactive-appearing duct-like cells (RDC) along canals of Hering, and myofibroblastic (MF) differentiation of hepatic stellate cells (HSC) in the space of Disse. Perivascular cells in stem cell niches produce pleiotrophin (PTN) to inactivate the PTN receptor, protein tyrosine phosphatase receptor zeta-1 (PTPRZ1), thereby augmenting phosphoprotein-dependent signalling. We hypothesised that the DR is regulated by PTN/PTPRZ1 signalling.PTN-GFP, PTN-knockout (KO), PTPRZ1-KO, and wild type (WT) mice were examined before and after bile duct ligation (BDL) for PTN, PTPRZ1 and the DR. RDC and HSC from WT, PTN-KO, and PTPRZ1-KO mice were also treated with PTN to determine effects on downstream signaling phosphoproteins, gene expression, growth, and migration. Liver biopsies from patients with DRs were also interrogated.Although quiescent HSC and RDC lines expressed PTN and PTPRZ1 mRNAs, neither PTN nor PTPRZ1 protein was demonstrated in healthy liver. BDL induced PTN in MF-HSC and increased PTPRZ1 in MF-HSC and RDC. In WT mice, BDL triggered a DR characterised by periportal accumulation of collagen, RDC and MF-HSC. All aspects of this DR were increased in PTN-KO mice and suppressed in PTPRZ1-KO mice. In vitro studies revealed PTN-dependent accumulation of phosphoproteins that control cell-cell adhesion and migration, with resultant inhibition of cell migration. PTPRZ1-positive cells were prominent in the DRs of patients with ductal plate defects and adult cholestatic diseases.PTN, and its receptor, PTPRZ1, regulate the DR to liver injury by controlling the migration of resident cells in adult liver progenitor niches.

Authors
Michelotti, GA; Tucker, A; Swiderska-Syn, M; Machado, MV; Choi, SS; Kruger, L; Soderblom, E; Thompson, JW; Mayer-Salman, M; Himburg, HA; Moylan, CA; Guy, CD; Garman, KS; Premont, RT; Chute, JP; Diehl, AM
MLA Citation
Michelotti, GA, Tucker, A, Swiderska-Syn, M, Machado, MV, Choi, SS, Kruger, L, Soderblom, E, Thompson, JW, Mayer-Salman, M, Himburg, HA, Moylan, CA, Guy, CD, Garman, KS, Premont, RT, Chute, JP, and Diehl, AM. "Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches." Gut 65.4 (April 2016): 683-692.
Website
http://hdl.handle.net/10161/13095
PMID
25596181
Source
epmc
Published In
Gut
Volume
65
Issue
4
Publish Date
2016
Start Page
683
End Page
692
DOI
10.1136/gutjnl-2014-308176

Sparstolonin B attenuates early liver inflammation in experimental NASH by modulating TLR4 trafficking in lipid rafts via NADPH oxidase activation.

Although significant research data exist on the pathophysiology of nonalcoholic steatohepatitis (NASH), finding an efficient treatment regimen for it remains elusive. The present study used sparstolonin B (SsnB), a novel TLR4 antagonist derived from the Chinese herb Sparganium stoloniferum, as a possible drug to mitigate early inflammation in NASH. This study used an early steatohepatitic injury model in high-fat-fed mice with CYP2E1-mediated oxidative stress as a second hit. SsnB was administered for 1 wk along with bromodichloromethane (BDCM), an inducer of CYP2E1-mediated oxidative stress. Results showed that SsnB administration attenuated inflammatory morphology and decreased elevation of the liver enzyme alanine aminotransferase (ALT). Mice administered SsnB also showed decreased mRNA expression of proinflammatory cytokines TNF-α, IFN-γ, IL-1β, and IL-23, while protein levels of both TNF-α and IL-1β were significantly decreased. SsnB significantly decreased Kupffer cell activation as evidenced by reduction in CD68 and monocyte chemoattractant protein-1 (MCP1) mRNA and protein levels with concomitant inhibition of macrophage infiltration in the injured liver. Mechanistically, SsnB decreased TLR4 trafficking to the lipid rafts, a phenomenon described by the colocalization of TLR4 and lipid raft marker flotillin in tissues and immortalized Kupffer cells. Since we have shown previously that NADPH oxidase drives TLR4 trafficking in NASH, we studied the role of SsnB in modulating this pathway. SsnB prevented NADPH oxidase activation in vivo and in vitro as indicated by decreased peroxynitrite formation. In summary, the present study reports a novel use of the TLR4 antagonist SsnB in mitigating inflammation in NASH and in parallel shows a unique molecular mechanism of decreasing nitrative stress.

Authors
Dattaroy, D; Seth, RK; Das, S; Alhasson, F; Chandrashekaran, V; Michelotti, G; Fan, D; Nagarkatti, M; Nagarkatti, P; Diehl, AM; Chatterjee, S
MLA Citation
Dattaroy, D, Seth, RK, Das, S, Alhasson, F, Chandrashekaran, V, Michelotti, G, Fan, D, Nagarkatti, M, Nagarkatti, P, Diehl, AM, and Chatterjee, S. "Sparstolonin B attenuates early liver inflammation in experimental NASH by modulating TLR4 trafficking in lipid rafts via NADPH oxidase activation." American journal of physiology. Gastrointestinal and liver physiology 310.7 (April 2016): G510-G525.
PMID
26718771
Source
epmc
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
310
Issue
7
Publish Date
2016
Start Page
G510
End Page
G525
DOI
10.1152/ajpgi.00259.2015

Inflammation-Dependent IL18 Signaling Restricts Hepatocellular Carcinoma Growth by Enhancing the Accumulation and Activity of Tumor-Infiltrating Lymphocytes.

Chronic inflammation in liver tissue is an underlying cause of hepatocellular carcinoma. High levels of inflammatory cytokine IL18 in the circulation of patients with hepatocellular carcinoma correlates with poor prognosis. However, conflicting results have been reported for IL18 in hepatocellular carcinoma development and progression. In this study, we used tissue specimens from hepatocellular carcinoma patients and clinically relevant mouse models of hepatocellular carcinoma to evaluate IL18 expression and function. In a mouse model of liver fibrosis that recapitulates a tumor-promoting microenvironment, global deletion of the IL18 receptor IL18R1 enhanced tumor growth and burden. Similarly, in a carcinogen-induced model of liver tumorigenesis, IL18R1 deletion increased tumor burden. Mechanistically, we found that IL18 exerted inflammation-dependent tumor-suppressive effects largely by promoting the differentiation, activity, and survival of tumor-infiltrating T cells. Finally, differences in the expression of IL18 in tumor tissue versus nontumor tissue were more predictive of patient outcome than overall tissue expression. Taken together, our findings resolve a long-standing contradiction regarding a tumor-suppressive role for IL18 in established hepatocellular carcinoma and provide a mechanistic explanation for the complex relationship between its expression pattern and hepatocellular carcinoma prognosis. Cancer Res; 76(8); 2394-405. ©2016 AACR.

Authors
Markowitz, GJ; Yang, P; Fu, J; Michelotti, GA; Chen, R; Sui, J; Yang, B; Qin, W-H; Zhang, Z; Wang, F-S; Diehl, AM; Li, Q-J; Wang, H; Wang, X-F
MLA Citation
Markowitz, GJ, Yang, P, Fu, J, Michelotti, GA, Chen, R, Sui, J, Yang, B, Qin, W-H, Zhang, Z, Wang, F-S, Diehl, AM, Li, Q-J, Wang, H, and Wang, X-F. "Inflammation-Dependent IL18 Signaling Restricts Hepatocellular Carcinoma Growth by Enhancing the Accumulation and Activity of Tumor-Infiltrating Lymphocytes." Cancer research 76.8 (April 2016): 2394-2405.
PMID
26893476
Source
epmc
Published In
Cancer Research
Volume
76
Issue
8
Publish Date
2016
Start Page
2394
End Page
2405
DOI
10.1158/0008-5472.can-15-1548

Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches

Authors
Michelotti, GA; Tucker, A; Swiderska-Syn, M; Machado, MV; Choi, SS; Kruger, L; Soderblom, E; Thompson, JW; Mayer-Salman, M; Himburg, HA; Moylan, CA; Guy, CD; Garman, KS; Premont, RT; Chute, JP; Diehl, AM
MLA Citation
Michelotti, GA, Tucker, A, Swiderska-Syn, M, Machado, MV, Choi, SS, Kruger, L, Soderblom, E, Thompson, JW, Mayer-Salman, M, Himburg, HA, Moylan, CA, Guy, CD, Garman, KS, Premont, RT, Chute, JP, and Diehl, AM. "Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches." GUT 65.4 (April 2016): 683-692.
Source
wos-lite
Published In
Gut
Volume
65
Issue
4
Publish Date
2016
Start Page
683
End Page
692
DOI
10.1136/gutjnl-2014-308176

Reply.

Authors
Guy, CD; Diehl, AM
MLA Citation
Guy, CD, and Diehl, AM. "Reply." Hepatology (Baltimore, Md.) 63.3 (March 2016): 1057-1058. (Letter)
PMID
26206676
Source
epmc
Published In
Hepatology
Volume
63
Issue
3
Publish Date
2016
Start Page
1057
End Page
1058
DOI
10.1002/hep.28011

Systematic transcriptome analysis reveals elevated expression of alcohol-metabolizing genes in NAFLD livers.

Obese animals and non-alcoholic fatty liver disease (NAFLD) patients exhibit elevated blood alcohol, suggesting potential contributions of alcohol metabolism to the development of NAFLD. Liver gene expression in patients with biopsy-proven mild (N = 40) and severe (N = 32) NAFLD were compared to that in healthy liver donors (N = 7) and alcoholic hepatitis (AH; N = 15) using microarrays. Principal components analyses (PCA) revealed similar gene expression patterns between mild and severe NAFLD which clustered with those of AH but were distinct from those of healthy livers. Differential gene expression between NAFLD and healthy livers was consistent with established NAFLD-associated genes and NAFLD pathophysiology. Alcohol-metabolizing enzymes including ADH, ALDH, CYP2E1, and CAT were up-regulated in NAFLD livers. The expression level of alcohol-metabolizing genes in severe NAFLD was similar to that in AH. The NAFLD gene expression profiles provide new directions for future investigations to identify disease markers and targets for prevention and treatment, as well as to foster our understanding of NAFLD pathogenesis and pathophysiology. Particularly, increased expression of alcohol-metabolizing genes in NAFLD livers supports a role for endogenous alcohol metabolism in NAFLD pathology and provides further support for gut microbiome therapy in NAFLD management. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley © Sons, Ltd.

Authors
Zhu, R; Baker, SS; Moylan, CA; Abdelmalek, MF; Guy, CD; Zamboni, F; Wu, D; Lin, W; Liu, W; Baker, RD; Govindarajan, S; Cao, Z; Farci, P; Diehl, AM; Zhu, L
MLA Citation
Zhu, R, Baker, SS, Moylan, CA, Abdelmalek, MF, Guy, CD, Zamboni, F, Wu, D, Lin, W, Liu, W, Baker, RD, Govindarajan, S, Cao, Z, Farci, P, Diehl, AM, and Zhu, L. "Systematic transcriptome analysis reveals elevated expression of alcohol-metabolizing genes in NAFLD livers." The Journal of pathology 238.4 (March 2016): 531-542.
PMID
26415102
Source
epmc
Published In
The Journal of Pathology
Volume
238
Issue
4
Publish Date
2016
Start Page
531
End Page
542
DOI
10.1002/path.4650

The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota.

Several animal studies have emphasized the role of gut microbiota in nonalcoholic fatty liver disease (NAFLD). However, data about gut dysbiosis in human NAFLD remain scarce in the literature, especially studies including the whole spectrum of NAFLD lesions. We aimed to evaluate the association between gut dysbiosis and severe NAFLD lesions, that is, nonalcoholic steatohepatitis (NASH) and fibrosis, in a well-characterized population of adult NAFLD. Fifty-seven patients with biopsy-proven NAFLD were enrolled. Taxonomic composition of gut microbiota was determined using 16S ribosomal RNA gene sequencing of stool samples. Thirty patients had F0/F1 fibrosis stage at liver biopsy (10 with NASH), and 27 patients had significant F≥2 fibrosis (25 with NASH). Bacteroides abundance was significantly increased in NASH and F≥2 patients, whereas Prevotella abundance was decreased. Ruminococcus abundance was significantly higher in F≥2 patients. By multivariate analysis, Bacteroides abundance was independently associated with NASH and Ruminococcus with F≥2 fibrosis. Stratification according to the abundance of these two bacteria generated three patient subgroups with increasing severity of NAFLD lesions. Based on imputed metagenomic profiles, Kyoto Encyclopedia of Genes and Genomes pathways significantly related to NASH and fibrosis F≥2 were mostly related to carbohydrate, lipid, and amino acid metabolism.NAFLD severity associates with gut dysbiosis and a shift in metabolic function of the gut microbiota. We identified Bacteroides as independently associated with NASH and Ruminococcus with significant fibrosis. Thus, gut microbiota analysis adds information to classical predictors of NAFLD severity and suggests novel metabolic targets for pre-/probiotics therapies.

Authors
Boursier, J; Mueller, O; Barret, M; Machado, M; Fizanne, L; Araujo-Perez, F; Guy, CD; Seed, PC; Rawls, JF; David, LA; Hunault, G; Oberti, F; Calès, P; Diehl, AM
MLA Citation
Boursier, J, Mueller, O, Barret, M, Machado, M, Fizanne, L, Araujo-Perez, F, Guy, CD, Seed, PC, Rawls, JF, David, LA, Hunault, G, Oberti, F, Calès, P, and Diehl, AM. "The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota." Hepatology (Baltimore, Md.) 63.3 (March 2016): 764-775.
PMID
26600078
Source
epmc
Published In
Hepatology
Volume
63
Issue
3
Publish Date
2016
Start Page
764
End Page
775
DOI
10.1002/hep.28356

Caspase-2 promotes obesity, the metabolic syndrome and nonalcoholic fatty liver disease.

Obesity and its resulting metabolic disturbances are major health threats. In response to energy surplus, overtaxed adipocytes release fatty acids and pro-inflammatory factors into the circulation, promoting organ fat accumulation (including nonalcoholic fatty liver disease), insulin resistance and the metabolic syndrome. Recently, caspase-2 was linked to lipoapoptosis, so we hypothesized that caspase-2 might be a critical determinant of metabolic syndrome pathogenesis. Caspase-2-deficient and wild-type mice were fed a Western diet (high-fat diet, enriched with saturated fatty acids and 0.2% cholesterol, supplemented with fructose and glucose in the drinking water) for 16 weeks. Metabolic and hepatic outcomes were evaluated. In vitro studies assessed the role of caspase-2 in adipose tissue proliferative properties and susceptibility for lipoapoptosis. Caspase-2-deficient mice fed a Western diet were protected from abdominal fat deposition, diabetes mellitus, dyslipidemia and hepatic steatosis. Adipose tissue in caspase-2-deficient mice was more proliferative, upregulated mitochondrial uncoupling proteins consistent with browning, and was resistant to cell hypertrophy and cell death. The liver was protected from steatohepatitis through a decrease in circulating fatty acids and more efficient hepatic fat metabolism, and from fibrosis as a consequence of reduced fibrogenic stimuli from fewer lipotoxic hepatocytes. Caspase-2 deficiency protected mice from diet-induced obesity, metabolic syndrome and nonalcoholic fatty liver disease. Further studies are necessary to assess caspase-2 as a therapeutic target for those conditions.

Authors
Machado, MV; Michelotti, GA; Jewell, ML; Pereira, TA; Xie, G; Premont, RT; Diehl, AM
MLA Citation
Machado, MV, Michelotti, GA, Jewell, ML, Pereira, TA, Xie, G, Premont, RT, and Diehl, AM. "Caspase-2 promotes obesity, the metabolic syndrome and nonalcoholic fatty liver disease." Cell death & disease 7 (February 18, 2016): e2096-.
PMID
26890135
Source
epmc
Published In
Cell Death and Disease
Volume
7
Publish Date
2016
Start Page
e2096
DOI
10.1038/cddis.2016.19

ReplyReply

Authors
Boursier, J; Barret, M; Diehl, AM; Boursier, J; Barret, M; Diehl, AM
MLA Citation
Boursier, J, Barret, M, Diehl, AM, Boursier, J, Barret, M, and Diehl, AM. "ReplyReply (PublishedAccepted)." Hepatology 64.3 (January 1, 2016): 994-995. (Letter)
Source
scopus
Published In
Hepatology
Volume
64
Issue
3
Publish Date
2016
Start Page
994
End Page
995
DOI
10.1002/hep.28562

Purinergic receptor X7 mediates leptin induced GLUT4 function in stellate cells in nonalcoholic steatohepatitis.

Metabolic oxidative stress via CYP2E1 can act as a second hit in NASH progression. Our previous studies have shown that oxidative stress in NASH causes higher leptin levels and induces purinergic receptor X7 (P2X7r). We tested the hypothesis that higher circulating leptin due to CYP2E1-mediated oxidative stress induces P2X7r. P2X7r in turn activates stellate cells and causes increased proliferation via modulating Glut4, the glucose transporter, and increased intracellular glucose. Using a high fat diet-fed NAFLD model where bromodichloromethane (BDCM) was administered to induce CYP2E1-mediated oxidative stress, we show that P2X7r expression and protein levels were leptin and CYP2E1 dependent. P2X7r KO mice had significantly decreased stellate cell proliferation. Human NASH livers showed marked increase in P2X7r, and Glut4 in α-SMA positive cells. NASH livers had significant increase in Glut4 protein and phosphorylated AKT, needed for Glut4 translocation while leptin KO and P2X7r KO mice showed marked decrease in Glut4 levels primarily in stellate cells. Mechanistically stellate cells showed increase in phosphorylated AKT, Glut4 protein and localization in the membrane following administration of P2X7r agonist or leptin+P2X7r agonist, while use of P2X7r antagonist or AKT inhibitor attenuated the response suggesting that leptin-P2X7r axis in concert but not leptin alone is responsible for the Glut4 induction and translocation. Finally P2X7r-agonist and leptin caused an increase in intracellular glucose and consumption by increasing the activity of hexokinase. In conclusion, the study shows a novel role of leptin-induced P2X7r in modulating Glut4 induction and translocation in hepatic stellate cells, that are key to NASH progression.

Authors
Chandrashekaran, V; Das, S; Seth, RK; Dattaroy, D; Alhasson, F; Michelotti, G; Nagarkatti, M; Nagarkatti, P; Diehl, AM; Chatterjee, S
MLA Citation
Chandrashekaran, V, Das, S, Seth, RK, Dattaroy, D, Alhasson, F, Michelotti, G, Nagarkatti, M, Nagarkatti, P, Diehl, AM, and Chatterjee, S. "Purinergic receptor X7 mediates leptin induced GLUT4 function in stellate cells in nonalcoholic steatohepatitis." Biochimica et biophysica acta 1862.1 (January 2016): 32-45.
PMID
26474534
Source
epmc
Published In
Biochimica et Biophysica Acta: international journal of biochemistry and biophysics
Volume
1862
Issue
1
Publish Date
2016
Start Page
32
End Page
45
DOI
10.1016/j.bbadis.2015.10.009

Vitamin B5 and N-Acetylcysteine in Nonalcoholic Steatohepatitis: A Preclinical Study in a Dietary Mouse Model.

Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease and second indication for liver transplantation in the Western world. Effective therapy is still not available. Previously we showed a critical role for caspase-2 in the pathogenesis of nonalcoholic steatohepatitis (NASH), the potentially progressive form of NAFLD. An imbalance between free coenzyme A (CoA) and acyl-CoA ratio is known to induce caspase-2 activation.We aimed to evaluate CoA metabolism and the effects of supplementation with CoA precursors, pantothenate and cysteine, in mouse models of NASH.CoA metabolism was evaluated in methionine-choline deficient (MCD) and Western diet mouse models of NASH. MCD diet-fed mice were treated with pantothenate and N-acetylcysteine or placebo to determine effects on NASH.Liver free CoA content was reduced, pantothenate kinase (PANK), the rate-limiting enzyme in the CoA biosynthesis pathway, was down-regulated, and CoA degrading enzymes were increased in mice with NASH. Decreased hepatic free CoA content was associated with increased caspase-2 activity and correlated with worse liver cell apoptosis, inflammation, and fibrosis. Treatment with pantothenate and N-acetylcysteine did not inhibit caspase-2 activation, improve NASH, normalize PANK expression, or restore free CoA levels in MCD diet-fed mice.In mice with NASH, hepatic CoA metabolism is impaired, leading to decreased free CoA content, activation of caspase-2, and increased liver cell apoptosis. Dietary supplementation with CoA precursors did not restore CoA levels or improve NASH, suggesting that alternative approaches are necessary to normalize free CoA during NASH.

Authors
Machado, MV; Kruger, L; Jewell, ML; Michelotti, GA; Pereira, TDA; Xie, G; Moylan, CA; Diehl, AM
MLA Citation
Machado, MV, Kruger, L, Jewell, ML, Michelotti, GA, Pereira, TDA, Xie, G, Moylan, CA, and Diehl, AM. "Vitamin B5 and N-Acetylcysteine in Nonalcoholic Steatohepatitis: A Preclinical Study in a Dietary Mouse Model." Digestive diseases and sciences 61.1 (January 2016): 137-148.
PMID
26403427
Source
epmc
Published In
Digestive Diseases and Sciences
Volume
61
Issue
1
Publish Date
2016
Start Page
137
End Page
148
DOI
10.1007/s10620-015-3871-x

Osteopontin is a proximal effector of leptin-mediated non-alcoholic steatohepatitis (NASH) fibrosis.

Liver fibrosis develops when hepatic stellate cells (HSC) are activated into collagen-producing myofibroblasts. In non-alcoholic steatohepatitis (NASH), the adipokine leptin is upregulated, and promotes liver fibrosis by directly activating HSC via the hedgehog pathway. We reported that hedgehog-regulated osteopontin (OPN) plays a key role in promoting liver fibrosis. Herein, we evaluated if OPN mediates leptin-profibrogenic effects in NASH.Leptin-deficient (ob/ob) and wild-type (WT) mice were fed control or methionine-choline deficient (MCD) diet. Liver tissues were assessed by Sirius-red, OPN and αSMA IHC, and qRT-PCR for fibrogenic genes. In vitro, HSC with stable OPN (or control) knockdown were treated with recombinant (r)leptin and OPN-neutralizing or sham-aptamers. HSC response to OPN loss was assessed by wound healing assay. OPN-aptamers were also added to precision-cut liver slices (PCLS), and administered to MCD-fed WT (leptin-intact) mice to determine if OPN neutralization abrogated fibrogenesis.MCD-fed WT mice developed NASH-fibrosis, upregulated OPN, and accumulated αSMA+ cells. Conversely, MCD-fed ob/ob mice developed less fibrosis and accumulated fewer αSMA+ and OPN+ cells. In vitro, leptin-treated HSC upregulated OPN, αSMA, collagen 1α1 and TGFβ mRNA by nearly 3-fold, but this effect was blunted by OPN loss. Inhibition of PI3K and transduction of dominant negative-Akt abrogated leptin-mediated OPN induction, while constitutive active-Akt upregulated OPN. Finally, OPN neutralization reduced leptin-mediated fibrogenesis in both PCLS and MCD-fed mice.OPN overexpression in NASH enhances leptin-mediated fibrogenesis via PI3K/Akt. OPN neutralization significantly reduces NASH fibrosis, reinforcing the potential utility of targeting OPN in the treatment of patients with advanced NASH.

Authors
Coombes, JD; Choi, SS; Swiderska-Syn, M; Manka, P; Reid, DT; Palma, E; Briones-Orta, MA; Xie, G; Younis, R; Kitamura, N; Della Peruta, M; Bitencourt, S; Dollé, L; Oo, YH; Mi, Z; Kuo, PC; Williams, R; Chokshi, S; Canbay, A; Claridge, LC; Eksteen, B; Diehl, AM; Syn, W-K
MLA Citation
Coombes, JD, Choi, SS, Swiderska-Syn, M, Manka, P, Reid, DT, Palma, E, Briones-Orta, MA, Xie, G, Younis, R, Kitamura, N, Della Peruta, M, Bitencourt, S, Dollé, L, Oo, YH, Mi, Z, Kuo, PC, Williams, R, Chokshi, S, Canbay, A, Claridge, LC, Eksteen, B, Diehl, AM, and Syn, W-K. "Osteopontin is a proximal effector of leptin-mediated non-alcoholic steatohepatitis (NASH) fibrosis." Biochimica et biophysica acta 1862.1 (January 2016): 135-144.
PMID
26529285
Source
epmc
Published In
Biochimica et Biophysica Acta: international journal of biochemistry and biophysics
Volume
1862
Issue
1
Publish Date
2016
Start Page
135
End Page
144
DOI
10.1016/j.bbadis.2015.10.028

PNPLA3 VARIANTS CONFER AN INCREASED RISK OF ADVANCED FIBROSIS DUE TO NON-ALCOHOLIC STEATOHEPATITIS

Authors
Shea, PR; Sanyal, A; Harrison, S; Ratziu, V; Loomba, R; Caldwell, S; Diehl, AM; Kleinstein, SE; Myers, RP; Subramanian, GM; McHutchison, JG; Abdelmalek, MF; Bosch, J; Afdhal, N; Goldstein, DB
MLA Citation
Shea, PR, Sanyal, A, Harrison, S, Ratziu, V, Loomba, R, Caldwell, S, Diehl, AM, Kleinstein, SE, Myers, RP, Subramanian, GM, McHutchison, JG, Abdelmalek, MF, Bosch, J, Afdhal, N, and Goldstein, DB. "PNPLA3 VARIANTS CONFER AN INCREASED RISK OF ADVANCED FIBROSIS DUE TO NON-ALCOHOLIC STEATOHEPATITIS." 2016.
Source
wos-lite
Published In
Journal of Hepatology
Volume
64
Publish Date
2016
Start Page
S493
End Page
S493

CORRELATION BETWEEN THE HEPATIC VENOUS PRESSURE GRADIENT AND.LPHA-SMOOTH MUSCLE ACTIN (SMA) EXPRESSION IN PATIENTS WITH COMPENSATED CIRRHOSIS DUE TO NONALCOHOLIC STEATOHEPATITIS

Authors
Sanyal, A; Goodman, Z; Harrison, S; Rockey, DC; Diehl, AM; Caldwell, S; Shiffman, ML; Thuluvath, P; Myers, RP; Subramanian, GM; McHutchison, JG; Abdelmalek, MF; Ratziu, V; Afdhal, N; Bosch, J
MLA Citation
Sanyal, A, Goodman, Z, Harrison, S, Rockey, DC, Diehl, AM, Caldwell, S, Shiffman, ML, Thuluvath, P, Myers, RP, Subramanian, GM, McHutchison, JG, Abdelmalek, MF, Ratziu, V, Afdhal, N, and Bosch, J. "CORRELATION BETWEEN THE HEPATIC VENOUS PRESSURE GRADIENT AND.LPHA-SMOOTH MUSCLE ACTIN (SMA) EXPRESSION IN PATIENTS WITH COMPENSATED CIRRHOSIS DUE TO NONALCOHOLIC STEATOHEPATITIS." 2016.
Source
wos-lite
Published In
Journal of Hepatology
Volume
64
Publish Date
2016
Start Page
S251
End Page
S251

GENOME-WIDE ASSOCIATION STUDY OF CLINICALLY SIGNIFICANT PORTAL HYPERTENSION IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS AND ADVANCED FIBROSIS

Authors
Shea, PR; Sanyal, A; Rockey, DC; Loomba, R; Diehl, AM; Kleinstein, SE; Myers, RP; Subramanian, GM; McHutchison, JG; Abdelmalek, MF; Ratziu, V; Afdhal, N; Harrison, S; Bosch, J; Goldstein, DB
MLA Citation
Shea, PR, Sanyal, A, Rockey, DC, Loomba, R, Diehl, AM, Kleinstein, SE, Myers, RP, Subramanian, GM, McHutchison, JG, Abdelmalek, MF, Ratziu, V, Afdhal, N, Harrison, S, Bosch, J, and Goldstein, DB. "GENOME-WIDE ASSOCIATION STUDY OF CLINICALLY SIGNIFICANT PORTAL HYPERTENSION IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS AND ADVANCED FIBROSIS." 2016.
Source
wos-lite
Published In
Journal of Hepatology
Volume
64
Publish Date
2016
Start Page
S280
End Page
S280

OSTEOPONTIN PROMOTES CHOLANGIOCYTE CHEMOKINE SECRETION AND MACROPHAGE ACCUMULATION IN MURINE LIVER FIBROSIS

Authors
Coombes, JD; Manka, PP; Swiderska-Syn, M; Reid, D; Riva, A; Claridge, LC; Dolle, L; Younis, R; Briones-Orta, MA; Kitamura, N; Mehta, K; Mi, Z; Kuo, PC; Williams, R; Diehl, AM; van Grunsven, LA; Chokshi, S; Eksteen, B; Canbay, A; Syn, W-K
MLA Citation
Coombes, JD, Manka, PP, Swiderska-Syn, M, Reid, D, Riva, A, Claridge, LC, Dolle, L, Younis, R, Briones-Orta, MA, Kitamura, N, Mehta, K, Mi, Z, Kuo, PC, Williams, R, Diehl, AM, van Grunsven, LA, Chokshi, S, Eksteen, B, Canbay, A, and Syn, W-K. "OSTEOPONTIN PROMOTES CHOLANGIOCYTE CHEMOKINE SECRETION AND MACROPHAGE ACCUMULATION IN MURINE LIVER FIBROSIS." 2016.
Source
wos-lite
Published In
Journal of Hepatology
Volume
64
Publish Date
2016
Start Page
S514
End Page
S515

Ductal metaplasia in oesophageal submucosal glands is associated with inflammation and oesophageal adenocarcinoma.

Recent studies have suggested that oesophageal submucosal gland (ESMG) ducts harbour progenitor cells that may contribute to oesophageal metaplasia. Our objective was to determine whether histological differences exist between the ESMGs of individuals with and without oesophageal adenocarcinoma (EAC).We performed histological assessment of 343 unique ESMGs from 30 control patients, 24 patients with treatment-naïve high-grade columnar dysplasia (HGD) or EAC, and 23 non-EAC oesophagectomy cases. A gastrointestinal pathologist assessed haematoxylin and eosin-stained ESMG images by using a scoring system that assigns individual ESMG acini to five histological types (mucous, serous, oncocytic, dilated, or ductal metaplastic). In our model, ductal metaplastic acini were more common in patients with HGD/EAC (12.7%) than in controls (3.5%) (P = 0.006). We also identified greater proportions of acini with dilation (21.9%, P < 0.001) and, to a lesser extent, ductal metaplasia (4.3%, P = 0.001) in non-EAC oesophagectomy cases than in controls. Ductal metaplasia tended to occur in areas of mucosal ulceration or tumour.We found a clear association between ductal metaplastic ESMG acini and HGD/EAC. Non-EAC cases had dilated acini and some ductal dilation. Because ESMGs and ducts harbour putative progenitor cells, these associations could have significance for understanding the pathogenesis of EAC.

Authors
Garman, KS; Kruger, L; Thomas, S; Swiderska-Syn, M; Moser, BK; Diehl, AM; McCall, SJ
MLA Citation
Garman, KS, Kruger, L, Thomas, S, Swiderska-Syn, M, Moser, BK, Diehl, AM, and McCall, SJ. "Ductal metaplasia in oesophageal submucosal glands is associated with inflammation and oesophageal adenocarcinoma." Histopathology 67.6 (December 2015): 771-782.
PMID
25847432
Source
epmc
Published In
Histopathology
Volume
67
Issue
6
Publish Date
2015
Start Page
771
End Page
782
DOI
10.1111/his.12707

Liver injury-on-a-chip: microfluidic co-cultures with integrated biosensors for monitoring liver cell signaling during injury.

Tissue injury triggers complex communication between cells via secreted signaling molecules such as cytokines and growth factors. Discerning when and where these signals begin and how they propagate over time is very challenging with existing cell culture and analysis tools. The goal of this study was to develop new tools in the form of microfluidic co-cultures with integrated biosensors for local and continuous monitoring of secreted signals. Specifically, we focused on how alcohol injury affects TGF-β signaling between two liver cell types, hepatocytes and stellate cells. Activation of stellate cells happens early during liver injury and is at the center of liver fibrosis. We demonstrated that alcohol injury to microfluidic co-cultures caused significantly higher levels of stellate cell activation compared to conditioned media and transwell injury experiments. This highlighted the advantage of the microfluidic co-culture: placement of two cell types in close proximity to ensure high local concentrations of injury-promoting secreted signals. Next, we developed a microsystem consisting of five chambers, two for co-culturing hepatocytes with stellate cells and three additional chambers containing miniature aptamer-modified electrodes for monitoring secreted TGF-β. Importantly, the walls separating microfluidic chambers were actuatable; they could be raised or lowered to create different configurations of the device. The use of reconfigurable microfluidics and miniature biosensors revealed that alcohol injury causes hepatocytes to secrete TGF-β molecules, which diffuse over to neighboring stellate cells and trigger production of additional TGF-β from stellate cells. Our results lend credence to the emerging view of hepatocytes as active participants of liver injury. Broadly speaking, our microsystem makes it possible to monitor paracrine crosstalk between two cell types communicating via the same signaling molecule (e.g. TGF-β).

Authors
Zhou, Q; Patel, D; Kwa, T; Haque, A; Matharu, Z; Stybayeva, G; Gao, Y; Diehl, AM; Revzin, A
MLA Citation
Zhou, Q, Patel, D, Kwa, T, Haque, A, Matharu, Z, Stybayeva, G, Gao, Y, Diehl, AM, and Revzin, A. "Liver injury-on-a-chip: microfluidic co-cultures with integrated biosensors for monitoring liver cell signaling during injury." Lab on a chip 15.23 (December 2015): 4467-4478.
PMID
26480303
Source
epmc
Published In
Lab on a Chip
Volume
15
Issue
23
Publish Date
2015
Start Page
4467
End Page
4478
DOI
10.1039/c5lc00874c

Dysregulated metabolism contributes to oncogenesis.

Cancer is a disease characterized by unrestrained cellular proliferation. In order to sustain growth, cancer cells undergo a complex metabolic rearrangement characterized by changes in metabolic pathways involved in energy production and biosynthetic processes. The relevance of the metabolic transformation of cancer cells has been recently included in the updated version of the review "Hallmarks of Cancer", where dysregulation of cellular metabolism was included as an emerging hallmark. While several lines of evidence suggest that metabolic rewiring is orchestrated by the concerted action of oncogenes and tumor suppressor genes, in some circumstances altered metabolism can play a primary role in oncogenesis. Recently, mutations of cytosolic and mitochondrial enzymes involved in key metabolic pathways have been associated with hereditary and sporadic forms of cancer. Together, these results demonstrate that aberrant metabolism, once seen just as an epiphenomenon of oncogenic reprogramming, plays a key role in oncogenesis with the power to control both genetic and epigenetic events in cells. In this review, we discuss the relationship between metabolism and cancer, as part of a larger effort to identify a broad-spectrum of therapeutic approaches. We focus on major alterations in nutrient metabolism and the emerging link between metabolism and epigenetics. Finally, we discuss potential strategies to manipulate metabolism in cancer and tradeoffs that should be considered. More research on the suite of metabolic alterations in cancer holds the potential to discover novel approaches to treat it.

Authors
Hirschey, MD; DeBerardinis, RJ; Diehl, AME; Drew, JE; Frezza, C; Green, MF; Jones, LW; Ko, YH; Le, A; Lea, MA; Locasale, JW; Longo, VD; Lyssiotis, CA; McDonnell, E; Mehrmohamadi, M; Michelotti, G; Muralidhar, V; Murphy, MP; Pedersen, PL; Poore, B; Raffaghello, L; Rathmell, JC; Sivanand, S; Vander Heiden, MG; Wellen, KE; Target Validation Team,
MLA Citation
Hirschey, MD, DeBerardinis, RJ, Diehl, AME, Drew, JE, Frezza, C, Green, MF, Jones, LW, Ko, YH, Le, A, Lea, MA, Locasale, JW, Longo, VD, Lyssiotis, CA, McDonnell, E, Mehrmohamadi, M, Michelotti, G, Muralidhar, V, Murphy, MP, Pedersen, PL, Poore, B, Raffaghello, L, Rathmell, JC, Sivanand, S, Vander Heiden, MG, Wellen, KE, and Target Validation Team, . "Dysregulated metabolism contributes to oncogenesis." Seminars in cancer biology 35 Suppl (December 2015): S129-S150. (Review)
PMID
26454069
Source
epmc
Published In
Seminars in Cancer Biology
Volume
35 Suppl
Publish Date
2015
Start Page
S129
End Page
S150
DOI
10.1016/j.semcancer.2015.10.002

Designing a broad-spectrum integrative approach for cancer prevention and treatment.

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered.

Authors
Block, KI; Gyllenhaal, C; Lowe, L; Amedei, A; Amin, ARMR; Amin, A; Aquilano, K; Arbiser, J; Arreola, A; Arzumanyan, A; Ashraf, SS; Azmi, AS; Benencia, F; Bhakta, D; Bilsland, A; Bishayee, A; Blain, SW; Block, PB; Boosani, CS; Carey, TE; Carnero, A; Carotenuto, M; Casey, SC; Chakrabarti, M; Chaturvedi, R; Chen, GZ; Chen, H; Chen, S; Chen, YC; Choi, BK; Ciriolo, MR; Coley, HM; Collins, AR; Connell, M; Crawford, S; Curran, CS; Dabrosin, C; Damia, G; Dasgupta, S; DeBerardinis, RJ; Decker, WK et al.
MLA Citation
Block, KI, Gyllenhaal, C, Lowe, L, Amedei, A, Amin, ARMR, Amin, A, Aquilano, K, Arbiser, J, Arreola, A, Arzumanyan, A, Ashraf, SS, Azmi, AS, Benencia, F, Bhakta, D, Bilsland, A, Bishayee, A, Blain, SW, Block, PB, Boosani, CS, Carey, TE, Carnero, A, Carotenuto, M, Casey, SC, Chakrabarti, M, Chaturvedi, R, Chen, GZ, Chen, H, Chen, S, Chen, YC, Choi, BK, Ciriolo, MR, Coley, HM, Collins, AR, Connell, M, Crawford, S, Curran, CS, Dabrosin, C, Damia, G, Dasgupta, S, DeBerardinis, RJ, and Decker, WK et al. "Designing a broad-spectrum integrative approach for cancer prevention and treatment." Seminars in cancer biology 35 Suppl (December 2015): S276-S304. (Review)
PMID
26590477
Source
epmc
Published In
Seminars in Cancer Biology
Volume
35 Suppl
Publish Date
2015
Start Page
S276
End Page
S304
DOI
10.1016/j.semcancer.2015.09.007

Schistosome-induced cholangiocyte proliferation and osteopontin secretion correlate with fibrosis and portal hypertension in human and murine schistosomiasis mansoni.

Schistosomiasis is a major cause of portal hypertension worldwide. It associates with portal fibrosis that develops during chronic infection. The mechanisms by which the pathogen evokes these host responses remain unclear. We evaluated the hypothesis that schistosome eggs release factors that directly stimulate liver cells to produce osteopontin (OPN), a pro-fibrogenic protein that stimulates hepatic stellate cells to become myofibroblasts. We also investigated the utility of OPN as a biomarker of fibrosis and/or severity of portal hypertension. Cultured cholangiocytes, Kupffer cells and hepatic stellate cells were treated with soluble egg antigen (SEA); OPN production was quantified by quantitative reverse transcriptase polymerase chain reaction (qRTPCR) and ELISA; cell proliferation was assessed by BrdU (5-bromo-2'-deoxyuridine). Mice were infected with Schistosoma mansoni for 6 or 16 weeks to cause early or advanced fibrosis. Liver OPN was evaluated by qRTPCR and immunohistochemistry (IHC) and correlated with liver fibrosis and serum OPN. Livers from patients with schistosomiasis mansoni (early fibrosis n=15; advanced fibrosis n=72) or healthy adults (n=22) were immunostained for OPN and fibrosis markers. Results were correlated with plasma OPN levels and splenic vein pressures. SEA-induced cholangiocyte proliferation and OPN secretion (P<0.001 compared with controls). Cholangiocytes were OPN (+) in Schistosoma-infected mice and humans. Liver and serum OPN levels correlated with fibrosis stage (mice: r=0.861; human r=0.672, P=0.0001) and myofibroblast accumulation (mice: r=0.800; human: r=0.761, P=0.0001). Numbers of OPN (+) bile ductules strongly correlated with splenic vein pressure (r=0.778; P=0.001). S. mansoni egg antigens stimulate cholangiocyte proliferation and OPN secretion. OPN levels in liver and blood correlate with fibrosis stage and portal hypertension severity.

Authors
Pereira, TA; Syn, W-K; Machado, MV; Vidigal, PV; Resende, V; Voieta, I; Xie, G; Otoni, A; Souza, MM; Santos, ET; Chan, IS; Trindade, GVM; Choi, SS; Witek, RP; Pereira, FE; Secor, WE; Andrade, ZA; Lambertucci, JR; Diehl, AM
MLA Citation
Pereira, TA, Syn, W-K, Machado, MV, Vidigal, PV, Resende, V, Voieta, I, Xie, G, Otoni, A, Souza, MM, Santos, ET, Chan, IS, Trindade, GVM, Choi, SS, Witek, RP, Pereira, FE, Secor, WE, Andrade, ZA, Lambertucci, JR, and Diehl, AM. "Schistosome-induced cholangiocyte proliferation and osteopontin secretion correlate with fibrosis and portal hypertension in human and murine schistosomiasis mansoni." Clinical science (London, England : 1979) 129.10 (November 2015): 875-883.
Website
http://hdl.handle.net/10161/11081
PMID
26201095
Source
epmc
Published In
Clinical science (London, England : 1979)
Volume
129
Issue
10
Publish Date
2015
Start Page
875
End Page
883
DOI
10.1042/cs20150117

Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease.

Mechanisms that regulate regeneration of injured livers are complex. YAP, a stem cell associated factor, controls liver growth in healthy adult mice. Increasing nuclear localization of YAP triggers accumulation of reactive-appearing ductular cells (YAP+RDC) with liver progenitor capabilities. The significance of YAP activation, and mechanisms involved, are unknown in diseased livers. We evaluated the hypothesis that YAP is more activated in injured livers that are scarring than in those that are regenerating effectively.Immunohistochemistry and qRT-PCR analysis were used to localize and quantify changes in YAP and RDC in 52 patients with non-alcoholic fatty liver disease (NAFLD) and two mouse models of diet-induced non-alcoholic steatohepatitis (NASH). Results were correlated with liver disease severity, metabolic risk factors, and factors proven to control NAFLD progression.YAP increased in NAFLD where it mainly localized in nuclei of RDC that expressed progenitor markers. Accumulation of YAP+RDC paralleled the severity of hepatocyte injury and accumulation of Sonic hedgehog, but not steatosis or metabolic risk factors. YAP+RDC expressed osteopontin, a Shh-regulated fibrogenic factor. Myofibroblast accumulation, fibrosis, and numbers of YAP+RDC strongly correlated. In murine NASH models, atrophic fibrotic livers contained significantly more YAP+RDC than livers with less severe NASH.YAP+RDC promote scarring, rather than effective regeneration, during NASH.

Authors
Machado, MV; Michelotti, GA; Pereira, TA; Xie, G; Premont, R; Cortez-Pinto, H; Diehl, AM
MLA Citation
Machado, MV, Michelotti, GA, Pereira, TA, Xie, G, Premont, R, Cortez-Pinto, H, and Diehl, AM. "Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease." Journal of hepatology 63.4 (October 2015): 962-970.
PMID
26070409
Source
epmc
Published In
Journal of Hepatology
Volume
63
Issue
4
Publish Date
2015
Start Page
962
End Page
970
DOI
10.1016/j.jhep.2015.05.031

LGR5 is associated with tumor aggressiveness in papillary thyroid cancer.

Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a cancer stem cell marker and a down-stream target in Wnt/β-catenin signaling. In human papillary thyroid cancer (PTC), over activation of Wnt/β-catenin has been associated with tumor aggressiveness.Using established human cell lines (TPC-1, KTC-1, Nthy-ori-3-1), we report LGR5 and R-spondin (RSPO1-3) overexpression in PTC and manipulate LGR5 and Wnt/β-catenin signaling via both pharmacologic and genetic interventions. We test the association of LGR5 tumor expression with markers of PTC aggressiveness using a Discovery Cohort (n = 26 patients) and a Validation Cohort (n = 157 patients). Lastly, we explore the association between LGR5 and the BRAFV600E mutation (n = 33 patients).Our results reveal that LGR5 and its ligand, RSPO, are overexpressed in human PTC, whereby Wnt/β-catenin signaling regulates LGR5 expression and promotes cellular migration. In two separate cohorts of patients, LGR5 and RSPO2 were associated with markers of tumor aggressiveness including: lymph node metastases, vascular invasion, increased tumor size, aggressive histology, advanced AJCC TNM stage, microscopic extra thyroidal extension, capsular invasion, and macroscopic invasion. As a biomarker, LGR5 positivity predicts lymph node metastasis with 95.5% sensitivity (95% CI 88.8%-98.7%) and 61% specificity (95% CI: 48.4%-72.4%) and has a negative predictive value (NPV) of 91.3% (95% CI 79.2%-97.5%) for lymph node metastatic disease. In human PTC, LGR5 is also strongly associated with the BRAFV600E mutation (p = 0.005).We conclude that overexpression of LGR5 is associated with markers of tumor aggressiveness in human PTC. LGR5 may serve as a future potential biomarker for patient risk stratification and loco regional metastases in PTC.

Authors
Michelotti, G; Jiang, X; Sosa, JA; Diehl, AM; Henderson, BB
MLA Citation
Michelotti, G, Jiang, X, Sosa, JA, Diehl, AM, and Henderson, BB. "LGR5 is associated with tumor aggressiveness in papillary thyroid cancer." Oncotarget 6.33 (October 2015): 34549-34560.
PMID
26416247
Source
epmc
Published In
Oncotarget
Volume
6
Issue
33
Publish Date
2015
Start Page
34549
End Page
34560
DOI
10.18632/oncotarget.5330

Statins activate the canonical hedgehog-signaling and aggravate non-cirrhotic portal hypertension, but inhibit the non-canonical hedgehog signaling and cirrhotic portal hypertension

Authors
Uschner, FE; Ranabhat, G; Granzow, M; Choi, SS; Klein, S; Schierwagen, R; Raskopf, E; Gautsch, S; Van der Ven, PF; Strassburg, CP; Fuerst, DO; Hiththetiya, K; Sauerbruch, T; Diehl, AM; Trebicka, J
MLA Citation
Uschner, FE, Ranabhat, G, Granzow, M, Choi, SS, Klein, S, Schierwagen, R, Raskopf, E, Gautsch, S, Van der Ven, PF, Strassburg, CP, Fuerst, DO, Hiththetiya, K, Sauerbruch, T, Diehl, AM, and Trebicka, J. "Statins activate the canonical hedgehog-signaling and aggravate non-cirrhotic portal hypertension, but inhibit the non-canonical hedgehog signaling and cirrhotic portal hypertension." October 2015.
Source
wos-lite
Published In
Hepatology
Volume
62
Publish Date
2015
Start Page
249A
End Page
249A

Increasing severity of NAFLD is associated with gut dysbiosis and modification of the metabolic function of the gut microbiota

Authors
Boursier, J; Mueller, O; Barret, M; Machado, MV; Fizanne, L; Guy, CD; Rawls, JF; David, L; Hunault, G; Oberti, F; Cales, P; Diehl, AM
MLA Citation
Boursier, J, Mueller, O, Barret, M, Machado, MV, Fizanne, L, Guy, CD, Rawls, JF, David, L, Hunault, G, Oberti, F, Cales, P, and Diehl, AM. "Increasing severity of NAFLD is associated with gut dysbiosis and modification of the metabolic function of the gut microbiota." October 2015.
Source
wos-lite
Published In
Hepatology
Volume
62
Publish Date
2015
Start Page
1274A
End Page
1274A

Ancestral starvation-activated caspase-2 promotes obesity, the metabolic syndrome and Nonalcoholic fatty liver disease

Authors
Machado, MV; Michelotti, GA; Xie, G; Pereira, TA; Jewell, M; Premont, RT; Diehl, AM
MLA Citation
Machado, MV, Michelotti, GA, Xie, G, Pereira, TA, Jewell, M, Premont, RT, and Diehl, AM. "Ancestral starvation-activated caspase-2 promotes obesity, the metabolic syndrome and Nonalcoholic fatty liver disease." October 2015.
Source
wos-lite
Published In
Hepatology
Volume
62
Publish Date
2015
Start Page
670A
End Page
670A

Serum lysyl oxidase-like-2 (sLOXL2) levels correlate with fibrosis stage in patients with nonalcoholic steatohepatitis (NASH)

Authors
Harrison, SA; Goodman, ZD; Ratziu, V; Loomba, R; Diehl, AM; Lawitz, E; Hinrichsen, H; Bambha, K; Abdelmalek, MF; Myers, RP; Schall, REA; Subramanian, M; McHutchison, JG; Afdhal, NH; Muir, AJ
MLA Citation
Harrison, SA, Goodman, ZD, Ratziu, V, Loomba, R, Diehl, AM, Lawitz, E, Hinrichsen, H, Bambha, K, Abdelmalek, MF, Myers, RP, Schall, REA, Subramanian, M, McHutchison, JG, Afdhal, NH, and Muir, AJ. "Serum lysyl oxidase-like-2 (sLOXL2) levels correlate with fibrosis stage in patients with nonalcoholic steatohepatitis (NASH)." October 2015.
Source
wos-lite
Published In
Hepatology
Volume
62
Publish Date
2015
Start Page
910A
End Page
910A

Plasma Metabolomic Profiles Predict Advanced Hepatic Fibrosis in Patients with Nonalcoholic Fatty Liver Disease

Authors
Henao, R; Hasanaliyeva, N; Bell, LN; Wulff, J; Perichon, R; Moylan, CA; Lu, JT; Guy, CD; Diehl, AM; Abdelmalek, MF
MLA Citation
Henao, R, Hasanaliyeva, N, Bell, LN, Wulff, J, Perichon, R, Moylan, CA, Lu, JT, Guy, CD, Diehl, AM, and Abdelmalek, MF. "Plasma Metabolomic Profiles Predict Advanced Hepatic Fibrosis in Patients with Nonalcoholic Fatty Liver Disease." October 2015.
Source
wos-lite
Published In
Hepatology
Volume
62
Publish Date
2015
Start Page
290A
End Page
291A

DNA Methylation Profiles of Fibrosis-Associated Gene in Blood Reflects Liver Fibrosis Severity in Human Nonalcoholic Fatty Liver Disease

Authors
Moylan, CA; Murphy, SK; Grenier, C; Abdelmalek, MF; Diehl, AM
MLA Citation
Moylan, CA, Murphy, SK, Grenier, C, Abdelmalek, MF, and Diehl, AM. "DNA Methylation Profiles of Fibrosis-Associated Gene in Blood Reflects Liver Fibrosis Severity in Human Nonalcoholic Fatty Liver Disease." October 2015.
Source
wos-lite
Published In
Hepatology
Volume
62
Publish Date
2015
Start Page
648A
End Page
649A

IL-8 and MCP1 are Independently Associated with Hepatic Fibrosis in Patients with Nonalcoholic Fatty Liver Disease

Authors
Hasanaliyeva, N; Patel, K; Guy, CD; Gruss, HJ; Streilein, R; Hall, R; Diehl, AM; Abdelmalek, MF
MLA Citation
Hasanaliyeva, N, Patel, K, Guy, CD, Gruss, HJ, Streilein, R, Hall, R, Diehl, AM, and Abdelmalek, MF. "IL-8 and MCP1 are Independently Associated with Hepatic Fibrosis in Patients with Nonalcoholic Fatty Liver Disease." October 2015.
Source
wos-lite
Published In
Hepatology
Volume
62
Publish Date
2015
Start Page
1265A
End Page
1265A

TRPV4 regulates inflammation and Kupffer cell activation in nonalcoholic steatohepatitis by attenuation of CYP2E1-mediated oxidative stress

Authors
Seth, RK; Das, S; Dattaroy, D; Alhasson, F; Bell, PD; Michelotti, GA; Nagarkatti, M; Nagarkatti, P; Liedtke, WB; Diehl, AM; Chatterjee, S
MLA Citation
Seth, RK, Das, S, Dattaroy, D, Alhasson, F, Bell, PD, Michelotti, GA, Nagarkatti, M, Nagarkatti, P, Liedtke, WB, Diehl, AM, and Chatterjee, S. "TRPV4 regulates inflammation and Kupffer cell activation in nonalcoholic steatohepatitis by attenuation of CYP2E1-mediated oxidative stress." October 2015.
Source
wos-lite
Published In
Hepatology
Volume
62
Publish Date
2015
Start Page
1248A
End Page
1248A

Characterization of obesity-related modifications in hepatic stellate cells

Authors
Xie, G; Swiderska-Syn, M; Machado, MV; Jewell, M; Premont, RT; Michelotti, GA; Teperino, R; Diehl, AM
MLA Citation
Xie, G, Swiderska-Syn, M, Machado, MV, Jewell, M, Premont, RT, Michelotti, GA, Teperino, R, and Diehl, AM. "Characterization of obesity-related modifications in hepatic stellate cells." October 2015.
Source
wos-lite
Published In
Hepatology
Volume
62
Publish Date
2015
Start Page
889A
End Page
889A

Osteopontin promotes cholangiocyte chemokine secretion and macrophage accumulation in mice

Authors
Coombes, JD; Manka, PP; Swiderska-Syn, M; Riva, A; Reid, D; Claridge, LC; Dolle, L; Younis, R; Briones-Orta, MA; Kitamura, N; Mi, Z; Kuo, PC; Williams, R; Diehl, AM; Chokshi, S; Eksteen, B; Canbay, A; Syn, W-K
MLA Citation
Coombes, JD, Manka, PP, Swiderska-Syn, M, Riva, A, Reid, D, Claridge, LC, Dolle, L, Younis, R, Briones-Orta, MA, Kitamura, N, Mi, Z, Kuo, PC, Williams, R, Diehl, AM, Chokshi, S, Eksteen, B, Canbay, A, and Syn, W-K. "Osteopontin promotes cholangiocyte chemokine secretion and macrophage accumulation in mice." October 2015.
Source
wos-lite
Published In
Hepatology
Volume
62
Publish Date
2015
Start Page
1251A
End Page
1251A

Clinical and histologic correlates of the hepatic venous pressure gradient (HVPG) in patients with compensated cirrhosis due to nonalcoholic steatohepatitis (NASH)

Authors
Sanyal, AJ; Goodman, ZD; Abdelmalek, MF; Harrison, SA; Rockey, DC; Diehl, AM; Caldwell, SH; Shiffman, ML; Myers, RP; Schall, REA; Subramanian, M; McHutchison, JG; Ratziu, V; Afdhal, NH; Bosch, J
MLA Citation
Sanyal, AJ, Goodman, ZD, Abdelmalek, MF, Harrison, SA, Rockey, DC, Diehl, AM, Caldwell, SH, Shiffman, ML, Myers, RP, Schall, REA, Subramanian, M, McHutchison, JG, Ratziu, V, Afdhal, NH, and Bosch, J. "Clinical and histologic correlates of the hepatic venous pressure gradient (HVPG) in patients with compensated cirrhosis due to nonalcoholic steatohepatitis (NASH)." October 2015.
Source
wos-lite
Published In
Hepatology
Volume
62
Publish Date
2015
Start Page
577A
End Page
577A

Nocturnal Hypoxia is associated with Hedgehog Signaling and Severity of Pediatric Non-Alcoholic Fatty Liver Disease (NAFLD)

Authors
Sundaram, S; Swiderska-Syn, M; Sokol, RJ; Pan, Z; Halbower, AC; Capocelli, KE; Robbins, KN; Diehl, AM
MLA Citation
Sundaram, S, Swiderska-Syn, M, Sokol, RJ, Pan, Z, Halbower, AC, Capocelli, KE, Robbins, KN, and Diehl, AM. "Nocturnal Hypoxia is associated with Hedgehog Signaling and Severity of Pediatric Non-Alcoholic Fatty Liver Disease (NAFLD)." October 2015.
Source
wos-lite
Published In
Hepatology
Volume
62
Publish Date
2015
Start Page
1044A
End Page
1045A

Statins activate the canonical hedgehog-signaling and aggravate non-cirrhotic portal hypertension, but inhibit the non-canonical hedgehog signaling and cirrhotic portal hypertension.

Liver cirrhosis but also portal vein obstruction cause portal hypertension (PHT) and angiogenesis. This study investigated the differences of angiogenesis in cirrhotic and non-cirrhotic PHT with special emphasis on the canonical (Shh/Gli) and non-canonical (Shh/RhoA) hedgehog pathway. Cirrhotic (bile duct ligation/BDL; CCl4 intoxication) and non-cirrhotic (partial portal vein ligation/PPVL) rats received either atorvastatin (15 mg/kg; 7d) or control chow before sacrifice. Invasive hemodynamic measurement and Matrigel implantation assessed angiogenesis in vivo. Angiogenesis in vitro was analysed using migration and tube formation assay. In liver and vessel samples from animals and humans, transcript expression was analyzed using RT-PCR and protein expression using Western blot. Atorvastatin decreased portal pressure, shunt flow and angiogenesis in cirrhosis, whereas atorvastatin increased these parameters in PPVL rats. Non-canonical Hh was upregulated in experimental and human liver cirrhosis and was blunted by atorvastatin. Moreover, atorvastatin blocked the non-canonical Hh-pathway RhoA dependently in activated hepatic steallate cells (HSCs). Interestingly, hepatic and extrahepatic Hh-pathway was enhanced in PPVL rats, which resulted in increased angiogenesis. In summary, statins caused contrary effects in cirrhotic and non-cirrhotic portal hypertension. Atorvastatin inhibited the non-canonical Hh-pathway and angiogenesis in cirrhosis. In portal vein obstruction, statins enhanced the canonical Hh-pathway and aggravated PHT and angiogenesis.

Authors
Uschner, FE; Ranabhat, G; Choi, SS; Granzow, M; Klein, S; Schierwagen, R; Raskopf, E; Gautsch, S; van der Ven, PFM; Fürst, DO; Strassburg, CP; Sauerbruch, T; Diehl, AM; Trebicka, J
MLA Citation
Uschner, FE, Ranabhat, G, Choi, SS, Granzow, M, Klein, S, Schierwagen, R, Raskopf, E, Gautsch, S, van der Ven, PFM, Fürst, DO, Strassburg, CP, Sauerbruch, T, Diehl, AM, and Trebicka, J. "Statins activate the canonical hedgehog-signaling and aggravate non-cirrhotic portal hypertension, but inhibit the non-canonical hedgehog signaling and cirrhotic portal hypertension." Scientific Reports 5 (September 28, 2015): 14573-.
PMID
26412302
Source
epmc
Published In
Scientific Reports
Volume
5
Publish Date
2015
Start Page
14573
DOI
10.1038/srep14573

Hedgehog signaling in the liver

© 2015 by John Wiley & Sons, Ltd. All rights reserved. The Hedgehog signaling pathway regulates tissue patterning during development. Because it is barely active in healthy adult livers, the Hedgehog pathway was generally presumed to be irrelevant in adult livers. However, that dogma was shattered by the demonstration that Hedgehog signaling is routinely reactivated after liver injury, and evidence that it controls various wound-healing responses. In fact, the Hedgehog pathway plays a critical role orchestrating liver repair, promoting progenitor cell proliferation to replace lost epithelial cells and activating stellate cells, immune cells, and endothelial cells to optimize the local microenvironment for repair. With improved understanding of Hedgehog's roles in injured adult livers has come the realization that modulating Hedgehog signaling provides a promising therapeutic approach for liver disease. In this chapter we will review the literature on the Hedgehog pathway in the liver, with particular focus on its role in regeneration, chronic liver disease, and cancer.

Authors
Machado, MV; Diehl, AM
MLA Citation
Machado, MV, and Diehl, AM. "Hedgehog signaling in the liver." Signaling Pathways in Liver Diseases: Third Edition. September 28, 2015. 262-274.
Source
scopus
Publish Date
2015
Start Page
262
End Page
274
DOI
10.1002/9781118663387.ch19

Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice.

Chronic liver injury triggers a progenitor cell repair response, and liver fibrosis occurs when repair becomes deregulated. Previously, we reported that reactivation of the hedgehog pathway promotes fibrogenic liver repair. Osteopontin (OPN) is a hedgehog-target, and a cytokine that is highly upregulated in fibrotic tissues, and regulates stem-cell fate. Thus, we hypothesised that OPN may modulate liver progenitor cell response, and thereby, modulate fibrotic outcomes. We further evaluated the impact of OPN-neutralisation on murine liver fibrosis.Liver progenitors (603B and bipotential mouse oval liver) were treated with OPN-neutralising aptamers in the presence or absence of transforming growth factor (TGF)-β, to determine if (and how) OPN modulates liver progenitor function. Effects of OPN-neutralisation (using OPN-aptamers or OPN-neutralising antibodies) on liver progenitor cell response and fibrogenesis were assessed in three models of liver fibrosis (carbon tetrachloride, methionine-choline deficient diet, 3,5,-diethoxycarbonyl-1,4-dihydrocollidine diet) by quantitative real time (qRT) PCR, Sirius-Red staining, hydroxyproline assay, and semiquantitative double-immunohistochemistry. Finally, OPN expression and liver progenitor response were corroborated in liver tissues obtained from patients with chronic liver disease.OPN is overexpressed by liver progenitors in humans and mice. In cultured progenitors, OPN enhances viability and wound healing by modulating TGF-β signalling. In vivo, OPN-neutralisation attenuates the liver progenitor cell response, reverses epithelial-mesenchymal-transition in Sox9+ cells, and abrogates liver fibrogenesis.OPN upregulation during liver injury is a conserved repair response, and influences liver progenitor cell function. OPN-neutralisation abrogates the liver progenitor cell response and fibrogenesis in mouse models of liver fibrosis.

Authors
Coombes, JD; Swiderska-Syn, M; Dollé, L; Reid, D; Eksteen, B; Claridge, L; Briones-Orta, MA; Shetty, S; Oo, YH; Riva, A; Chokshi, S; Papa, S; Mi, Z; Kuo, PC; Williams, R; Canbay, A; Adams, DH; Diehl, AM; van Grunsven, LA; Choi, SS; Syn, WK
MLA Citation
Coombes, JD, Swiderska-Syn, M, Dollé, L, Reid, D, Eksteen, B, Claridge, L, Briones-Orta, MA, Shetty, S, Oo, YH, Riva, A, Chokshi, S, Papa, S, Mi, Z, Kuo, PC, Williams, R, Canbay, A, Adams, DH, Diehl, AM, van Grunsven, LA, Choi, SS, and Syn, WK. "Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice." Gut 64.7 (July 2015): 1120-1131.
PMID
24902765
Source
epmc
Published In
Gut
Volume
64
Issue
7
Publish Date
2015
Start Page
1120
End Page
1131
DOI
10.1136/gutjnl-2013-306484

Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis.

OBJECTIVE: Caspase-2 is an initiator caspase involved in multiple apoptotic pathways, particularly in response to specific intracellular stressors (eg, DNA damage, ER stress). We recently reported that caspase-2 was pivotal for the induction of cell death triggered by excessive intracellular accumulation of long-chain fatty acids, a response known as lipoapoptosis. The liver is particularly susceptible to lipid-induced damage, explaining the pandemic status of non-alcoholic fatty liver disease (NAFLD). Progression from NAFLD to non-alcoholic steatohepatitis (NASH) results, in part, from hepatocyte apoptosis and consequential paracrine-mediated fibrogenesis. We evaluated the hypothesis that caspase-2 promotes NASH-related cirrhosis. DESIGN: Caspase-2 was localised in liver biopsies from patients with NASH. Its expression was evaluated in different mouse models of NASH, and outcomes of diet-induced NASH were compared in wild-type (WT) and caspase-2-deficient mice. Lipotoxicity was modelled in vitro using hepatocytes derived from WT and caspase-2-deficient mice. RESULTS: We showed that caspase-2 is integral to the pathogenesis of NASH-related cirrhosis. Caspase-2 is localised in injured hepatocytes and its expression was markedly upregulated in patients and animal models of NASH. During lipotoxic stress, caspase-2 deficiency reduced apoptosis, inhibited induction of profibrogenic hedgehog target genes in mice and blocked production of hedgehog ligands in cultured hepatocytes. CONCLUSIONS: These data point to a critical role for caspase-2 in lipid-induced hepatocyte apoptosis in vivo for the production of apoptosis-associated fibrogenic factors and in the progression of lipid-induced liver fibrosis. This raises the intriguing possibility that caspase-2 may be a promising therapeutic target to prevent progression to NASH.

Authors
Machado, MV; Michelotti, GA; Pereira, TDA; Boursier, J; Kruger, L; Swiderska-Syn, M; Karaca, G; Xie, G; Guy, CD; Bohinc, B; Lindblom, KR; Johnson, E; Kornbluth, S; Diehl, AM
MLA Citation
Machado, MV, Michelotti, GA, Pereira, TDA, Boursier, J, Kruger, L, Swiderska-Syn, M, Karaca, G, Xie, G, Guy, CD, Bohinc, B, Lindblom, KR, Johnson, E, Kornbluth, S, and Diehl, AM. "Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis." Gut 64.7 (July 2015): 1148-1157.
PMID
25053716
Source
pubmed
Published In
Gut
Volume
64
Issue
7
Publish Date
2015
Start Page
1148
End Page
1157
DOI
10.1136/gutjnl-2014-307362

NADPH Oxidase-Derived Peroxynitrite Drives Inflammation in Mice and Human Nonalcoholic Steatohepatitis via TLR4-Lipid Raft Recruitment.

The molecular events that link NADPH oxidase activation and the induction of Toll-like receptor (TLR)-4 recruitment into hepatic lipid rafts in nonalcoholic steatohepatitis (NASH) are unclear. We hypothesized that in liver, NADPH oxidase activation is key in TLR4 recruitment into lipid rafts, which in turn up-regulates NF-κB translocation to the nucleus and subsequent DNA binding, leading to NASH progression. Results from confocal microscopy showed that liver from murine and human NASH had NADPH oxidase activation, which led to the formation of highly reactive peroxynitrite, as shown by 3-nitrotyrosine formation in diseased liver. Expression and recruitment of TLR4 into the lipid rafts were significantly greater in rodent and human NASH. The described phenomenon was NADPH oxidase, p47phox, and peroxynitrite dependent, as liver from p47phox-deficient mice and from mice treated with a peroxynitrite decomposition catalyst [iron(III) tetrakis(p-sulfonatophenyl)porphyrin] or a peroxynitrite scavenger (phenylboronic acid) had markedly less Tlr4 recruitment into lipid rafts. Mechanistically, peroxynitrite-induced TLR4 recruitment was linked to increased IL-1β, sinusoidal injury, and Kupffer cell activation while blocking peroxynitrite-attenuated NASH symptoms. The results strongly suggest that NADPH oxidase-mediated peroxynitrite drove TLR4 recruitment into hepatic lipid rafts and inflammation, whereas the in vivo use of the peroxynitrite scavenger phenylboronic acid, a novel synthetic molecule having high reactivity with peroxynitrite, attenuates inflammatory pathogenesis in NASH.

Authors
Das, S; Alhasson, F; Dattaroy, D; Pourhoseini, S; Seth, RK; Nagarkatti, M; Nagarkatti, PS; Michelotti, GA; Diehl, AM; Kalyanaraman, B; Chatterjee, S
MLA Citation
Das, S, Alhasson, F, Dattaroy, D, Pourhoseini, S, Seth, RK, Nagarkatti, M, Nagarkatti, PS, Michelotti, GA, Diehl, AM, Kalyanaraman, B, and Chatterjee, S. "NADPH Oxidase-Derived Peroxynitrite Drives Inflammation in Mice and Human Nonalcoholic Steatohepatitis via TLR4-Lipid Raft Recruitment." The American Journal of Pathology 185.7 (July 2015): 1944-1957.
PMID
25989356
Source
epmc
Published In
The American journal of pathology
Volume
185
Issue
7
Publish Date
2015
Start Page
1944
End Page
1957
DOI
10.1016/j.ajpath.2015.03.024

Fibrosis in nonalcoholic Fatty liver disease: mechanisms and clinical implications.

Nonalcoholic fatty liver disease (NAFLD) is tightly associated with obesity and the metabolic syndrome in the United States and other Western countries. It is also the liver disease most rapidly increasing in prevalence in the United States, and has become a major indication for liver transplantation worldwide. Compelling evidence shows that the degree of liver fibrosis dictates liver prognosis in NAFLD. This review focuses on fibrosis based on clinical and basic perspectives. The authors summarize the physiopathology of fibrosis development and progression in NAFLD, highlighting its molecular mechanisms, clinical consequences of fibrosis, the diagnostic approach and management strategies.

Authors
Angulo, P; Machado, MV; Diehl, AM
MLA Citation
Angulo, P, Machado, MV, and Diehl, AM. "Fibrosis in nonalcoholic Fatty liver disease: mechanisms and clinical implications." Seminars in liver disease 35.2 (May 14, 2015): 132-145. (Review)
PMID
25974899
Source
epmc
Published In
Seminars in Liver Disease
Volume
35
Issue
2
Publish Date
2015
Start Page
132
End Page
145
DOI
10.1055/s-0035-1550065

Reply

Authors
Guy, C; Suzuki, A; Abdelmalek, M; Burchette, J; Diehl, AM
MLA Citation
Guy, C, Suzuki, A, Abdelmalek, M, Burchette, J, and Diehl, AM. "Reply." Hepatology 61.5 (May 2015): 1770-1771.
Source
crossref
Published In
Hepatology
Volume
61
Issue
5
Publish Date
2015
Start Page
1770
End Page
1771
DOI
10.1002/hep.27430

Reply: To PMID 24849310.

Authors
Guy, C; Suzuki, A; Abdelmalek, M; Burchette, J; Diehl, AM
MLA Citation
Guy, C, Suzuki, A, Abdelmalek, M, Burchette, J, and Diehl, AM. "Reply: To PMID 24849310." Hepatology (Baltimore, Md.) 61.5 (May 2015): 1770-1771. (Letter)
PMID
25209009
Source
epmc
Published In
Hepatology
Volume
61
Issue
5
Publish Date
2015
Start Page
1770
End Page
1771
DOI
10.1002/hep.27430

Prometheus and progenitors.

Authors
Diehl, AM
MLA Citation
Diehl, AM. "Prometheus and progenitors." Hepatology (Baltimore, Md.) 61.4 (April 2015): 1427-1429.
PMID
25545250
Source
epmc
Published In
Hepatology
Volume
61
Issue
4
Publish Date
2015
Start Page
1427
End Page
1429
DOI
10.1002/hep.27676

Inflammatory models drastically alter tumor growth and the immune microenvironment in hepatocellular carcinoma.

Initiation and progression of hepatocellular carcinoma (HCC) is intimately associated with a chronically diseased liver tissue. This diseased liver tissue background is a drastically different microenvironment from the healthy liver, especially with regard to immune cell prevalence and presence of mediators of immune function. To better understand the consequences of liver disease on tumor growth and the interplay with its microenvironment, we utilized two standard methods of fibrosis induction and orthotopic implantation of tumors into the inflamed and fibrotic liver to mimic the liver condition in human HCC patients. Compared to non-diseased controls, tumor growth was significantly enhanced under fibrotic conditions. The immune cells that infiltrated the tumors were also drastically different, with decreased numbers of natural killer cells but greatly increased numbers of immune-suppressive CD11b+ Gr1hi myeloid cells in both models of fibrosis. In addition, there were model-specific differences: Increased numbers of CD11b+ myeloid cells and CD4+ CD25+ T cells were found in tumors in the bile duct ligation model but not in the carbon tetrachloride model. Induction of fibrosis altered the cytokine production of implanted tumor cells, which could have farreaching consequences on the immune infiltrate and its functionality. Taken together, this work demonstrates that the combination of fibrosis induction with orthotopic tumor implantation results in a markedly different tumor microenvironment and tumor growth kinetics, emphasizing the necessity for more accurate modeling of HCC progression in mice, which takes into account the drastic changes in the tissue caused by chronic liver disease.

Authors
Markowitz, GJ; Michelotti, GA; Diehl, AM; Wang, X-F
MLA Citation
Markowitz, GJ, Michelotti, GA, Diehl, AM, and Wang, X-F. "Inflammatory models drastically alter tumor growth and the immune microenvironment in hepatocellular carcinoma." Science bulletin 60.8 (April 2015): 762-772.
PMID
26029472
Source
epmc
Published In
Science bulletin (Beijing)
Volume
60
Issue
8
Publish Date
2015
Start Page
762
End Page
772
DOI
10.1007/s11434-015-0772-5

Systematic Analysis of NAFLD Transcriptome Revealed Elevated Expression of Alcohol Metabolizing Genes in Mild and Severe NAFLD Livers

Authors
Zhu, R; Baker, SS; Moylan, CA; Abdelmalek, MF; Guy, CD; Zamboni, F; Wu, D; Lin, W; Liu, W; Baker, RD; Govindarajan, S; Cao, Z; Farci, P; Diehl, AM; Zhu, L
MLA Citation
Zhu, R, Baker, SS, Moylan, CA, Abdelmalek, MF, Guy, CD, Zamboni, F, Wu, D, Lin, W, Liu, W, Baker, RD, Govindarajan, S, Cao, Z, Farci, P, Diehl, AM, and Zhu, L. "Systematic Analysis of NAFLD Transcriptome Revealed Elevated Expression of Alcohol Metabolizing Genes in Mild and Severe NAFLD Livers." April 2015.
Source
wos-lite
Published In
Gastroenterology
Volume
148
Issue
4
Publish Date
2015
Start Page
S1054
End Page
S1054

NON-ALCOHOLIC STEATOHEPATITIS (NASH): 2 COMPLEMENTARY DIETARY MOUSE MODELS

Authors
Machado, MV; Michelotti, GA; Xie, G; Boursier, J; de Almeida, TP; Kruger, L; Karaca, G; Guy, C; Diehl, AM
MLA Citation
Machado, MV, Michelotti, GA, Xie, G, Boursier, J, de Almeida, TP, Kruger, L, Karaca, G, Guy, C, and Diehl, AM. "NON-ALCOHOLIC STEATOHEPATITIS (NASH): 2 COMPLEMENTARY DIETARY MOUSE MODELS." April 2015.
Source
wos-lite
Published In
Journal of Hepatology
Volume
62
Publish Date
2015
Start Page
S695
End Page
S695

MARKERS OF TISSUE REPAIR AND CELLULAR AGING ARE INCREASED IN LIVER TISSUE OF PATIENTS WITH DUAL CHRONIC HIV/HCV INFECTIONS

Authors
Swiderska-Syn, M; Choi, S; Lan, A; Ferrari, G; Diehl, AM; Naggie, S
MLA Citation
Swiderska-Syn, M, Choi, S, Lan, A, Ferrari, G, Diehl, AM, and Naggie, S. "MARKERS OF TISSUE REPAIR AND CELLULAR AGING ARE INCREASED IN LIVER TISSUE OF PATIENTS WITH DUAL CHRONIC HIV/HCV INFECTIONS." April 2015.
Source
wos-lite
Published In
Journal of Hepatology
Volume
62
Publish Date
2015
Start Page
S489
End Page
S489

CROSS-TALK BETWEEN IL13 AND HEDGEHOG PATHWAYS CONTRIBUTES TO SCHISTOSOMIASIS MANSONI FIBROSIS

Authors
De Almeida Pereira, T; Borthwick, L; Xie, G; Vidigal, P; Machado, M; Voieta, I; Resende, V; Cheever, A; Andrade, Z; Lambertucci, J; Wynn, T; Diehl, AM
MLA Citation
De Almeida Pereira, T, Borthwick, L, Xie, G, Vidigal, P, Machado, M, Voieta, I, Resende, V, Cheever, A, Andrade, Z, Lambertucci, J, Wynn, T, and Diehl, AM. "CROSS-TALK BETWEEN IL13 AND HEDGEHOG PATHWAYS CONTRIBUTES TO SCHISTOSOMIASIS MANSONI FIBROSIS." April 2015.
Source
wos-lite
Published In
Journal of Hepatology
Volume
62
Publish Date
2015
Start Page
S204
End Page
S204

Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.

The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis.We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase -24%, 95% CI -45 to -3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0·0024) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498.Between March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group (relative risk 1·9, 95% CI 1·3 to 2·8; p=0·0002). 33 (23%) of 141 patients in the obeticholic acid developed pruritus compared with nine (6%) of 142 in the placebo group.Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification.National Institute of Diabetes and Digestive and Kidney Diseases, Intercept Pharmaceuticals.

Authors
Neuschwander-Tetri, BA; Loomba, R; Sanyal, AJ; Lavine, JE; Van Natta, ML; Abdelmalek, MF; Chalasani, N; Dasarathy, S; Diehl, AM; Hameed, B; Kowdley, KV; McCullough, A; Terrault, N; Clark, JM; Tonascia, J; Brunt, EM; Kleiner, DE; Doo, E; NASH Clinical Research Network,
MLA Citation
Neuschwander-Tetri, BA, Loomba, R, Sanyal, AJ, Lavine, JE, Van Natta, ML, Abdelmalek, MF, Chalasani, N, Dasarathy, S, Diehl, AM, Hameed, B, Kowdley, KV, McCullough, A, Terrault, N, Clark, JM, Tonascia, J, Brunt, EM, Kleiner, DE, Doo, E, and NASH Clinical Research Network, . "Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial." Lancet (London, England) 385.9972 (March 2015): 956-965.
PMID
25468160
Source
epmc
Published In
The Lancet
Volume
385
Issue
9972
Publish Date
2015
Start Page
956
End Page
965
DOI
10.1016/s0140-6736(14)61933-4

Role of Fn14 in acute alcoholic steatohepatitis in mice.

TNF-like weak inducer of apoptosis (TWEAK) is a growth factor for bipotent liver progenitors that express its receptor, fibroblast growth factor-inducible 14 (Fn14), a TNF receptor superfamily member. Accumulation of Fn14(+) progenitors occurs in severe acute alcoholic steatohepatitis (ASH) and correlates with acute mortality. In patients with severe ASH, inhibition of TNF-α increases acute mortality. The aim of this study was to determine whether deletion of Fn14 improves the outcome of liver injury in alcohol-consuming mice. Wild-type (WT) and Fn14 knockout (KO) mice were fed control high-fat Lieber deCarli diet or high-fat Lieber deCarli diet with 2% alcohol (ETOH) and injected intraperitoneally with CCl₄ for 2 wk to induce liver injury. Mice were euthanized 3 or 10 days after CCl₄ treatment. Survival was assessed. Liver tissues were analyzed for cell death, inflammation, proliferation, progenitor accumulation, and fibrosis by quantitative RT-PCR, immunoblot, hydroxyproline content, and quantitative immunohistochemistry. During liver injury, Fn14 expression, apoptosis, inflammation, hepatocyte replication, progenitor and myofibroblast accumulation, and fibrosis increased in WT mice fed either diet. Mice fed either diet expressed similar TWEAK/Fn14 levels, but ETOH-fed mice had higher TNF-α expression. The ETOH-fed group developed more apoptosis, inflammation, fibrosis, and regenerative responses. Fn14 deletion did not reduce hepatic TNF-α expression but improved all injury parameters in mice fed the control diet. In ETOH-fed mice, Fn14 deletion inhibited TNF-α induction and increased acute mortality, despite improvement in liver injury. Fn14 mediates wound-healing responses that are necessary to survive acute liver injury during alcohol exposure.

Authors
Karaca, G; Xie, G; Moylan, C; Swiderska-Syn, M; Guy, CD; Krüger, L; Machado, MV; Choi, SS; Michelotti, GA; Burkly, LC; Diehl, AM
MLA Citation
Karaca, G, Xie, G, Moylan, C, Swiderska-Syn, M, Guy, CD, Krüger, L, Machado, MV, Choi, SS, Michelotti, GA, Burkly, LC, and Diehl, AM. "Role of Fn14 in acute alcoholic steatohepatitis in mice." American journal of physiology. Gastrointestinal and liver physiology 308.4 (February 2015): G325-G334.
PMID
25524063
Source
epmc
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
308
Issue
4
Publish Date
2015
Start Page
G325
End Page
G334
DOI
10.1152/ajpgi.00429.2013

Micro-RNA 21 inhibition of SMAD7 enhances fibrogenesis via leptin-mediated NADPH oxidase in experimental and human nonalcoholic steatohepatitis.

Hepatic fibrosis in nonalcoholic steatohepatitis (NASH) is the common pathophysiological process resulting from chronic liver inflammation and oxidative stress. Although significant research has been carried out on the role of leptin-induced NADPH oxidase in fibrogenesis, the molecular mechanisms that connect the leptin-NADPH oxidase axis in upregulation of transforming growth factor (TGF)-β signaling have been unclear. We aimed to investigate the role of leptin-mediated upregulation of NADPH oxidase and its subsequent induction of micro-RNA 21 (miR21) in fibrogenesis. Human NASH livers and a high-fat (60% kcal) diet-fed chronic mouse model, where hepatotoxin bromodichloromethane was used to induce NASH, were used for this study. To prove the role of the leptin-NADPH oxidase-miR21 axis, mice deficient in genes for leptin, p47phox, and miR21 were used. Results showed that wild-type mice and human livers with NASH had increased oxidative stress, increased p47phox expression, augmented NF-κB activation, and increased miR21 levels. These mice and human livers showed increased TGF-β, SMAD2/3-SMAD4 colocalizations in the nucleus, increased immunoreactivity against Col1α, and α-SMA with a concomitant decrease in protein levels of SMAD7. Mice that were deficient in leptin or p47phox had decreased activated NF-κB and miR21 levels, suggesting the role of leptin and NADPH oxidase in inducing NF-κB-mediated miR21 expression. Further miR21 knockout mice had decreased colocalization events of SMAD2/3-SMAD4 in the nucleus, increased SMAD7 levels, and decreased fibrogenesis. Taken together, the studies show the novel role of leptin-NADPH oxidase induction of miR21 as a key regulator of TGF-β signaling and fibrogenesis in experimental and human NASH.

Authors
Dattaroy, D; Pourhoseini, S; Das, S; Alhasson, F; Seth, RK; Nagarkatti, M; Michelotti, GA; Diehl, AM; Chatterjee, S
MLA Citation
Dattaroy, D, Pourhoseini, S, Das, S, Alhasson, F, Seth, RK, Nagarkatti, M, Michelotti, GA, Diehl, AM, and Chatterjee, S. "Micro-RNA 21 inhibition of SMAD7 enhances fibrogenesis via leptin-mediated NADPH oxidase in experimental and human nonalcoholic steatohepatitis." American journal of physiology. Gastrointestinal and liver physiology 308.4 (February 2015): G298-G312.
PMID
25501551
Source
epmc
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
308
Issue
4
Publish Date
2015
Start Page
G298
End Page
G312
DOI
10.1152/ajpgi.00346.2014

Implication of gut microbiota in nonalcoholic fatty liver disease.

Authors
Boursier, J; Diehl, AM
MLA Citation
Boursier, J, and Diehl, AM. "Implication of gut microbiota in nonalcoholic fatty liver disease." PLoS pathogens 11.1 (January 27, 2015): e1004559-.
PMID
25625278
Source
epmc
Published In
PLoS pathogens
Volume
11
Issue
1
Publish Date
2015
Start Page
e1004559
DOI
10.1371/journal.ppat.1004559

Treatment response in the PIVENS trial is associated with decreased hedgehog pathway activity

© 2014 by the American Association for the Study of Liver Diseases. Hedgehog (Hh) ligand production by ballooned hepatocytes drives nonalcoholic steatohepatitis (NASH) progression in mice. The NIDDK-sponsored PIVENS trial (NCT00063622) showed that vitamin E (VitE) improved NASH. We investigated whether VitE treatment and improvement in NASH were associated with changes in Hh pathway activity. Immunohistochemistry (IHC) was performed on both pre- and posttreatment liver biopsies of 59 PIVENS patients randomized to VitE (n=30) or placebo (n=29). Sonic Hh (Shh) ligand-producing cells and Shh-responsive cells were quantified. The latter was accomplished by triple IHC for gli2+ (marker of Hh signaling), sox-9 (progenitor marker), and α-smooth muscle actin (α-SMA; myofibroblast marker). Ballooned hepatocytes were quantified by keratin 8/18 and ubiquitin (K8/18/Ub) staining. IHC results were correlated with primary clinical and histologic PIVENS data. Pretreatment clinical, histologic, and IHC parameters did not differ significantly in the two treatment groups. Regardless of treatment arm, the number of Shh+ hepatocytes correlated with K8/18/Ub foci (r 2 =0.47, P < 0.001) and aspartate aminotransferase (AST) (r 2 =0.15, P=0.002). Treatment-related changes in the numbers of Shh+ hepatocytes correlated with changes in serum AST (partial r 2 =0.75, P < 0.0001), hepatocyte ballooning (P=0.004), the ductular reaction (i.e., numbers of gli2+/sox9+ cells; P=0.03 and α-SMA+ cells; P=0.10), and fibrosis stage (P=0.02). Treatment response was associated with a greater decrease in Shh+ hepatocytes than nonresponse (P=0.007). The VitE group demonstrated a greater reduction in K8/18/Ub+ foci (P < 0.08) and Shh+ hepatocytes (P < 0.05) than the placebo group, effects that became more significant after correction for baseline differences and multiple linear regression analysis. Conclusion: During PIVENS, treatment response correlated with loss of Shh+ hepatocytes and improvement in Hh-regulated processes that promote NASH progression.

Authors
Guy, CD; Suzuki, A; Abdelmalek, MF; Burchette, JL; Diehl, AM
MLA Citation
Guy, CD, Suzuki, A, Abdelmalek, MF, Burchette, JL, and Diehl, AM. "Treatment response in the PIVENS trial is associated with decreased hedgehog pathway activity." Hepatology 61.1 (January 1, 2015): 98-107.
Source
scopus
Published In
Hepatology
Volume
61
Issue
1
Publish Date
2015
Start Page
98
End Page
107
DOI
10.1002/hep.27235

Animal models of nonalcoholic fatty liver disease

© Springer International Publishing Switzerland 2016. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, accompanying the rise in obesity and its related metabolic disorders. Though research in the field is vibrant, enormous gaps in knowledge still remain about its physiology, how to identify patients who are most susceptible for adverse outcomes, and the best therapeutic approach. It is difficult to study NAFLD in humans, since the disease evolves slowly and encompasses diverse liver phenotypes that are challenging to differentiate noninvasively. Steatosis is the most clinically benign NAFLD phenotype, while nonalcoholic steatohepatitis (NASH) has a much more variable prognosis that seems to depend upon the severity of hepatocyte injury and propensity for progressive fibrosis. NASH patients in whom fibrosis progresses to cirrhosis ultimately develop the worst liver-related outcomes because cirrhosis increases the risk for primary liver cancer, liver-related morbidity, and death from liver disease. Animal models that mimic the spectrum of human NAFLD pathology are crucial to overcome the challenges inherent in human NAFLD research so that knowledge about this disease can advance. There are many animal models for NAFLD, none of them perfect. Some are more suitable for studying the metabolic derangements, others for studying inflammation and fibrogenesis. The most used animals are rodents, particularly mice. NAFLD can be induced through specific diets or through genetic manipulation. This chapter will review the different animal models available, with a critical appraisal of their advantages and limitations.

Authors
Machado, MLVM; Diehl, AM
MLA Citation
Machado, MLVM, and Diehl, AM. "Animal models of nonalcoholic fatty liver disease." Alcoholic and Non-Alcoholic Fatty Liver Disease: Bench to Bedside. January 1, 2015. 121-145.
Source
scopus
Publish Date
2015
Start Page
121
End Page
145
DOI
10.1007/978-3-319-20538-0_6

Treatment response in the PIVENS trial is associated with decreased Hedgehog pathway activity.

Hedgehog (Hh) ligand production by ballooned hepatocytes drives nonalcoholic steatohepatitis (NASH) progression in mice. The NIDDK-sponsored PIVENS trial (NCT00063622) showed that vitamin E (VitE) improved NASH. We investigated whether VitE treatment and improvement in NASH were associated with changes in Hh pathway activity. Immunohistochemistry (IHC) was performed on both pre- and posttreatment liver biopsies of 59 PIVENS patients randomized to VitE (n = 30) or placebo (n = 29). Sonic Hh (Shh) ligand-producing cells and Shh-responsive cells were quantified. The latter was accomplished by triple IHC for gli2+ (marker of Hh signaling), sox-9 (progenitor marker), and α-smooth muscle actin (α-SMA; myofibroblast marker). Ballooned hepatocytes were quantified by keratin 8/18 and ubiquitin (K8/18/Ub) staining. IHC results were correlated with primary clinical and histologic PIVENS data. Pretreatment clinical, histologic, and IHC parameters did not differ significantly in the two treatment groups. Regardless of treatment arm, the number of Shh+ hepatocytes correlated with K8/18/Ub foci (r(2) = 0.47, P < 0.001) and aspartate aminotransferase (AST) (r(2) = 0.15, P = 0.002). Treatment-related changes in the numbers of Shh+ hepatocytes correlated with changes in serum AST (partial r(2) = 0.75, P < 0.0001), hepatocyte ballooning (P = 0.004), the ductular reaction (i.e., numbers of gli2+/sox9+ cells; P = 0.03 and α-SMA+ cells; P = 0.10), and fibrosis stage (P = 0.02). Treatment response was associated with a greater decrease in Shh+ hepatocytes than nonresponse (P = 0.007). The VitE group demonstrated a greater reduction in K8/18/Ub+ foci (P < 0.08) and Shh+ hepatocytes (P < 0.05) than the placebo group, effects that became more significant after correction for baseline differences and multiple linear regression analysis.During PIVENS, treatment response correlated with loss of Shh+ hepatocytes and improvement in Hh-regulated processes that promote NASH progression.

Authors
Guy, CD; Suzuki, A; Abdelmalek, MF; Burchette, JL; Diehl, AM; NASH CRN,
MLA Citation
Guy, CD, Suzuki, A, Abdelmalek, MF, Burchette, JL, Diehl, AM, and NASH CRN, . "Treatment response in the PIVENS trial is associated with decreased Hedgehog pathway activity." Hepatology (Baltimore, Md.) 61.1 (January 2015): 98-107.
PMID
24849310
Source
epmc
Published In
Hepatology
Volume
61
Issue
1
Publish Date
2015
Start Page
98
End Page
107
DOI
10.1002/hep.27235

M1 polarization bias and subsequent nonalcoholic steatohepatitis progression is attenuated by nitric oxide donor DETA NONOate via inhibition of CYP2E1-induced oxidative stress in obese mice.

Activation of M1 macrophages in nonalcoholic steatohepatitis (NASH) is produced by several external or endogenous factors: inflammatory stimuli, oxidative stress, and cytokines are known. However, any direct role of oxidative stress in causing M1 polarization in NASH has been unclear. We hypothesized that CYP2E1-mediated oxidative stress causes M1 polarization in experimental NASH, and that nitric oxide (NO) donor administration inhibits CYP2E1-mediated inflammation with concomitant attenuation of M1 polarization. Because CYP2E1 takes center stage in these studies, we used a toxin model of NASH that uses a ligand and a substrate of CYP2E1 for inducing NASH. Subsequently, we used a methionine and choline-deficient diet-induced rodent NASH model where the role of CYP2E1 in disease progression has been shown. Our results show that CYP2E1 causes M1 polarization bias, which includes a significant increase in interleukin-1β (IL-1β) and IL-12 in both models of NASH, whereas CYP2E1-null mice or diallyl sulfide administration prevented it. Administration of gadolinium chloride (GdCl3), a macrophage toxin, attenuated both the initial M1 response and the subsequent M2 response, showing that the observed increase in cytokine levels is primarily from macrophages. Based on the evidence of an adaptive NO increase, the NO donor administration in vivo that mechanistically inhibited CYP2E1 catalyzed the oxidative stress during the entire study in NASH-abrogated M1 polarization and NASH progression. The results obtained show the association of CYP2E1 in M1 polarization, and that inhibition of CYP2E1 catalyzed oxidative stress by an NO donor (DETA NONOate [(Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate]) can be a promising therapeutic strategy in NASH.

Authors
Seth, RK; Das, S; Pourhoseini, S; Dattaroy, D; Igwe, S; Ray, JB; Fan, D; Michelotti, GA; Diehl, AM; Chatterjee, S
MLA Citation
Seth, RK, Das, S, Pourhoseini, S, Dattaroy, D, Igwe, S, Ray, JB, Fan, D, Michelotti, GA, Diehl, AM, and Chatterjee, S. "M1 polarization bias and subsequent nonalcoholic steatohepatitis progression is attenuated by nitric oxide donor DETA NONOate via inhibition of CYP2E1-induced oxidative stress in obese mice." The Journal of pharmacology and experimental therapeutics 352.1 (January 2015): 77-89.
PMID
25347994
Source
epmc
Published In
The Journal of pharmacology and experimental therapeutics
Volume
352
Issue
1
Publish Date
2015
Start Page
77
End Page
89
DOI
10.1124/jpet.114.218131

Elaboration of tubules with active hedgehog drives parenchymal fibrogenesis in gestational alloimmune liver disease.

Gestational alloimmune liver disease (GALD) produces severe neonatal liver disease that is notable for paucity of hepatocytes, large numbers of parenchymal tubules, and extensive fibrosis. Liver specimens from 19 GALD cases were studied in comparison with 14 infants without liver disease (normal newborn liver; NNL) to better understand the pathophysiology that would produce this characteristic histopathology. GALD liver parenchyma contained large numbers of tubules comprising epithelium expressing KRT7/19, EPCAM, and SOX9, suggesting biliary progenitor status. Quantitative morphometry demonstrated that in GALD, the area density of KRT19+ tubules was 16.4 ± 6.2 versus 2.0 ± 2.6 area% in NNL (P < .0001). Functional hepatocyte mass was markedly reduced in GALD, 16.3 ± 6.2 versus 61.9 ± 11.0 area% of CPS1+ cells in NNL (P < .0001). A strong inverse correlation was established between CPS1+ area density and KRT19+ area density (r(2) = 0.66, P < .0001). Tubules showed active hedgehog signaling as determined by SHH and nuclear GLI2 expression and expressed the profibrogenic cytokine SPP1. SPP1 protein content and SPP1 expression were greater in GALD than NNL (15- and 13-fold respectively; P = .002). GALD liver contained large numbers of activated myofibroblasts and showed greater than 10-fold more fibrosis than NNL. The extent of fibrosis correlated with the area density of KRT19+ tubules (r(2) = 0.387, P = .001). The data support a pathogenic model in which immune injury to fetal hepatocytes provides a stimulus for expansion of parenchymal tubules, which, by way of Hh activation, produce fibrogenic signals leading to vibrant fibrosis.

Authors
Asai, A; Malladi, S; Misch, J; Pan, X; Malladi, P; Diehl, AM; Whitington, PF
MLA Citation
Asai, A, Malladi, S, Misch, J, Pan, X, Malladi, P, Diehl, AM, and Whitington, PF. "Elaboration of tubules with active hedgehog drives parenchymal fibrogenesis in gestational alloimmune liver disease." Human pathology 46.1 (January 2015): 84-93.
PMID
25387814
Source
epmc
Published In
Human Pathology
Volume
46
Issue
1
Publish Date
2015
Start Page
84
End Page
93
DOI
10.1016/j.humpath.2014.09.010

Patatin-like phospholipase domain-containing protein 3 and liver disease: opportunities to unravel mechanisms underlying statistical associations.

Authors
Boursier, J; Diehl, AM
MLA Citation
Boursier, J, and Diehl, AM. "Patatin-like phospholipase domain-containing protein 3 and liver disease: opportunities to unravel mechanisms underlying statistical associations." Hepatology (Baltimore, Md.) 61.1 (January 2015): 18-20.
PMID
25234690
Source
epmc
Published In
Hepatology
Volume
61
Issue
1
Publish Date
2015
Start Page
18
End Page
20
DOI
10.1002/hep.27445

Upregulation of miR21 and repression of Grhl3 by leptin mediates sinusoidal endothelial injury in experimental nonalcoholic steatohepatitis.

Sinusoidal endothelial dysfunction (SED) has been found to be an early event in nonalcoholic steatohepatitis (NASH) progression but the molecular mechanisms underlying its causation remains elusive. We hypothesized that adipokine leptin worsens sinusoidal injury by decreasing functionally active nitric oxide synthase 3 (NOS)3 via miR21. Using rodent models of NASH, and transgenic mice lacking leptin and leptin receptor, results showed that hyperleptinemia caused a 4-5 fold upregulation of hepatic miR21 as assessed by qRTPCR. The upregulation of miR21 led to a time-dependent repression of its target protein Grhl3 levels as shown by western blot analyses. NOS3-p/NOS3 ratio which is controlled by Grhl3 was significantly decreased in NASH models. SED markers ICAM-1, VEGFR-2, and E-selectin as assessed by immunofluorescence microscopy were significantly up regulated in the progressive phases of NASH. Lack of leptin or its receptor in vivo, reversed the upregulation of miR21 and restored the levels of Grhl3 and NOS3-p/NOS3 ratio coupled with decreased SED dysfunction markers. Interestingly, leptin supplementation in mice lacking leptin, significantly enhanced miR21 levels, decreased Grhl3 repression and NOS3 phosphorylation. Leptin supplementation in isolated primary endothelial cells, Kupffer cells and stellate cells showed increased mir21 expression in stellate cells while sinusoidal injury was significantly higher in all cell types. Finally miR21 KO mice showed increased NOS3-p/NOS3 ratio and reversed SED markers in the rodent models of NASH. The experimental results described here show a close association of leptin-induced miR21 in aiding sinusoidal injury in NASH.

Authors
Pourhoseini, S; Seth, RK; Das, S; Dattaroy, D; Kadiiska, MB; Xie, G; Michelotti, GA; Nagarkatti, M; Diehl, AM; Chatterjee, S
MLA Citation
Pourhoseini, S, Seth, RK, Das, S, Dattaroy, D, Kadiiska, MB, Xie, G, Michelotti, GA, Nagarkatti, M, Diehl, AM, and Chatterjee, S. "Upregulation of miR21 and repression of Grhl3 by leptin mediates sinusoidal endothelial injury in experimental nonalcoholic steatohepatitis." PloS one 10.2 (January 2015): e0116780-.
PMID
25658689
Source
epmc
Published In
PloS one
Volume
10
Issue
2
Publish Date
2015
Start Page
e0116780
DOI
10.1371/journal.pone.0116780

Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease.

Non-alcoholic steatohepatitis (NASH), the potentially progressive form of nonalcoholic fatty liver disease (NAFLD), is the pandemic liver disease of our time. Although there are several animal models of NASH, consensus regarding the optimal model is lacking. We aimed to compare features of NASH in the two most widely-used mouse models: methionine-choline deficient (MCD) diet and Western diet.Mice were fed standard chow, MCD diet for 8 weeks, or Western diet (45% energy from fat, predominantly saturated fat, with 0.2% cholesterol, plus drinking water supplemented with fructose and glucose) for 16 weeks. Liver pathology and metabolic profile were compared.The metabolic profile associated with human NASH was better mimicked by Western diet. Although hepatic steatosis (i.e., triglyceride accumulation) was also more severe, liver non-esterified fatty acid content was lower than in the MCD diet group. NASH was also less severe and less reproducible in the Western diet model, as evidenced by less liver cell death/apoptosis, inflammation, ductular reaction, and fibrosis. Various mechanisms implicated in human NASH pathogenesis/progression were also less robust in the Western diet model, including oxidative stress, ER stress, autophagy deregulation, and hedgehog pathway activation.Feeding mice a Western diet models metabolic perturbations that are common in humans with mild NASH, whereas administration of a MCD diet better models the pathobiological mechanisms that cause human NAFLD to progress to advanced NASH.

Authors
Machado, MV; Michelotti, GA; Xie, G; Almeida Pereira, T; Boursier, J; Bohnic, B; Guy, CD; Diehl, AM
MLA Citation
Machado, MV, Michelotti, GA, Xie, G, Almeida Pereira, T, Boursier, J, Bohnic, B, Guy, CD, and Diehl, AM. "Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease." PloS one 10.5 (January 2015): e0127991-.
PMID
26017539
Source
epmc
Published In
PloS one
Volume
10
Issue
5
Publish Date
2015
Start Page
e0127991
DOI
10.1371/journal.pone.0127991

Correction: Mouse Models of Diet-Induced Nonalcoholic Steatohepatitis Reproduce the Heterogeneity of the Human Disease.

Authors
Machado, MV; Michelotti, GA; Xie, G; de Almeida, TP; Boursier, J; Bohnic, B; Guy, CD; Diehl, AM
MLA Citation
Machado, MV, Michelotti, GA, Xie, G, de Almeida, TP, Boursier, J, Bohnic, B, Guy, CD, and Diehl, AM. "Correction: Mouse Models of Diet-Induced Nonalcoholic Steatohepatitis Reproduce the Heterogeneity of the Human Disease." PloS one 10.6 (January 2015): e0132315-.
PMID
26121577
Source
epmc
Published In
PloS one
Volume
10
Issue
6
Publish Date
2015
Start Page
e0132315
DOI
10.1371/journal.pone.0132315

Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis

Objective Caspase-2 is an initiator caspase involved in multiple apoptotic pathways, particularly in response to specific intracellular stressors (eg, DNA damage, ER stress). We recently reported that caspase-2 was pivotal for the induction of cell death triggered by excessive intracellular accumulation of long-chain fatty acids, a response known as lipoapoptosis. The liver is particularly susceptible to lipid-induced damage, explaining the pandemic status of non-alcoholic fatty liver disease (NAFLD). Progression from NAFLD to non-alcoholic steatohepatitis (NASH) results, in part, from hepatocyte apoptosis and consequential paracrine-mediated fibrogenesis. We evaluated the hypothesis that caspase-2 promotes NASH-related cirrhosis. Design Caspase-2 was localised in liver biopsies from patients with NASH. Its expression was evaluated in different mouse models of NASH, and outcomes of dietinduced NASH were compared in wild-type (WT) and caspase-2-deficient mice. Lipotoxicity was modelled in vitro using hepatocytes derived from WT and caspase-2-deficient mice. Results We showed that caspase-2 is integral to the pathogenesis of NASH-related cirrhosis. Caspase-2 is localised in injured hepatocytes and its expression was markedly upregulated in patients and animal models of NASH. During lipotoxic stress, caspase-2 deficiency reduced apoptosis, inhibited induction of profibrogenic hedgehog target genes in mice and blocked production of hedgehog ligands in cultured hepatocytes. Conclusions These data point to a critical role for caspase-2 in lipid-induced hepatocyte apoptosis in vivo for the production of apoptosis-associated fibrogenic factors and in the progression of lipid-induced liver fibrosis. This raises the intriguing possibility that caspase-2 may be a promising therapeutic target to prevent progression to NASH.

Authors
Machado, MV; Michelotti, GA; Pereira, TDA; Boursier, J; Kruger, L; Swiderska-Syn, M; Karaca, G; Xie, G; Guy, CD; Bohinc, B; Lindblom, KR; Johnson, E; Kornbluth, S; Diehl, AM
MLA Citation
Machado, MV, Michelotti, GA, Pereira, TDA, Boursier, J, Kruger, L, Swiderska-Syn, M, Karaca, G, Xie, G, Guy, CD, Bohinc, B, Lindblom, KR, Johnson, E, Kornbluth, S, and Diehl, AM. "Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis." Gut 64.7 (2015): 1148-1157.
Source
scival
Published In
Gut
Volume
64
Issue
7
Publish Date
2015
Start Page
1148
End Page
1157
DOI
10.1136/gutjnl-2014-307362

Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice

Background: Chronic liver injury triggers a progenitor cell repair response, and liver fibrosis occurs when repair becomes deregulated. Previously, we reported that reactivation of the hedgehog pathway promotes fibrogenic liver repair. Osteopontin (OPN) is a hedgehog-target, and a cytokine that is highly upregulated in fibrotic tissues, and regulates stem-cell fate. Thus, we hypothesised that OPN may modulate liver progenitor cell response, and thereby, modulate fibrotic outcomes. We further evaluated the impact of OPN-neutralisation on murine liver fibrosis. Methods: Liver progenitors (603B and bipotential mouse oval liver) were treated with OPN-neutralising aptamers in the presence or absence of transforming growth factor (TGF)-β, to determine if (and how) OPN modulates liver progenitor function. Effects of OPN-neutralisation (using OPN-aptamers or OPN-neutralising antibodies) on liver progenitor cell response and fibrogenesis were assessed in three models of liver fibrosis (carbon tetrachloride, methionine-choline deficient diet, 3, 5,-diethoxycarbonyl-1, 4-dihydrocollidine diet) by quantitative real time (qRT) PCR, Sirius-Red staining, hydroxyproline assay, and semiquantitative double-immunohistochemistry. Finally, OPN expression and liver progenitor response were corroborated in liver tissues obtained from patients with chronic liver disease. Results: OPN is overexpressed by liver progenitors in humans and mice. In cultured progenitors, OPN enhances viability and wound healing by modulating TGF-β signalling. In vivo, OPN-neutralisation attenuates the liver progenitor cell response, reverses epithelial-mesenchymal-transition in Sox9+ cells, and abrogates liver fibrogenesis. Conclusions: OPN upregulation during liver injury is a conserved repair response, and influences liver progenitor cell function. OPN-neutralisation abrogates the liver progenitor cell response and fibrogenesis in mouse models of liver fibrosis.

Authors
Coombes, JD; Swiderska-Syn, M; Dollé, L; Reid, D; Eksteen, B; Claridge, L; Briones-Orta, MA; Shetty, S; Oo, YH; Riva, A; Chokshi, S; Papa, S; Mi, Z; Kuo, PC; Williams, R; Canbay, A; Adams, DH; Diehl, AM; Grunsven, LAV; Choi, SS; Syn, WK
MLA Citation
Coombes, JD, Swiderska-Syn, M, Dollé, L, Reid, D, Eksteen, B, Claridge, L, Briones-Orta, MA, Shetty, S, Oo, YH, Riva, A, Chokshi, S, Papa, S, Mi, Z, Kuo, PC, Williams, R, Canbay, A, Adams, DH, Diehl, AM, Grunsven, LAV, Choi, SS, and Syn, WK. "Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice." Gut 64.7 (2015): 1120-1131.
Source
scival
Published In
Gut
Volume
64
Issue
7
Publish Date
2015
Start Page
1120
End Page
1131
DOI
10.1136/gutjnl-2013-306484

NADPH oxidase-induced TLR4 recruitment to hepatic lipid rafts mediates NASH progression

Authors
Das, S; Seth, RK; Pourhoseini, S; Dattaroy, D; Alhasson, F; Nagarkatti, M; Michelotti, GA; Diehl, AM; Chatterjee, S
MLA Citation
Das, S, Seth, RK, Pourhoseini, S, Dattaroy, D, Alhasson, F, Nagarkatti, M, Michelotti, GA, Diehl, AM, and Chatterjee, S. "NADPH oxidase-induced TLR4 recruitment to hepatic lipid rafts mediates NASH progression." HEPATOLOGY 60.6 (December 2014): 1289A-1289A.
Source
wos-lite
Published In
Hepatology
Volume
60
Issue
6
Publish Date
2014
Start Page
1289A
End Page
1289A

Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism.

Thyroid hormone (TH) is important for tissue repair because it regulates cellular differentiation. Intrahepatic TH activity is controlled by both serum TH levels and hepatic deiodinases. TH substrate (T4) is converted into active hormone (T3) by deiodinase 1 (D1) but into inactive hormone (rT3) by deiodinase 3 (D3). Although the relative expressions of D1 and D3 are known to change during liver injury, the cell types and signaling mechanisms involved are unclear. We evaluated the hypothesis that changes in hepatic deiodinases result from repair-related activation of the Hedgehog pathway in stromal cells. We localized deiodinase expression, assessed changes during injury, and determined how targeted manipulation of Hedgehog signaling in stromal cells impacted hepatic deiodinase expression, TH content, and TH action in rodents. Humans with chronic liver disease were also studied. In healthy liver, hepatocytes strongly expressed D1 and stromal cells weakly expressed D3. During injury, hepatocyte expression of D1 decreased, whereas stromal expression of D3 increased, particularly in myofibroblasts. Conditionally disrupting Hedgehog signaling in myofibroblasts normalized deiodinase expression. Repair-related changes in deiodinases were accompanied by reduced hepatic TH content and TH-regulated gene expression. In patients, this was reflected by increased serum rT3. Moreover, the decreases in the free T3 to rT3 and free T4 to rT3 ratios distinguished advanced from mild fibrosis, even in individuals with similar serum levels of TSH and free T4. In conclusion, the Hedgehog-dependent changes in liver stromal cells drive repair-related changes in hepatic deiodinase expression that promote intrahepatic hypothyroidism, thereby limiting exposure to T3, an important factor for cellular differentiation.

Authors
Bohinc, BN; Michelotti, G; Xie, G; Pang, H; Suzuki, A; Guy, CD; Piercy, D; Kruger, L; Swiderska-Syn, M; Machado, M; Pereira, T; Zavacki, AM; Abdelmalek, M; Diehl, AM
MLA Citation
Bohinc, BN, Michelotti, G, Xie, G, Pang, H, Suzuki, A, Guy, CD, Piercy, D, Kruger, L, Swiderska-Syn, M, Machado, M, Pereira, T, Zavacki, AM, Abdelmalek, M, and Diehl, AM. "Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism." Endocrinology 155.11 (November 2014): 4591-4601.
PMID
25121996
Source
epmc
Published In
Endocrinology
Volume
155
Issue
11
Publish Date
2014
Start Page
4591
End Page
4601
DOI
10.1210/en.2014-1302

Abstract 4117: Utilizing RNA aptamers for biomarker discovery in a novel cell culture system for hepatocellular carcinoma

Authors
Naqvi, IA; White, RR; Moylan, CA; Diehl, AM; Choi, SS
MLA Citation
Naqvi, IA, White, RR, Moylan, CA, Diehl, AM, and Choi, SS. "Abstract 4117: Utilizing RNA aptamers for biomarker discovery in a novel cell culture system for hepatocellular carcinoma." October 1, 2014.
Source
crossref
Published In
Cancer Research
Volume
74
Issue
19 Supplement
Publish Date
2014
Start Page
4117
End Page
4117
DOI
10.1158/1538-7445.AM2014-4117

Review of nonalcoholic fatty liver disease in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women. Women with PCOS frequently have metabolic complications including insulin resistance (IR), early diabetes, hypertension and dyslipidemia. Recent studies have demonstrated an association between PCOS and another metabolic complication: nonalcoholic fatty liver disease (NAFLD). NAFLD occurs as a result of abnormal lipid handling by the liver, which sensitizes the liver to injury and inflammation. It can progress to nonalcoholic steatohepatitis (NASH), which is characterized by hepatocyte injury and apoptosis. With time and further inflammation, NASH can progress to cirrhosis. Thus, given the young age at which NAFLD may occur in PCOS, these women may be at significant risk for progressive hepatic injury over the course of their lives. Many potential links between PCOS and NAFLD have been proposed, most notably IR and hyperandrogenemia. Further studies are needed to clarify the association between PCOS and NAFLD. In the interim, clinicians should be aware of this connection and consider screening for NAFLD in PCOS patients who have other metabolic risk factors. The optimal method of screening is unknown. However, measuring alanine aminotransferase and/or obtaining ultrasound on high-risk patients can be considered. First line treatment consists of lifestyle interventions and weight loss, with possible pharmacologic interventions in some cases.

Authors
Kelley, CE; Brown, AJ; Diehl, AM; Setji, TL
MLA Citation
Kelley, CE, Brown, AJ, Diehl, AM, and Setji, TL. "Review of nonalcoholic fatty liver disease in women with polycystic ovary syndrome." World journal of gastroenterology 20.39 (October 2014): 14172-14184. (Review)
PMID
25339805
Source
epmc
Published In
World journal of gastroenterology : WJG
Volume
20
Issue
39
Publish Date
2014
Start Page
14172
End Page
14184
DOI
10.3748/wjg.v20.i39.14172

Reply

Authors
Moylan, CA; Pang, H; Michelotti, G; Diehl, AM
MLA Citation
Moylan, CA, Pang, H, Michelotti, G, and Diehl, AM. "Reply." Hepatology 60.4 (October 2014): 1445-1446.
Source
crossref
Published In
Hepatology
Volume
60
Issue
4
Publish Date
2014
Start Page
1445
End Page
1446
DOI
10.1002/hep.27038

Reply: To PMID 23913408.

Authors
Moylan, CA; Pang, H; Michelotti, G; Diehl, AM
MLA Citation
Moylan, CA, Pang, H, Michelotti, G, and Diehl, AM. "Reply: To PMID 23913408." Hepatology (Baltimore, Md.) 60.4 (October 2014): 1445-1446. (Letter)
PMID
24493022
Source
epmc
Published In
Hepatology
Volume
60
Issue
4
Publish Date
2014
Start Page
1445
End Page
1446
DOI
10.1002/hep.27038

The β-adrenoceptor agonist isoproterenol rescues acetaminophen-injured livers through increasing progenitor numbers by Wnt in mice.

Acetaminophen (APAP)-induced acute liver injury (AILI) is a major health problem. Accumulating evidence suggests that the sympathetic nervous system (SNS) regulates neuronal and hematopoietic progenitors. SNS signaling affects hepatic progenitor/oval cells (HPCs) and β-adrenoceptor agonism will expand HPCs to reduce AILI. Dopamine β-hydroxylase-deficient mice (Dbh-/-), lacking catecholamine SNS neurotransmitters, isolated HPCs, and immature ductular 603B cells were initially used to investigate SNS involvement in HPC physiology. Subsequently, control mice were treated with APAP (350 mg/kg) followed by the β-adrenoceptor agonist, isoproterenol (ISO), or the β-adrenoceptor antagonist, propranolol. Mechanistic studies examined effects of non-SNS HPC expansion on AILI, involvement of the canonical Wnt/β-catenin pathway (CWP) in the action of ISO on HPC expansion and comparison of ISO with the current standard of care, N-acetylcysteine (NAC). Dbh-/- mice lacking catecholamines had low HPC numbers, reconstituted by ISO. In vitro, ISO-induced proliferation of 603B cells was CWP dependent. In control mice, AILI raised HPC numbers, further increased by ISO, with attenuation of liver injury. Delayed administration of NAC did not, but delayed ISO did, reverse AILI. Propranolol worsened AILI. AILI activated the CWP, and ISO enhanced Wnt-ligand production. HPCs were the major source of Wnt ligands. Recombinant Wnt3a and ISO-603B-conditioned media, but not ISO alone, protected isolated hepatocytes from death, reversed by DKK1-a Wnt antagonist. Additionally, tumor-associated weak inducer of apoptosis expanded HPCs and protected against AILI. Furthermore, allotransplantation of HPCs from APAP+ISO-treated mice to other APAP-injured mice improved AILI, an effect antagonized by DKK1.SNS catecholamines expand HPCs, which are both targets and sources of Wnt ligands. Hepatoprotection by ISO is mediated by para- and autocrine effects of Wnt signaling. ISO represents novel pharmacotherapy for AILI.

Authors
Soeda, J; Mouralidarane, A; Ray, S; Novelli, M; Thomas, S; Roskams, T; Diehl, AM; Oben, JA
MLA Citation
Soeda, J, Mouralidarane, A, Ray, S, Novelli, M, Thomas, S, Roskams, T, Diehl, AM, and Oben, JA. "The β-adrenoceptor agonist isoproterenol rescues acetaminophen-injured livers through increasing progenitor numbers by Wnt in mice." Hepatology (Baltimore, Md.) 60.3 (September 2014): 1023-1034.
PMID
24923719
Source
epmc
Published In
Hepatology
Volume
60
Issue
3
Publish Date
2014
Start Page
1023
End Page
1034
DOI
10.1002/hep.27266

Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy.

OBJECTIVE: Smoothened (SMO), a coreceptor of the Hedgehog (Hh) pathway, promotes fibrogenic repair of chronic liver injury. We investigated the roles of SMO+ myofibroblast (MF) in liver regeneration by conditional deletion of SMO in α smooth muscle actin (αSMA)+ cells after partial hepatectomy (PH). DESIGN: αSMA-Cre-ER(T2)×SMO/flox mice were treated with vehicle (VEH) or tamoxifen (TMX), and sacrificed 24-96 h post-PH. Regenerating livers were analysed for proliferation, progenitors and fibrosis by qRT-PCR and quantitative immunohistochemistry (IHC). Results were normalised to liver segments resected at PH. For lineage-tracing studies, αSMA-Cre-ER(T2)×ROSA-Stop-flox-yellow fluorescent protein (YFP) mice were treated with VEH or TMX; livers were stained for YFP, and hepatocytes isolated 48 and 72 h post-PH were analysed for YFP by flow cytometric analysis (FACS). RESULTS: Post-PH, VEH-αSMA-SMO mice increased expression of Hh-genes, transiently accumulated MF, fibrosis and liver progenitors, and ultimately exhibited proliferation of hepatocytes and cholangiocytes. In contrast, TMX-αSMA-SMO mice showed loss of whole liver SMO expression, repression of Hh-genes, enhanced accumulation of quiescent HSC but reduced accumulation of MF, fibrosis and progenitors, as well as inhibition of hepatocyte and cholangiocyte proliferation, and reduced recovery of liver weight. In TMX-αSMA-YFP mice, many progenitors, cholangiocytes and up to 25% of hepatocytes were YFP+ by 48-72 h after PH, indicating that liver epithelial cells were derived from αSMA-YFP+ cells. CONCLUSIONS: Hh signalling promotes transition of quiescent hepatic stellate cells to fibrogenic MF, some of which become progenitors that regenerate the liver epithelial compartment after PH. Hence, scarring is a component of successful liver regeneration.

Authors
Swiderska-Syn, M; Syn, WK; Xie, G; Krüger, L; Machado, MV; Karaca, G; Michelotti, GA; Choi, SS; Premont, RT; Diehl, AM
MLA Citation
Swiderska-Syn, M, Syn, WK, Xie, G, Krüger, L, Machado, MV, Karaca, G, Michelotti, GA, Choi, SS, Premont, RT, and Diehl, AM. "Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy." Gut 63.8 (August 2014): 1333-1344.
PMID
24173292
Source
pubmed
Published In
Gut
Volume
63
Issue
8
Publish Date
2014
Start Page
1333
End Page
1344
DOI
10.1136/gutjnl-2013-305962

Iron deficiency in patients with nonalcoholic Fatty liver disease is associated with obesity, female gender, and low serum hepcidin.

Iron deficiency is often observed in obese individuals. The iron regulatory hormone hepcidin is regulated by iron and cytokines interleukin (IL) 6 and IL1β. We examine the relationship between obesity, circulating levels of hepcidin, and IL6 and IL1β, and other risk factors in patients with nonalcoholic fatty liver disease (NAFLD) with iron deficiency.We collected data on 675 adult subjects (>18 years old) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Subjects with transferrin saturation <20% were categorized as iron deficient, whereas those with transferrin saturation ≥20% were classified as iron normal. We assessed clinical, demographic, anthropometric, laboratory, dietary, and histologic data from patients, and serum levels of hepcidin and cytokines IL6 and IL1β. Univariate and multivariate analysis were used to identify risk factors for iron deficiency.One-third of patients (231 of 675; 34%) were iron deficient. Obesity, diabetes, and metabolic syndrome were more common in subjects with iron deficiency (P < .01), compared with those that were iron normal. Serum levels of hepcidin were significantly lower in subjects with iron deficiency (61 ± 45 vs 81 ± 51 ng/mL; P < .0001). Iron deficiency was significantly associated with female gender, obesity, increased body mass index and waist circumference, presence of diabetes, lower alcohol consumption, black or American Indian/Alaska Native race (P ≤ .018), and increased levels of IL6 and IL1β (6.6 vs 4.8 for iron normal, P ≤ .0001; and 0.45 vs 0.32 for iron normal, P ≤ .005).Iron deficiency is prevalent in patients with NAFLD and associated with female gender, increased body mass index, and nonwhite race. Serum levels of hepcidin were lower in iron-deficient subjects, reflecting an appropriate physiologic response to decreased circulating levels of iron, rather than a primary cause of iron deficiency in the setting of obesity and NAFLD.

Authors
Siddique, A; Nelson, JE; Aouizerat, B; Yeh, MM; Kowdley, KV; NASH Clinical Research Network,
MLA Citation
Siddique, A, Nelson, JE, Aouizerat, B, Yeh, MM, Kowdley, KV, and NASH Clinical Research Network, . "Iron deficiency in patients with nonalcoholic Fatty liver disease is associated with obesity, female gender, and low serum hepcidin." Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 12.7 (July 2014): 1170-1178.
PMID
24269922
Source
epmc
Published In
Clinical Gastroenterology and Hepatology
Volume
12
Issue
7
Publish Date
2014
Start Page
1170
End Page
1178
DOI
10.1016/j.cgh.2013.11.017

Osteopontin is up-regulated in chronic hepatitis C and is associated with cellular permissiveness for hepatitis C virus replication.

OPN (osteopontin)) is a Hh (Hedgehog)-regulated cytokine that is up-regulated during chronic liver injury and directly promotes fibrosis. We have reported that Hh signalling enhances viral permissiveness and replication in HCV (hepatitis C virus)-infected cells. Hence we hypothesized that OPN directly promotes HCV replication, and that targeting OPN could be beneficial in HCV. In the present study, we compared the expression of OPN mRNA and protein in HCV (JFH1)-infected Huh7 and Huh7.5 cells, and evaluated whether modulating OPN levels using exogenous OPN ligands (up-regulate OPN) or OPN-specific RNA-aptamers (neutralize OPN) leads to changes in HCV expression. Sera and livers from patients with chronic HCV were analysed to determine whether OPN levels were associated with disease severity or response to therapy. Compared with Huh7 cells, Huh7.5 cells support higher levels of HCV replication (15-fold) and expressed significantly more OPN mRNA (30-fold) and protein. Treating Huh7 cells with OPN ligands led to a dose-related increase in HCV (15-fold) and OPN (8-fold) mRNA. Conversely, treating Huh7.5 cells with OPN-specific RNA aptamers inhibited HCV RNA and protein by >50% and repressed OPN mRNA to basal levels. Liver OPN expression was significantly higher (3-fold) in patients with advanced fibrosis. Serum OPN positively correlated with fibrosis-stage (P=0.009), but negatively correlated with ETBCR (end-of-treatment biochemical response), ETVR (end-of-treatment virological response), SBCR (sustained biochemical response) and SVR (sustained virological response) (P=0.007). The OPN fibrosis score (serum OPN and presence of fibrosis ≥F2) may be a predictor of SVR. In conclusion, OPN is up-regulated in the liver and serum of patients with chronic hepatitis C, and supports increased viral replication. OPN neutralization may be a novel therapeutic strategy in chronic hepatitis C.

Authors
Choi, SS; Claridge, LC; Jhaveri, R; Swiderska-Syn, M; Clark, P; Suzuki, A; Pereira, TA; Mi, Z; Kuo, PC; Guy, CD; Pereira, FEL; Diehl, AM; Patel, K; Syn, W-K
MLA Citation
Choi, SS, Claridge, LC, Jhaveri, R, Swiderska-Syn, M, Clark, P, Suzuki, A, Pereira, TA, Mi, Z, Kuo, PC, Guy, CD, Pereira, FEL, Diehl, AM, Patel, K, and Syn, W-K. "Osteopontin is up-regulated in chronic hepatitis C and is associated with cellular permissiveness for hepatitis C virus replication." Clinical science (London, England : 1979) 126.12 (June 2014): 845-855.
PMID
24438228
Source
epmc
Published In
Clinical science (London, England : 1979)
Volume
126
Issue
12
Publish Date
2014
Start Page
845
End Page
855
DOI
10.1042/cs20130473

Associations of Sleep Duration and Sleep Quality With Clinical and Histologic Features of Nonalcoholic Fatty Liver Disease (NAFLD)

Authors
Kochhar, S; Abdelmalek, MF; Guy, CD; Piercy, D; Pan, Y; Diehl, AM; Suzuki, A
MLA Citation
Kochhar, S, Abdelmalek, MF, Guy, CD, Piercy, D, Pan, Y, Diehl, AM, and Suzuki, A. "Associations of Sleep Duration and Sleep Quality With Clinical and Histologic Features of Nonalcoholic Fatty Liver Disease (NAFLD)." May 2014.
Source
wos-lite
Published In
Gastroenterology
Volume
146
Issue
5
Publish Date
2014
Start Page
S931
End Page
S931

Associations of Sex and Menopause With Histologic Severity of Necroinflammation and Portal Inflammation Among Patients With Nonalcoholic Fatty Liver Disease (NAFLD)

Authors
Yang, JD; Abdelmalek, MF; Guy, CD; Gill, RM; Yates, KP; Unalp, A; Lavine, JE; Diehl, AM; Suzuki, A
MLA Citation
Yang, JD, Abdelmalek, MF, Guy, CD, Gill, RM, Yates, KP, Unalp, A, Lavine, JE, Diehl, AM, and Suzuki, A. "Associations of Sex and Menopause With Histologic Severity of Necroinflammation and Portal Inflammation Among Patients With Nonalcoholic Fatty Liver Disease (NAFLD)." May 2014.
Source
wos-lite
Published In
Gastroenterology
Volume
146
Issue
5
Publish Date
2014
Start Page
S945
End Page
S945

Gene Expression and Pathway Analyses Reveal Distinctions Between Hepatocellular Carcinoma Arising in Fibrotic and Non-Fibrotic Nonalcoholic Fatty Liver Disease

Authors
Moylan, CA; Owzar, K; Muir, AJ; Cauchy, F; Belghiti, J; Diehl, AM; Paradis, V
MLA Citation
Moylan, CA, Owzar, K, Muir, AJ, Cauchy, F, Belghiti, J, Diehl, AM, and Paradis, V. "Gene Expression and Pathway Analyses Reveal Distinctions Between Hepatocellular Carcinoma Arising in Fibrotic and Non-Fibrotic Nonalcoholic Fatty Liver Disease." May 2014.
Source
wos-lite
Published In
Gastroenterology
Volume
146
Issue
5
Publish Date
2014
Start Page
S998
End Page
S999

OSTEOPONTIN NEUTRALIZATION ABROGATES THE LIVER PROGENITOR CELL RESPONSE AND FIBROGENIC OUTCOMES IN MICE

Authors
Coombes, JD; Swiderska-Syn, M; Dolle, L; Reid, DT; Eksteen, B; Claridge, LC; Briones-Orta, MA; Shishir, S; Oo, YH; Riva, A; Chokshi, S; Papa, S; Mi, Z; Kuo, C; Williams, R; Canbay, A; Adams, DH; van Grunsven, LA; Diehl, AM; Choi, SS; Syn, W-K
MLA Citation
Coombes, JD, Swiderska-Syn, M, Dolle, L, Reid, DT, Eksteen, B, Claridge, LC, Briones-Orta, MA, Shishir, S, Oo, YH, Riva, A, Chokshi, S, Papa, S, Mi, Z, Kuo, C, Williams, R, Canbay, A, Adams, DH, van Grunsven, LA, Diehl, AM, Choi, SS, and Syn, W-K. "OSTEOPONTIN NEUTRALIZATION ABROGATES THE LIVER PROGENITOR CELL RESPONSE AND FIBROGENIC OUTCOMES IN MICE." April 2014.
Source
wos-lite
Published In
Journal of Hepatology
Volume
60
Issue
1
Publish Date
2014
Start Page
S273
End Page
S273

Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis.

BACKGROUND: Alcohol consumption promotes hepatocellular carcinoma (HCC). The responsible mechanisms are not well understood. Hepatocarcinogenesis increases with age and is enhanced by factors that impose a demand for liver regeneration. Because alcohol is hepatotoxic, habitual alcohol ingestion evokes a recurrent demand for hepatic regeneration. The alcohol-preferring (P) rat model mimics the level of alcohol consumption by humans who habitually abuse alcohol. Previously, we showed that habitual heavy alcohol ingestion amplified age-related hepatocarcinogenesis in P rats, with over 80% of alcohol-consuming P rats developing HCCs after 18 months of alcohol exposure, compared with only 5% of water-drinking controls. METHODS: Herein, we used quantitative real-time PCR and quantitative immunocytochemistry to compare liver tissues from alcohol-consuming P rats and water-fed P rat controls after 6, 12, or 18 months of drinking. We aimed to identify potential mechanisms that might underlie the differences in liver cancer formation and hypothesized that chronic alcohol ingestion would activate Hedgehog (HH), a regenerative signaling pathway that is overactivated in HCC. RESULTS: Chronic alcohol ingestion amplified age-related degenerative changes in hepatocytes, but did not cause appreciable liver inflammation or fibrosis even after 18 months of heavy drinking. HH signaling was also enhanced by alcohol exposure, as evidenced by increased levels of mRNAs encoding HH ligands, HH-regulated transcription factors, and HH target genes. Immunocytochemistry confirmed increased alcohol-related accumulation of HH ligand-producing cells and HH-responsive target cells. HH-related regenerative responses were also induced in alcohol-exposed rats. Three of these processes (i.e., deregulated progenitor expansion, the reverse Warburg effect, and epithelial-to-mesenchymal transitions) are known to promote cancer growth in other tissues. CONCLUSIONS: Alcohol-related changes in Hedgehog signaling and resultant deregulation of liver cell replacement might promote hepatocarcinogenesis.

Authors
Chan, IS; Guy, CD; Machado, MV; Wank, A; Kadiyala, V; Michelotti, G; Choi, S; Swiderska-Syn, M; Karaca, G; Pereira, TA; Yip-Schneider, MT; Max Schmidt, C; Diehl, AM
MLA Citation
Chan, IS, Guy, CD, Machado, MV, Wank, A, Kadiyala, V, Michelotti, G, Choi, S, Swiderska-Syn, M, Karaca, G, Pereira, TA, Yip-Schneider, MT, Max Schmidt, C, and Diehl, AM. "Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis." Alcohol Clin Exp Res 38.3 (March 2014): 787-800.
PMID
24164383
Source
pubmed
Published In
Alcoholism: Clinical and Experimental Research
Volume
38
Issue
3
Publish Date
2014
Start Page
787
End Page
800
DOI
10.1111/acer.12279

Potential role of Hedgehog signaling and microRNA-29 in liver fibrosis of IKKβ-deficient mouse

Recent studies have reported that NF-κB mediated down-regulation of miRNA-29 and lower expression of miRNA-29 promoted the deposition of collagens in fibrotic liver. Our previous research demonstrated that the increased Hedgehog (Hh) signaling, a key regulator for hepatic fibrogenesis, induced the severe hepatic fibrosis in the livers with impaired NF-κB signaling. These findings led us to investigate the effect of Hh and miRNA-29 on the hepatic fibrosis under dysregulated NF-κB signaling. In this study, we used IKKβ F/F and IKKβ-deficient IKKβ ΔHEP mouse model with a defective NF-κB signaling pathway, and assessed the expression of the miRNA-29 family (miRNA-29a, miRNA-29b, and miRNA-29c), Hh, and proliferation of MF-HSCs in liver from IKKβ F/F mice and IKKβ ΔHEP mice both before and after MCDE treatment. The activation of NF-κB was significantly increased in MCDE diet-fed IKKβ F/F mice compared to IKKβ ΔHEP mice. Expression of miRNA-29 family was greater in MCDE diet-fed IKKβ ΔHEP mice than IKKβ F/F mice, demonstrating that the impaired NF-κB pathway was unable to suppress the expression of miRNA-29s after injury. However, expression of the Hh signaling pathway was greatly enhanced, and activation of Hh promoted the accumulation of MF-HSCs with impaired NF-κB, eventually increasing fibrogenesis in the damaged liver of IKKβ ΔHEP mice. Therefore, these results demonstrated that Hh signaling regulates the proliferation of MF-HSCs irrespective of the action of miRNA-29, eventually contributing hepatic fibrosis, when the NF-κB pathway is disrupted. © 2013 Springer Science+Business Media Dordrecht.

Authors
Hyun, J; Choi, SS; Diehl, AM; Jung, Y
MLA Citation
Hyun, J, Choi, SS, Diehl, AM, and Jung, Y. "Potential role of Hedgehog signaling and microRNA-29 in liver fibrosis of IKKβ-deficient mouse." Journal of Molecular Histology 45.1 (February 1, 2014): 103-112.
Source
scopus
Published In
Journal of Molecular Histology
Volume
45
Issue
1
Publish Date
2014
Start Page
103
End Page
112
DOI
10.1007/s10735-013-9532-5

Hepatic gene expression profiles differentiate presymptomatic patients with mild versus severe nonalcoholic fatty liver disease.

UNLABELLED: Clinicians rely upon the severity of liver fibrosis to segregate patients with well-compensated nonalcoholic fatty liver disease (NAFLD) into subpopulations at high- versus low-risk for eventual liver-related morbidity and mortality. We compared hepatic gene expression profiles in high- and low-risk NAFLD patients to identify processes that distinguish the two groups and hence might be novel biomarkers or treatment targets. Microarray analysis was used to characterize gene expression in percutaneous liver biopsies from low-risk, "mild" NAFLD patients (fibrosis stage 0-1; n = 40) and high-risk, "severe" NAFLD patients (fibrosis stage 3-4; n = 32). Findings were validated in a second, independent cohort and confirmed by real-time polymerase chain reaction and immunohistochemistry (IHC). As a group, patients at risk for bad NAFLD outcomes had significantly worse liver injury and more advanced fibrosis (severe NAFLD) than clinically indistinguishable NAFLD patients with a good prognosis (mild NAFLD). A 64-gene profile reproducibly differentiated severe NAFLD from mild NAFLD, and a 20-gene subset within this profile correlated with NAFLD severity, independent of other factors known to influence NAFLD progression. Multiple genes involved with tissue repair/regeneration and certain metabolism-related genes were induced in severe NAFLD. Ingenuity Pathway Analysis and IHC confirmed deregulation of metabolic and regenerative pathways in severe NAFLD and revealed overlap among the gene expression patterns of severe NAFLD, cardiovascular disease, and cancer. CONCLUSION: By demonstrating specific metabolic and repair pathways that are differentially activated in livers with severe NAFLD, gene profiling identified novel targets that can be exploited to improve diagnosis and treatment of patients who are at greatest risk for NAFLD-related morbidity and mortality.

Authors
Moylan, CA; Pang, H; Dellinger, A; Suzuki, A; Garrett, ME; Guy, CD; Murphy, SK; Ashley-Koch, AE; Choi, SS; Michelotti, GA; Hampton, DD; Chen, Y; Tillmann, HL; Hauser, MA; Abdelmalek, MF; Diehl, AM
MLA Citation
Moylan, CA, Pang, H, Dellinger, A, Suzuki, A, Garrett, ME, Guy, CD, Murphy, SK, Ashley-Koch, AE, Choi, SS, Michelotti, GA, Hampton, DD, Chen, Y, Tillmann, HL, Hauser, MA, Abdelmalek, MF, and Diehl, AM. "Hepatic gene expression profiles differentiate presymptomatic patients with mild versus severe nonalcoholic fatty liver disease." Hepatology 59.2 (February 2014): 471-482.
PMID
23913408
Source
pubmed
Published In
Hepatology
Volume
59
Issue
2
Publish Date
2014
Start Page
471
End Page
482
DOI
10.1002/hep.26661

TWEAK/Fn14 signaling is required for liver regeneration after partial hepatectomy in mice.

Pro-inflammatory cytokines are important for liver regeneration after partial hepatectomy (PH). Expression of Fibroblast growth factor-inducible 14 (Fn14), the receptor for TNF-like weak inducer of apoptosis (TWEAK), is induced rapidly after PH and remains elevated throughout the period of peak hepatocyte replication. The role of Fn14 in post-PH liver regeneration is uncertain because Fn14 is expressed by liver progenitors and TWEAK-Fn14 interactions stimulate progenitor growth, but replication of mature hepatocytes is thought to drive liver regeneration after PH.To clarify the role of TWEAK-Fn14 after PH, we compared post-PH regenerative responses in wild type (WT) mice, Fn14 knockout (KO) mice, TWEAK KO mice, and WT mice treated with anti-TWEAK antibodies.In WT mice, rare Fn14(+) cells localized with other progenitor markers in peri-portal areas before PH. PH rapidly increased proliferation of Fn14(+) cells; hepatocytic cells that expressed Fn14 and other progenitor markers, such as Lgr5, progressively accumulated from 12-8 h post-PH and then declined to baseline by 96 h. When TWEAK/Fn14 signaling was disrupted, progenitor accumulation, induction of pro-regenerative cytokines, hepatocyte and cholangiocyte proliferation, and over-all survival were inhibited, while post-PH liver damage and bilirubin levels were increased. TWEAK stimulated proliferation and increased Lgr5 expression in cultured liver progenitors, but had no effect on either parameter in cultured primary hepatocytes.TWEAK-FN14 signaling is necessary for the healthy adult liver to regenerate normally after acute partial hepatectomy.

Authors
Karaca, G; Swiderska-Syn, M; Xie, G; Syn, W-K; Krüger, L; Machado, MV; Garman, K; Choi, SS; Michelotti, GA; Burkly, LC; Ochoa, B; Diehl, AM
MLA Citation
Karaca, G, Swiderska-Syn, M, Xie, G, Syn, W-K, Krüger, L, Machado, MV, Garman, K, Choi, SS, Michelotti, GA, Burkly, LC, Ochoa, B, and Diehl, AM. "TWEAK/Fn14 signaling is required for liver regeneration after partial hepatectomy in mice." PloS one 9.1 (January 9, 2014): e83987-.
Website
http://hdl.handle.net/10161/11083
PMID
24416188
Source
epmc
Published In
PloS one
Volume
9
Issue
1
Publish Date
2014
Start Page
e83987
DOI
10.1371/journal.pone.0083987

Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis

Background: Alcohol consumption promotes hepatocellular carcinoma (HCC). The responsible mechanisms are not well understood. Hepatocarcinogenesis increases with age and is enhanced by factors that impose a demand for liver regeneration. Because alcohol is hepatotoxic, habitual alcohol ingestion evokes a recurrent demand for hepatic regeneration. The alcohol-preferring (P) rat model mimics the level of alcohol consumption by humans who habitually abuse alcohol. Previously, we showed that habitual heavy alcohol ingestion amplified age-related hepatocarcinogenesis in P rats, with over 80% of alcohol-consuming P rats developing HCCs after 18 months of alcohol exposure, compared with only 5% of water-drinking controls. Methods: Herein, we used quantitative real-time PCR and quantitative immunocytochemistry to compare liver tissues from alcohol-consuming P rats and water-fed P rat controls after 6, 12, or 18 months of drinking. We aimed to identify potential mechanisms that might underlie the differences in liver cancer formation and hypothesized that chronic alcohol ingestion would activate Hedgehog (HH), a regenerative signaling pathway that is overactivated in HCC. Results: Chronic alcohol ingestion amplified age-related degenerative changes in hepatocytes, but did not cause appreciable liver inflammation or fibrosis even after 18 months of heavy drinking. HH signaling was also enhanced by alcohol exposure, as evidenced by increased levels of mRNAs encoding HH ligands, HH-regulated transcription factors, and HH target genes. Immunocytochemistry confirmed increased alcohol-related accumulation of HH ligand-producing cells and HH-responsive target cells. HH-related regenerative responses were also induced in alcohol-exposed rats. Three of these processes (i.e., deregulated progenitor expansion, the reverse Warburg effect, and epithelial-to-mesenchymal transitions) are known to promote cancer growth in other tissues. Conclusions: Alcohol-related changes in Hedgehog signaling and resultant deregulation of liver cell replacement might promote hepatocarcinogenesis. © 2013 by the Research Society on Alcoholism.

Authors
Chan, IS; Guy, CD; Machado, MV; Wank, A; Kadiyala, V; Michelotti, G; Choi, S; Swiderska-Syn, M; Karaca, G; Pereira, TA; Yip-Schneider, MT; Max Schmidt, C; Diehl, AM
MLA Citation
Chan, IS, Guy, CD, Machado, MV, Wank, A, Kadiyala, V, Michelotti, G, Choi, S, Swiderska-Syn, M, Karaca, G, Pereira, TA, Yip-Schneider, MT, Max Schmidt, C, and Diehl, AM. "Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis." Alcoholism: Clinical and Experimental Research 38.3 (January 1, 2014): 787-800.
Source
scopus
Published In
Alcoholism: Clinical and Experimental Research
Volume
38
Issue
3
Publish Date
2014
Start Page
787
End Page
800
DOI
10.1111/acer.12279

Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis

Estrogens inhibit stellate cell activation and fibrogenesis. Thus, gender and reproductive states may influence the degree of fibrosis in patients with nonalcoholic steatohepatitis (NASH). To investigate the association between gender, menopause, and the severity of liver fibrosis in patients with NASH, we analyzed 541 adult patients enrolled from our Duke Liver Clinics (n=338) and the Duke Metabolic and Weight Loss Surgery Program (n=203) who had a histologic diagnosis of NASH. Multiple ordinal logistic regression models were used to assess the association between gender, menopause, and severity of liver fibrosis. Overall, men, premenopausal, and postmenopausal women composed 35.1%, 28.4%, and 36.5% of the population, respectively. The mean age was 48 years and 22% had advanced fibrosis. After adjusting for covariates (enrolling site, grades of portal inflammation, and hepatocyte ballooning) and potential confounders (race, body mass index, diabetes/prediabetes, hypertension), adjusted cumulative odd ratio (ACOR) and 95% confidence interval (CI) for greater fibrosis severity was 1.4 (0.9, 2.1) (P=0.17) for postmenopausal women and 1.6 (1.0, 2.5) (P=0.03) for men, having premenopausal women as a reference. There was borderline interaction between gender and age group divided by age 50, the average age at menopause in the U.S. (P=0.08): ACOR and 95% CI of having greater fibrosis severity in men compared to women was 1.8 (1.1, 2.9) for patients with age < 50 years (P=0.02) and 1.2 (0.7, 2.1) for patients with age ≥50 years (P=0.59). Conclusion: Men are at a higher risk of having more severe fibrosis compared to women before menopause, while postmenopausal women have a similar severity of liver fibrosis compared to men. These findings may be explained by the protective effects of estrogen against fibrogenesis. © 2014 by the American Association for the Study of Liver Diseases.

Authors
Yang, JD; Abdelmalek, MF; Pang, H; Guy, CD; Smith, AD; Diehl, AM; Suzuki, A
MLA Citation
Yang, JD, Abdelmalek, MF, Pang, H, Guy, CD, Smith, AD, Diehl, AM, and Suzuki, A. "Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis." Hepatology 59.4 (January 1, 2014): 1406-1414.
Source
scopus
Published In
Hepatology
Volume
59
Issue
4
Publish Date
2014
Start Page
1406
End Page
1414
DOI
10.1002/hep.26761

Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy

Objective Smoothened (SMO), a coreceptor of the Hedgehog (Hh) pathway, promotes fibrogenic repair of chronic liver injury. We investigated the roles of SMO+ myofibroblast (MF) in liver regeneration by conditional deletion of SMO in α smooth muscle actin (αSMA)+ cells after partial hepatectomy (PH). Design αSMA-Cre-ERT2×SMO/flox mice were treated with vehicle (VEH) or tamoxifen (TMX), and sacrificed 24-96 h post-PH. Regenerating livers were analysed for proliferation, progenitors and fibrosis by qRT-PCR and quantitative immunohistochemistry (IHC). Results were normalised to liver segments resected at PH. For lineagetracing studies, αSMA-Cre-ERT2×ROSA-Stop-flox- yellow fluorescent protein (YFP) mice were treated with VEH or TMX; livers were stained for YFP, and hepatocytes isolated 48 and 72 h post-PH were analysed for YFP by flow cytometric analysis (FACS). Results Post-PH, VEH-αSMA-SMO mice increased expression of Hh-genes, transiently accumulated MF, fibrosis and liver progenitors, and ultimately exhibited proliferation of hepatocytes and cholangiocytes. In contrast, TMX-αSMA-SMO mice showed loss of whole liver SMO expression, repression of Hh-genes, enhanced accumulation of quiescent HSC but reduced accumulation of MF, fibrosis and progenitors, as well as inhibition of hepatocyte and cholangiocyte proliferation, and reduced recovery of liver weight. In TMX-αSMA-YFP mice, many progenitors, cholangiocytes and up to 25% of hepatocytes were YFP+ by 48-72 h after PH, indicating that liver epithelial cells were derived from αSMA-YFP+ cells. Conclusions Hh signalling promotes transition of quiescent hepatic stellate cells to fibrogenic MF, some of which become progenitors that regenerate the liver epithelial compartment after PH. Hence, scarring is a component of successful liver regeneration.

Authors
Swiderska-Syn, M; Syn, WK; Xie, G; Krüger, L; Machado, MV; Karaca, G; Michelotti, GA; Choi, SS; Premont, RT; Diehl, AM
MLA Citation
Swiderska-Syn, M, Syn, WK, Xie, G, Krüger, L, Machado, MV, Karaca, G, Michelotti, GA, Choi, SS, Premont, RT, and Diehl, AM. "Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy." Gut 63.8 (January 1, 2014): 1333-1344.
Source
scopus
Published In
Gut
Volume
63
Issue
8
Publish Date
2014
Start Page
1333
End Page
1344
DOI
10.1136/gutjnl-2013-305962

The beta-adrenoceptor agonist isoproterenol rescues acetaminophen-injured livers through increasing progenitor numbers by Wnt in mice

Acetaminophen (APAP)-induced acute liver injury (AILI) is a major health problem. Accumulating evidence suggests that the sympathetic nervous system (SNS) regulates neuronal and hematopoietic progenitors. SNS signaling affects hepatic progenitor/oval cells (HPCs) and β-adrenoceptor agonism will expand HPCs to reduce AILI. Dopamine β-hydroxylase-deficient mice (Dbh -/- ), lacking catecholamine SNS neurotransmitters, isolated HPCs, and immature ductular 603B cells were initially used to investigate SNS involvement in HPC physiology. Subsequently, control mice were treated with APAP (350 mg/kg) followed by the β-adrenoceptor agonist, isoproterenol (ISO), or the β-adrenoceptor antagonist, propranolol. Mechanistic studies examined effects of non-SNS HPC expansion on AILI, involvement of the canonical Wnt/β-catenin pathway (CWP) in the action of ISO on HPC expansion and comparison of ISO with the current standard of care, N-acetylcysteine (NAC). Dbh -/- mice lacking catecholamines had low HPC numbers, reconstituted by ISO. In vitro, ISO-induced proliferation of 603B cells was CWP dependent. In control mice, AILI raised HPC numbers, further increased by ISO, with attenuation of liver injury. Delayed administration of NAC did not, but delayed ISO did, reverse AILI. Propranolol worsened AILI. AILI activated the CWP, and ISO enhanced Wnt-ligand production. HPCs were the major source of Wnt ligands. Recombinant Wnt3a and ISO-603B-conditioned media, but not ISO alone, protected isolated hepatocytes from death, reversed by DKK1-a Wnt antagonist. Additionally, tumor-associated weak inducer of apoptosis expanded HPCs and protected against AILI. Furthermore, allotransplantation of HPCs from APAP+ISO-treated mice to other APAP-injured mice improved AILI, an effect antagonized by DKK1. Conclusion: SNS catecholamines expand HPCs, which are both targets and sources of Wnt ligands. Hepatoprotection by ISO is mediated by para- and autocrine effects of Wnt signaling. ISO represents novel pharmacotherapy for AILI. © 2014 by the American Association for the Study of Liver Diseases.

Authors
Soeda, J; Mouralidarane, A; Ray, S; Novelli, M; Thomas, S; Roskams, T; Diehl, AM; Oben, JA
MLA Citation
Soeda, J, Mouralidarane, A, Ray, S, Novelli, M, Thomas, S, Roskams, T, Diehl, AM, and Oben, JA. "The beta-adrenoceptor agonist isoproterenol rescues acetaminophen-injured livers through increasing progenitor numbers by Wnt in mice." Hepatology 60.3 (January 1, 2014): 1023-1034.
Source
scopus
Published In
Hepatology
Volume
60
Issue
3
Publish Date
2014
Start Page
1023
End Page
1034
DOI
10.1002/hep.27266

CYP2E1-dependent and leptin-mediated hepatic CD57 expression on CD8+ T cells aid progression of environment-linked nonalcoholic steatohepatitis.

Environmental toxins induce a novel CYP2E1/leptin signaling axis in liver. This in turn activates a poorly characterized innate immune response that contributes to nonalcoholic steatohepatitis (NASH) progression. To identify the relevant subsets of T-lymphocytes in CYP2E1-dependent, environment-linked NASH, we utilized a model of diet induced obese (DIO) mice that are chronically exposed to bromodichloromethane. Mice deficient in CYP2E1, leptin (ob/ob mice), or both T and B cells (Pfp/Rag2 double knockout (KO) mice) were used to delineate the role of each of these factors in metabolic oxidative stress-induced T cell activation. Results revealed that elevated levels of lipid peroxidation, tyrosyl radical formation, mitochondrial tyrosine nitration and hepatic leptin as a consequence of metabolic oxidative stress caused increased levels of hepatic CD57, a marker of peripheral blood lymphocytes including NKT cells. CD8+CD57+ cytotoxic T cells but not CD4+CD57+ cells were significantly decreased in mice lacking CYP2E1 and leptin. There was a significant increase in the levels of T cell cytokines IL-2, IL-1β, and IFN-γ in bromodichloromethane exposed DIO mice but not in mice that lacked CYP2E1, leptin or T and B cells. Apoptosis as evidenced by TUNEL assay and levels of cleaved caspase-3 was significantly lower in leptin and Pfp/Rag2 KO mice and highly correlated with protection from NASH. The results described above suggest that higher levels of oxidative stress-induced leptin mediated CD8+CD57+ T cells play an important role in the development of NASH. It also provides a novel insight of immune dysregulation and may be a key biomarker in NASH.

Authors
Seth, RK; Das, S; Kumar, A; Chanda, A; Kadiiska, MB; Michelotti, G; Manautou, J; Diehl, AM; Chatterjee, S
MLA Citation
Seth, RK, Das, S, Kumar, A, Chanda, A, Kadiiska, MB, Michelotti, G, Manautou, J, Diehl, AM, and Chatterjee, S. "CYP2E1-dependent and leptin-mediated hepatic CD57 expression on CD8+ T cells aid progression of environment-linked nonalcoholic steatohepatitis." Toxicology and applied pharmacology 274.1 (January 2014): 42-54.
PMID
24211274
Source
epmc
Published In
Toxicology and Applied Pharmacology
Volume
274
Issue
1
Publish Date
2014
Start Page
42
End Page
54
DOI
10.1016/j.taap.2013.10.029

Liver renewal: detecting misrepair and optimizing regeneration.

UNLABELLED: Cirrhosis and liver cancer, the main causes of liver-related morbidity and mortality, result from defective repair of liver injury. This article summarizes rapidly evolving knowledge about liver myofibroblasts and progenitors, the 2 key cell types that interact to orchestrate effective repair, because deregulation of these cells is likely to be central to the pathogenesis of both cirrhosis and liver cancer. We focus on cirrhosis pathogenesis because cirrhosis is the main risk factor for primary liver cancer. Emerging evidence suggests that the defective repair process has certain characteristics that might be exploited for biomarker development. Recent findings in preclinical models also indicate that the newly identified cellular and molecular targets are amenable to therapeutic manipulation. Thus, recent advances in our understanding about key cell types and fundamental mechanisms that regulate liver regeneration have opened new avenues to improve the outcomes of liver injury. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01899859.

Authors
Machado, MV; Diehl, AM
MLA Citation
Machado, MV, and Diehl, AM. "Liver renewal: detecting misrepair and optimizing regeneration." Mayo Clin Proc 89.1 (January 2014): 120-130.
PMID
24388030
Source
pubmed
Published In
Mayo Clinic Proceedings
Volume
89
Issue
1
Publish Date
2014
Start Page
120
End Page
130
DOI
10.1016/j.mayocp.2013.10.009

Osteopontin mediates fibrogenic effects of leptin and enhances NASH progression

Authors
Coombes, JD; Choi, SS; Manka, PP; Briones-Orta, MA; Swiderska-Syn, M; Kitamura, N; Younis, R; Bitencourt, S; Dolle, L; Williams, R; van Grunsven, LA; Diehl, AM; Canbay, A; Syn, W-K
MLA Citation
Coombes, JD, Choi, SS, Manka, PP, Briones-Orta, MA, Swiderska-Syn, M, Kitamura, N, Younis, R, Bitencourt, S, Dolle, L, Williams, R, van Grunsven, LA, Diehl, AM, Canbay, A, and Syn, W-K. "Osteopontin mediates fibrogenic effects of leptin and enhances NASH progression." 2014.
Source
wos-lite
Published In
Hepatology
Volume
60
Publish Date
2014
Start Page
748A
End Page
749A

Hedgehog-signaling and angiogenesis in cirrhotic and non-cirrhotic portal hypertension

Authors
Uschner, FE; Ranabhat, G; Granzow, M; Choi, SS; Klein, S; Schierwagen, R; Raskopf, E; Strassburg, CP; Hiththetiya, K; Sauerbruch, T; Diehl, AM; Trebicka, J
MLA Citation
Uschner, FE, Ranabhat, G, Granzow, M, Choi, SS, Klein, S, Schierwagen, R, Raskopf, E, Strassburg, CP, Hiththetiya, K, Sauerbruch, T, Diehl, AM, and Trebicka, J. "Hedgehog-signaling and angiogenesis in cirrhotic and non-cirrhotic portal hypertension." 2014.
Source
wos-lite
Published In
Hepatology
Volume
60
Publish Date
2014
Start Page
1178A
End Page
1178A

M1 Polarization bias and subsequent NASH progression is attenuated by nitric oxide donor DETA NONOate via inhibition of CYP2E1 induced oxidative stress

Authors
Seth, RK; Das, S; Pourhoseini, S; Dattaroy, D; Igwe, S; Ray, JB; Michelotti, GA; Diehl, AM; Chatterjee, S
MLA Citation
Seth, RK, Das, S, Pourhoseini, S, Dattaroy, D, Igwe, S, Ray, JB, Michelotti, GA, Diehl, AM, and Chatterjee, S. "M1 Polarization bias and subsequent NASH progression is attenuated by nitric oxide donor DETA NONOate via inhibition of CYP2E1 induced oxidative stress." 2014.
Source
wos-lite
Published In
Hepatology
Volume
60
Publish Date
2014
Start Page
762A
End Page
762A

Whole Exome Sequencing of Extreme Phenotypes of NAFLD Identifies Potential Genetic Risk Factors for Advanced Hepatic Fibrosis

Authors
Urban, TJ; Moylan, CA; Rein, M; Abdelmalek, MF; Goldstein, DB; Diehl, AM
MLA Citation
Urban, TJ, Moylan, CA, Rein, M, Abdelmalek, MF, Goldstein, DB, and Diehl, AM. "Whole Exome Sequencing of Extreme Phenotypes of NAFLD Identifies Potential Genetic Risk Factors for Advanced Hepatic Fibrosis." 2014.
Source
wos-lite
Published In
Hepatology
Volume
60
Publish Date
2014
Start Page
744A
End Page
744A

Hepatic Stellate Cells Express the Hepatocyte-enriched Transcription Factor, Hepatocyte Nuclear Factor 4 alpha

Authors
Swiderska-Syn, M; Xie, G; Coombes, JD; Michelotti, GA; Diehl, AM
MLA Citation
Swiderska-Syn, M, Xie, G, Coombes, JD, Michelotti, GA, and Diehl, AM. "Hepatic Stellate Cells Express the Hepatocyte-enriched Transcription Factor, Hepatocyte Nuclear Factor 4 alpha." 2014.
Source
wos-lite
Published In
Hepatology
Volume
60
Publish Date
2014
Start Page
578A
End Page
578A

Micro RNA 21 inhibition of SMAD 7 enhances fibrogenesis via leptin mediated NADPH oxidase in experimental nonalcoholic steatohepatitis

Authors
Dattaroy, D; Seth, RK; Das, S; Pourhoseini, S; Nagarkatti, M; Michelotti, GA; Diehl, AM; Chatterjee, S
MLA Citation
Dattaroy, D, Seth, RK, Das, S, Pourhoseini, S, Nagarkatti, M, Michelotti, GA, Diehl, AM, and Chatterjee, S. "Micro RNA 21 inhibition of SMAD 7 enhances fibrogenesis via leptin mediated NADPH oxidase in experimental nonalcoholic steatohepatitis." 2014.
Source
wos-lite
Published In
Hepatology
Volume
60
Publish Date
2014
Start Page
249A
End Page
249A

Risk of severe fibrosis is associated with age at menopause in nonalcoholic fatty liver disease (NAFLD)

Authors
Klair, JS; Yang, JD; Abdelmalek, MF; Guy, CD; Gill, RM; Yates, KP; Unalp-Arida, A; Lavine, JE; Clark, JM; Diehl, AM; Suzuki, A
MLA Citation
Klair, JS, Yang, JD, Abdelmalek, MF, Guy, CD, Gill, RM, Yates, KP, Unalp-Arida, A, Lavine, JE, Clark, JM, Diehl, AM, and Suzuki, A. "Risk of severe fibrosis is associated with age at menopause in nonalcoholic fatty liver disease (NAFLD)." 2014.
Source
wos-lite
Published In
Hepatology
Volume
60
Publish Date
2014
Start Page
621A
End Page
621A

Repair-related Activation of Hedgehog Signaling in Stromal Cells Promotes Intrahepatic Hypothyroidism

Authors
Bohinc, B; Michelotti, GA; Xie, G; Pang, H; Suzuki, A; Guy, CD; Piercy, DL; Kruger, L; Swiderska-Syn, M; Machado, MV; Pereira, TA; Zavacki, AM; Abdelmalek, MF; Diehl, AM
MLA Citation
Bohinc, B, Michelotti, GA, Xie, G, Pang, H, Suzuki, A, Guy, CD, Piercy, DL, Kruger, L, Swiderska-Syn, M, Machado, MV, Pereira, TA, Zavacki, AM, Abdelmalek, MF, and Diehl, AM. "Repair-related Activation of Hedgehog Signaling in Stromal Cells Promotes Intrahepatic Hypothyroidism." 2014.
Source
wos-lite
Published In
Hepatology
Volume
60
Publish Date
2014
Start Page
411A
End Page
412A

Evidence for and against epithelial-to-mesenchymal transition in the liver.

The outcome of liver injury is determined by the success of repair. Liver repair involves replacement of damaged liver tissue with healthy liver epithelial cells (including both hepatocytes and cholangiocytes) and reconstruction of normal liver structure and function. Current dogma posits that replication of surviving mature hepatocytes and cholangiocytes drives the regeneration of liver epithelium after injury, whereas failure of liver repair commonly leads to fibrosis, a scarring condition in which hepatic stellate cells, the main liver-resident mesenchymal cells, play the major role. The present review discusses other mechanisms that might be responsible for the regeneration of new liver epithelial cells and outgrowth of matrix-producing mesenchymal cells during hepatic injury. This theory proposes that, during liver injury, some epithelial cells undergo epithelial-to-mesenchymal transition (EMT), acquire myofibroblastic phenotypes/features, and contribute to fibrogenesis, whereas certain mesenchymal cells (namely hepatic stellate cells and stellate cell-derived myofibroblasts) undergo mesenchymal-to-epithelial transition (MET), revert to epithelial cells, and ultimately differentiate into either hepatocytes or cholangiocytes. Although this theory is highly controversial, it suggests that the balance between EMT and MET modulates the outcome of liver injury. This review summarizes recent advances that support or refute the concept that certain types of liver cells are capable of phenotype transition (i.e., EMT and MET) during both culture conditions and chronic liver injury.

Authors
Xie, G; Diehl, AM
MLA Citation
Xie, G, and Diehl, AM. "Evidence for and against epithelial-to-mesenchymal transition in the liver." Am J Physiol Gastrointest Liver Physiol 305.12 (December 2013): G881-G890.
PMID
24157970
Source
pubmed
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
305
Issue
12
Publish Date
2013
Start Page
G881
End Page
G890
DOI
10.1152/ajpgi.00289.2013

Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis.

Recent studies indicate that metabolic oxidative stress, autophagy, and inflammation are hallmarks of nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanisms that link these important events in NASH remain unclear. In this study, we investigated the mechanistic role of purinergic receptor X7 (P2X7) in modulating autophagy and resultant inflammation in NASH in response to metabolic oxidative stress. The study uses two rodent models of NASH. In one of them, a CYP2E1 substrate bromodichloromethane is used to induce metabolic oxidative stress and NASH. Methyl choline-deficient diet feeding is used for the other NASH model. CYP2E1 and P2X7 receptor gene-deleted mice are used to establish their roles in regulating metabolic oxidative stress and autophagy. Autophagy gene expression, protein levels, confocal microscopy based-immunolocalization of lysosome-associated membrane protein (LAMP)2A and histopathological analysis were performed. CYP2E1-dependent metabolic oxidative stress induced increases in P2X7 receptor expression and chaperone-mediated autophagy markers LAMP2A and heat shock cognate 70 but caused depletion of light chain 3 isoform B (LC3B) protein levels. P2X7 receptor gene deletion significantly decreased LAMP2A and inflammatory indicators while significantly increasing LC3B protein levels compared with wild-type mice treated with bromodichloromethane. P2X7 receptor-deleted mice were also protected from NASH pathology as evidenced by decreased inflammation and fibrosis. Our studies establish that P2X7 receptor is a key regulator of autophagy induced by metabolic oxidative stress in NASH, thereby modulating hepatic inflammation. Furthermore, our findings presented here form a basis for P2X7 receptor as a potential therapeutic target in the treatment for NASH.

Authors
Das, S; Seth, RK; Kumar, A; Kadiiska, MB; Michelotti, G; Diehl, AM; Chatterjee, S
MLA Citation
Das, S, Seth, RK, Kumar, A, Kadiiska, MB, Michelotti, G, Diehl, AM, and Chatterjee, S. "Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis." American journal of physiology. Gastrointestinal and liver physiology 305.12 (December 2013): G950-G963.
PMID
24157968
Source
epmc
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
305
Issue
12
Publish Date
2013
Start Page
G950
End Page
G963
DOI
10.1152/ajpgi.00235.2013

Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice

Liver repair involves phenotypic changes in hepatic stellate cells (HSCs) and reactivation of morphogenic signaling pathways that modulate epithelial-to-mesenchymal/mesenchymal-to-epithelial transitions, such as Notch and Hedgehog (Hh). Hh stimulates HSCs to become myofibroblasts (MFs). Recent lineage tracing studies in adult mice with injured livers showed that some MFs became multipotent progenitors to regenerate hepatocytes, cholangiocytes, and HSCs. We studied primary HSC cultures and two different animal models of fibrosis to evaluate the hypothesis that activating the Notch pathway in HSCs stimulates them to become (and remain) MFs through a mechanism that involves an epithelial-to-mesenchymal-like transition and requires cross-talk with the canonical Hh pathway. We found that when cultured HSCs transitioned into MFs, they activated Hh signaling, underwent an epithelial-to-mesenchymal-like transition, and increased Notch signaling. Blocking Notch signaling in MFs/HSCs suppressed Hh activity and caused a mesenchymal-to-epithelial-like transition. Inhibiting the Hh pathway suppressed Notch signaling and also induced a mesenchymal-to-epithelial-like transition. Manipulating Hh and Notch signaling in a mouse multipotent progenitor cell line evoked similar responses. In mice, liver injury increased Notch activity in MFs and Hh-responsive MF progeny (i.e., HSCs and ductular cells). Conditionally disrupting Hh signaling in MFs of bile-duct-ligated mice inhibited Notch signaling and blocked accumulation of both MF and ductular cells. Conclusions: The Notch and Hedgehog pathways interact to con trol the fate of key cell types involved in adult liver repair by modulating epithelial-to-mesenchymal-like/mesenchymal-to-epithelial-like transitions. © 2013 by the American Association for the Study of Liver Diseases.

Authors
Xie, G; Karaca, G; Swiderska-Syn, M; Michelotti, GA; Krüger, L; Chen, Y; Premont, RT; Choi, SS; Diehl, AM
MLA Citation
Xie, G, Karaca, G, Swiderska-Syn, M, Michelotti, GA, Krüger, L, Chen, Y, Premont, RT, Choi, SS, and Diehl, AM. "Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice." Hepatology 58.5 (November 1, 2013): 1801-1813.
Source
scopus
Published In
Hepatology
Volume
58
Issue
5
Publish Date
2013
Start Page
1801
End Page
1813
DOI
10.1002/hep.26511

NAFLD, NASH and liver cancer

NAFLD affects a large proportion of the US population and its incidence and prevalence are increasing to epidemic proportions around the world. As with other liver diseases that cause cirrhosis, NAFLD increases the risk of liver cancer, a disease with poor outcomes and limited therapeutic options. The incidences of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma are also rising, and HCC is now the leading cause of obesity-related cancer deaths in middle-aged men in the USA. In this Review, we summarize the correlations between liver cancer and NAFLD-related cirrhosis, and the role of the metabolic syndrome in the development of liver cancer from diverse aetiologies, including HCV-mediated cirrhosis. Recent advances in understanding the progression of NAFLD to HCC from preclinical models will also be discussed. Targeted genetic manipulation of certain metabolic or stress-response pathways, including one-carbon metabolism, NF-κB, PTEN and microRNAs, has been valuable in elucidating the pathways that regulate carcinogenesis in NAFLD. Although tremendous advances have occurred in the identification of diagnostic and therapeutic opportunities to reduce the progression of NAFLD, considerable gaps in our knowledge remain with regard to the mechanisms by which NAFLD and its risk factors promote liver cancer. © 2013 Macmillan Publishers Limited. All rights reserved.

Authors
Michelotti, GA; Machado, MV; Diehl, AM
MLA Citation
Michelotti, GA, Machado, MV, and Diehl, AM. "NAFLD, NASH and liver cancer." Nature Reviews Gastroenterology and Hepatology 10.11 (November 1, 2013): 656-665. (Review)
Source
scopus
Published In
Nature Reviews Gastroenterology & Hepatology
Volume
10
Issue
11
Publish Date
2013
Start Page
656
End Page
665
DOI
10.1038/nrgastro.2013.183

MicroRNA expression differentiates squamous epithelium from barrett's esophagus and esophageal cancer

Background: Current strategies fail to identify most patients with esophageal adenocarcinoma (EAC) before the disease becomes advanced and incurable. Given the dismal prognosis associated with EAC, improvements in detection of early-stage esophageal neoplasia are needed. Aim: We sought to assess whether differential expression of microRNAs could discriminate between squamous epithelium, Barrett's esophagus (BE), and EAC. Methods: We analyzed microRNA expression in a discovery cohort of human endoscopic biopsy samples from 36 patients representing normal squamous esophagus (n = 11), BE (n = 14), and high-grade dysplasia/EAC (n = 11). RNA was assessed using microarrays representing 847 human microRNAs followed by quantitative real-time polymerase chain reaction (qRT-PCR) verification of nine microRNAs. In a second cohort (n = 18), qRT-PCR validation of five miRNAs was performed. Expression of 59 microRNAs associated with BE/EAC in the literature was assessed in our training cohort. Known esophageal cell lines were used to compare miRNA expression to tissue miRNAs. Results: After controlling for multiple comparisons, we found 34 miRNAs differentially expressed between squamous esophagus and BE/EAC by microarray analysis. However, miRNA expression did not reliably differentiate non-dysplastic BE from EAC. In the validation cohort, all five microRNAs selected for qRT-PCR validation differentiated between squamous samples and BE/EAC. Microarray results supported 14 of the previously reported microRNAs associated with BE/EAC in the literature. Cell lines did not generally reflect miRNA expression found in vivo. Conclusions: These data indicate that miRNAs differ between squamous esophageal epithelium and BE/EAC, but do not distinguish between BE and EAC. We suggest prospective evaluation of miRNAs in patients at high risk for EAC. © 2013 Springer Science+Business Media New York.

Authors
Garman, KS; Owzar, K; Hauser, ER; Westfall, K; Anderson, BR; Souza, RF; Diehl, AM; Provenzale, D; Shaheen, NJ
MLA Citation
Garman, KS, Owzar, K, Hauser, ER, Westfall, K, Anderson, BR, Souza, RF, Diehl, AM, Provenzale, D, and Shaheen, NJ. "MicroRNA expression differentiates squamous epithelium from barrett's esophagus and esophageal cancer." Digestive Diseases and Sciences 58.11 (November 1, 2013): 3178-3188.
Source
scopus
Published In
Digestive Diseases and Sciences
Volume
58
Issue
11
Publish Date
2013
Start Page
3178
End Page
3188
DOI
10.1007/s10620-013-2806-7

Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice.

UNLABELLED: Liver repair involves phenotypic changes in hepatic stellate cells (HSCs) and reactivation of morphogenic signaling pathways that modulate epithelial-to-mesenchymal/mesenchymal-to-epithelial transitions, such as Notch and Hedgehog (Hh). Hh stimulates HSCs to become myofibroblasts (MFs). Recent lineage tracing studies in adult mice with injured livers showed that some MFs became multipotent progenitors to regenerate hepatocytes, cholangiocytes, and HSCs. We studied primary HSC cultures and two different animal models of fibrosis to evaluate the hypothesis that activating the Notch pathway in HSCs stimulates them to become (and remain) MFs through a mechanism that involves an epithelial-to-mesenchymal-like transition and requires cross-talk with the canonical Hh pathway. We found that when cultured HSCs transitioned into MFs, they activated Hh signaling, underwent an epithelial-to-mesenchymal-like transition, and increased Notch signaling. Blocking Notch signaling in MFs/HSCs suppressed Hh activity and caused a mesenchymal-to-epithelial-like transition. Inhibiting the Hh pathway suppressed Notch signaling and also induced a mesenchymal-to-epithelial-like transition. Manipulating Hh and Notch signaling in a mouse multipotent progenitor cell line evoked similar responses. In mice, liver injury increased Notch activity in MFs and Hh-responsive MF progeny (i.e., HSCs and ductular cells). Conditionally disrupting Hh signaling in MFs of bile-duct-ligated mice inhibited Notch signaling and blocked accumulation of both MF and ductular cells. CONCLUSIONS: The Notch and Hedgehog pathways interact to control the fate of key cell types involved in adult liver repair by modulating epithelial-to-mesenchymal-like/mesenchymal-to-epithelial-like transitions.

Authors
Xie, G; Karaca, G; Swiderska-Syn, M; Michelotti, GA; Krüger, L; Chen, Y; Premont, RT; Choi, SS; Diehl, AM
MLA Citation
Xie, G, Karaca, G, Swiderska-Syn, M, Michelotti, GA, Krüger, L, Chen, Y, Premont, RT, Choi, SS, and Diehl, AM. "Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice." Hepatology 58.5 (November 2013): 1801-1813.
PMID
23703657
Source
pubmed
Published In
Hepatology
Volume
58
Issue
5
Publish Date
2013
Start Page
1801
End Page
1813
DOI
10.1002/hep.26511

Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Cirrhosis and liver cancer are potential outcomes of advanced nonalcoholic fatty liver disease (NAFLD). It is not clear what factors determine whether patients will develop advanced or mild NAFLD, limiting noninvasive diagnosis and treatment before clinical sequelae emerge. We investigated whether DNA methylation profiles can distinguish patients with mild disease from those with advanced NAFLD, and how these patterns are functionally related to hepatic gene expression. METHODS: We collected frozen liver biopsies and clinical data from patients with biopsy-proven NAFLD (56 in the discovery cohort and 34 in the replication cohort). Samples were divided into groups based on histologic severity of fibrosis: F0-1 (mild) and F3-4 (advanced). DNA methylation profiles were determined and coupled with gene expression data from the same biopsies; differential methylation was validated in subsets of the discovery and replication cohorts. We then analyzed interactions between the methylome and transcriptome. RESULTS: Clinical features did not differ between patients known to have mild or advanced fibrosis based on biopsy analysis. There were 69,247 differentially methylated CpG sites (76% hypomethylated, 24% hypermethylated) in patients with advanced vs mild NAFLD (P < .05). Methylation at fibroblast growth factor receptor 2, methionine adenosyl methyltransferase 1A, and caspase 1 was validated by bisulfite pyrosequencing and the findings were reproduced in the replication cohort. Methylation correlated with gene transcript levels for 7% of differentially methylated CpG sites, indicating that differential methylation contributes to differences in expression. In samples with advanced NAFLD, many tissue repair genes were hypomethylated and overexpressed, and genes in certain metabolic pathways, including 1-carbon metabolism, were hypermethylated and underexpressed. CONCLUSIONS: Functionally relevant differences in methylation can distinguish patients with advanced vs mild NAFLD. Altered methylation of genes that regulate processes such as steatohepatitis, fibrosis, and carcinogenesis indicate the role of DNA methylation in progression of NAFLD.

Authors
Murphy, SK; Yang, H; Moylan, CA; Pang, H; Dellinger, A; Abdelmalek, MF; Garrett, ME; Ashley-Koch, A; Suzuki, A; Tillmann, HL; Hauser, MA; Diehl, AM
MLA Citation
Murphy, SK, Yang, H, Moylan, CA, Pang, H, Dellinger, A, Abdelmalek, MF, Garrett, ME, Ashley-Koch, A, Suzuki, A, Tillmann, HL, Hauser, MA, and Diehl, AM. "Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease." Gastroenterology 145.5 (November 2013): 1076-1087.
PMID
23916847
Source
pubmed
Published In
Gastroenterology
Volume
145
Issue
5
Publish Date
2013
Start Page
1076
End Page
1087
DOI
10.1053/j.gastro.2013.07.047

MicroRNA expression differentiates squamous epithelium from Barrett's esophagus and esophageal cancer.

BACKGROUND: Current strategies fail to identify most patients with esophageal adenocarcinoma (EAC) before the disease becomes advanced and incurable. Given the dismal prognosis associated with EAC, improvements in detection of early-stage esophageal neoplasia are needed. AIM: We sought to assess whether differential expression of microRNAs could discriminate between squamous epithelium, Barrett's esophagus (BE), and EAC. METHODS: We analyzed microRNA expression in a discovery cohort of human endoscopic biopsy samples from 36 patients representing normal squamous esophagus (n = 11), BE (n = 14), and high-grade dysplasia/EAC (n = 11). RNA was assessed using microarrays representing 847 human microRNAs followed by quantitative real-time polymerase chain reaction (qRT-PCR) verification of nine microRNAs. In a second cohort (n = 18), qRT-PCR validation of five miRNAs was performed. Expression of 59 microRNAs associated with BE/EAC in the literature was assessed in our training cohort. Known esophageal cell lines were used to compare miRNA expression to tissue miRNAs. RESULTS: After controlling for multiple comparisons, we found 34 miRNAs differentially expressed between squamous esophagus and BE/EAC by microarray analysis. However, miRNA expression did not reliably differentiate non-dysplastic BE from EAC. In the validation cohort, all five microRNAs selected for qRT-PCR validation differentiated between squamous samples and BE/EAC. Microarray results supported 14 of the previously reported microRNAs associated with BE/EAC in the literature. Cell lines did not generally reflect miRNA expression found in vivo. CONCLUSIONS: These data indicate that miRNAs differ between squamous esophageal epithelium and BE/EAC, but do not distinguish between BE and EAC. We suggest prospective evaluation of miRNAs in patients at high risk for EAC.

Authors
Garman, KS; Owzar, K; Hauser, ER; Westfall, K; Anderson, BR; Souza, RF; Diehl, AM; Provenzale, D; Shaheen, NJ
MLA Citation
Garman, KS, Owzar, K, Hauser, ER, Westfall, K, Anderson, BR, Souza, RF, Diehl, AM, Provenzale, D, and Shaheen, NJ. "MicroRNA expression differentiates squamous epithelium from Barrett's esophagus and esophageal cancer." Dig Dis Sci 58.11 (November 2013): 3178-3188.
PMID
23925817
Source
pubmed
Published In
Digestive Diseases and Sciences
Volume
58
Issue
11
Publish Date
2013
Start Page
3178
End Page
3188
DOI
10.1007/s10620-013-2806-7

NAFLD, NASH and liver cancer.

NAFLD affects a large proportion of the US population and its incidence and prevalence are increasing to epidemic proportions around the world. As with other liver diseases that cause cirrhosis, NAFLD increases the risk of liver cancer, a disease with poor outcomes and limited therapeutic options. The incidences of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma are also rising, and HCC is now the leading cause of obesity-related cancer deaths in middle-aged men in the USA. In this Review, we summarize the correlations between liver cancer and NAFLD-related cirrhosis, and the role of the metabolic syndrome in the development of liver cancer from diverse aetiologies, including HCV-mediated cirrhosis. Recent advances in understanding the progression of NAFLD to HCC from preclinical models will also be discussed. Targeted genetic manipulation of certain metabolic or stress-response pathways, including one-carbon metabolism, NF-κB, PTEN and microRNAs, has been valuable in elucidating the pathways that regulate carcinogenesis in NAFLD. Although tremendous advances have occurred in the identification of diagnostic and therapeutic opportunities to reduce the progression of NAFLD, considerable gaps in our knowledge remain with regard to the mechanisms by which NAFLD and its risk factors promote liver cancer.

Authors
Michelotti, GA; Machado, MV; Diehl, AM
MLA Citation
Michelotti, GA, Machado, MV, and Diehl, AM. "NAFLD, NASH and liver cancer." Nat Rev Gastroenterol Hepatol 10.11 (November 2013): 656-665. (Review)
PMID
24080776
Source
pubmed
Published In
Nature Reviews Gastroenterology & Hepatology
Volume
10
Issue
11
Publish Date
2013
Start Page
656
End Page
665
DOI
10.1038/nrgastro.2013.183

STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis bythe protein kinase inhibitor sorafenib

There have been major advances in defining the immunological events associated with fibrosis in various chronic liver diseases. We have taken advantage of this data to focus on the mechanisms of action of a unique multi-kinase inhibitor, coined sorafenib, on CCl 4 -induced murine liver fibrosis, including the effects of this agent in models of both acute and chronic CCl 4 -mediated pathology. Importantly, sorafenib significantly attenuated chronic liver injury and fibrosis, including reduction in liver inflammation and histopathology as well as decreased expression of liver fibrosis-related genes, including α-smooth muscle actin, collagen, matrix metalloproteinases and the tissue inhibitor of metalloproteinase-1. Furthermore, sorafenib treatment resulted in translocation of cytoplasmic STAT3 to the nucleus in its active form. Based on this observation, we used hepatocyte-specific STAT3 knockout (STAT3 Hep-/- ) mice to demonstrate that hepatic STAT3 was critical for sorafenib-mediated protection against liver fibrosis, and that the upregulation of STAT3 phosphorylation was dependent on Kupffer cell-derived IL-6. In conclusion, these data reflect the clinical potential of the multi-kinase inhibitor sorafenib for the prevention of fibrosis as well as the treatment of established liver fibrosis and illustrate the immunological mechanisms that underlie the protective effects of sorafenib. © 2013 Elsevier Ltd.

Authors
Deng, YR; Ma, HD; Tsuneyama, K; Yang, W; Wang, YH; Lu, FT; Liu, CH; Liu, P; He, XS; Diehl, AM; Gershwin, ME; Lian, ZX
MLA Citation
Deng, YR, Ma, HD, Tsuneyama, K, Yang, W, Wang, YH, Lu, FT, Liu, CH, Liu, P, He, XS, Diehl, AM, Gershwin, ME, and Lian, ZX. "STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis bythe protein kinase inhibitor sorafenib." Journal of Autoimmunity 46 (October 1, 2013): 25-34.
Source
scopus
Published In
Journal of Autoimmunity
Volume
46
Publish Date
2013
Start Page
25
End Page
34
DOI
10.1016/j.jaut.2013.07.008

Hedgehog Pathway Targeted by Vitamin E Therapy in NASH

Authors
Guy, CD; Suzuki, A; Abdelmalek, MF; Burchette, J; Diehl, AM
MLA Citation
Guy, CD, Suzuki, A, Abdelmalek, MF, Burchette, J, and Diehl, AM. "Hedgehog Pathway Targeted by Vitamin E Therapy in NASH." October 2013.
Source
wos-lite
Published In
Hepatology
Volume
58
Publish Date
2013
Start Page
249A
End Page
249A

Absence of FN14 Ameliorates Acute Ethanol-Induced Steatohepatitis

Authors
Karaca, G; Xie, G; Swiderska-Syn, M; Michelotti, GA; Choi, SS; Burkly, LC; Diehl, AM
MLA Citation
Karaca, G, Xie, G, Swiderska-Syn, M, Michelotti, GA, Choi, SS, Burkly, LC, and Diehl, AM. "Absence of FN14 Ameliorates Acute Ethanol-Induced Steatohepatitis." October 2013.
Source
wos-lite
Published In
Hepatology
Volume
58
Publish Date
2013
Start Page
831A
End Page
831A

Cholangiocyte proliferation and Osteopontin secretion is induced by Schistosoma mansoni egg antigens and correlates with fibrosis and portal hypertension in human and murine schistosomiasis

Authors
Pereira, TA; Syn, W-K; Choi, SS; Voieta, I; Resende, V; Souza, MM; Secor, WE; Vidigal, PV; Witek, RP; Andrade, ZA; Pereira, FE; Lambertucci, JR; Diehl, AM
MLA Citation
Pereira, TA, Syn, W-K, Choi, SS, Voieta, I, Resende, V, Souza, MM, Secor, WE, Vidigal, PV, Witek, RP, Andrade, ZA, Pereira, FE, Lambertucci, JR, and Diehl, AM. "Cholangiocyte proliferation and Osteopontin secretion is induced by Schistosoma mansoni egg antigens and correlates with fibrosis and portal hypertension in human and murine schistosomiasis." October 2013.
Source
wos-lite
Published In
Hepatology
Volume
58
Publish Date
2013
Start Page
847A
End Page
847A

The Role of Pleiotrophin Signaling in the Hepatic Stem Cell Niche

Authors
Tucker, A; Michelotti, GA; Choi, SS; Xie, G; Karaca, G; Swiderska-Syn, M; Kruger, L; Machado, MV; Garman, KS; Diehl, AM
MLA Citation
Tucker, A, Michelotti, GA, Choi, SS, Xie, G, Karaca, G, Swiderska-Syn, M, Kruger, L, Machado, MV, Garman, KS, and Diehl, AM. "The Role of Pleiotrophin Signaling in the Hepatic Stem Cell Niche." October 2013.
Source
wos-lite
Published In
Hepatology
Volume
58
Publish Date
2013
Start Page
1007A
End Page
1007A

Hedgehog Signaling by Hepatic Epithelial Progenitor Cells Forming Neotubules Drives Parenchymal Fibrogenesis in Gestational Alloimmune Liver Disease

Authors
Asai, A; Malladi, S; Misch, J; Malladi, P; Diehl, AM; Whitington, PF
MLA Citation
Asai, A, Malladi, S, Misch, J, Malladi, P, Diehl, AM, and Whitington, PF. "Hedgehog Signaling by Hepatic Epithelial Progenitor Cells Forming Neotubules Drives Parenchymal Fibrogenesis in Gestational Alloimmune Liver Disease." October 2013.
Source
wos-lite
Published In
Hepatology
Volume
58
Publish Date
2013
Start Page
592A
End Page
592A

CYP2E1-dependent and Leptin-induced CD57-positive cytotoxic T cells are crucial for progression of nonalcoholic steatohepatitis

Authors
Seth, RK; Das, S; Kumar, A; Chanda, A; Kadiiska, MB; Michelotti, GA; Diehl, AM; Chatterjee, S
MLA Citation
Seth, RK, Das, S, Kumar, A, Chanda, A, Kadiiska, MB, Michelotti, GA, Diehl, AM, and Chatterjee, S. "CYP2E1-dependent and Leptin-induced CD57-positive cytotoxic T cells are crucial for progression of nonalcoholic steatohepatitis." October 2013.
Source
wos-lite
Published In
Hepatology
Volume
58
Publish Date
2013
Start Page
538A
End Page
538A

Purinergic Receptor X7 is a Key Modulator of Metabolic Oxidative Stress - Mediated Autophagy and Inflammation in Experimental Nonalcoholic Steatohepatitis

Authors
Das, S; Seth, RK; Kumar, A; Kadiiska, MB; Michelotti, GA; Diehl, AM; Chatterjee, S
MLA Citation
Das, S, Seth, RK, Kumar, A, Kadiiska, MB, Michelotti, GA, Diehl, AM, and Chatterjee, S. "Purinergic Receptor X7 is a Key Modulator of Metabolic Oxidative Stress - Mediated Autophagy and Inflammation in Experimental Nonalcoholic Steatohepatitis." October 2013.
Source
wos-lite
Published In
Hepatology
Volume
58
Publish Date
2013
Start Page
538A
End Page
538A

Hedgehog-Induced Serine Biogenesis is Required for Activation of Hepatic Stellate Cells

Authors
Chen, Y; Michelotti, GA; Xie, G; Moylan, CA; Diehl, AM
MLA Citation
Chen, Y, Michelotti, GA, Xie, G, Moylan, CA, and Diehl, AM. "Hedgehog-Induced Serine Biogenesis is Required for Activation of Hepatic Stellate Cells." October 2013.
Source
wos-lite
Published In
Hepatology
Volume
58
Publish Date
2013
Start Page
572A
End Page
572A

Osteopontin enhances liver progenitor cell responses in progressive Nonalcoholic Steatohepatitis

Authors
Coombes, J; Claridge, LC; Swiderska-Syn, M; Briones-Orta, MA; Younis, R; Shah, H; Papa, S; Diehl, AM; Eksteen, B; Canbay, A; Syn, W-K
MLA Citation
Coombes, J, Claridge, LC, Swiderska-Syn, M, Briones-Orta, MA, Younis, R, Shah, H, Papa, S, Diehl, AM, Eksteen, B, Canbay, A, and Syn, W-K. "Osteopontin enhances liver progenitor cell responses in progressive Nonalcoholic Steatohepatitis." October 2013.
Source
wos-lite
Published In
Hepatology
Volume
58
Publish Date
2013
Start Page
535A
End Page
535A

Hedgehog signaling in human medullary thyroid carcinoma: a novel signaling pathway.

BACKGROUND: Locally or widely metastatic medullary thyroid carcinoma (MTC) is difficult to treat, and therapeutic options are limited. Recently, kinase inhibitors have shown partial efficacy in this cancer, but there is a continued need for the development of novel therapeutics. Within this context, the Hedgehog (Hh) pathway has been implicated in several types of human tumors, and early clinical trials with Hh antagonists have validated Hh as a novel therapeutic target. For the first time, we evaluated Hh pathway activity in MTC, and examined the effect of Hh pathway perturbation in highly characterized MTC cell lines. METHODS: We examined immunohistochemical expression of the Hh signaling mediators Sonic Hedgehog (Shh) and Glioblastoma (Gli)2 in paraffin-embedded normal versus histologically characterized human MTC tissue. We examined pharmacologic disruption of Hh signaling in vitro using two established MTC cell lines (TT and MZ-CRC-1). Hh signaling was either pharmacologically activated (SAG) or inhibited (GDC-0449) in MTC cell lines; Hh activity was assessed by quantitative real-time polymerase chain reaction, Western blot analysis, and quantification of cellular growth and apoptotic activity. RESULTS: Our data showed increased expression of Hh signaling factors in human MTC compared to normal tissue. In vitro, activation of the Hh pathway resulted in increased expression of key Hh signaling components Smoothened (Smo) and Gli2. Conversely, inhibition of the Hh pathway decreased expression of these genes, leading to significantly reduced cellular growth and increased apoptosis. CONCLUSIONS: Hedgehog signaling components are markedly upregulated in MTC. Hh pathway inhibitors have potential as novel therapeutic options in patients with metastatic and/or surgically unresectable MTC.

Authors
Bohinc, B; Michelotti, G; Diehl, AM
MLA Citation
Bohinc, B, Michelotti, G, and Diehl, AM. "Hedgehog signaling in human medullary thyroid carcinoma: a novel signaling pathway." Thyroid 23.9 (September 2013): 1119-1126.
PMID
23410206
Source
pubmed
Published In
Thyroid
Volume
23
Issue
9
Publish Date
2013
Start Page
1119
End Page
1126
DOI
10.1089/thy.2012.0474

Associations of depression, anxiety and antidepressants with histological severity of nonalcoholic fatty liver disease.

BACKGROUND: Depression and anxiety are common in patients with nonalcoholic fatty liver disease (NAFLD). However, their associations with histological severity of NAFLD are unknown. AIM: This study examined the association(s) of depression, anxiety and antidepressant pharmacotherapy with severity of histological features in patients with NAFLD. METHODS: We analysed 567 patients with biopsy-proven NAFLD enrolled in the Duke NAFLD Clinical Database. Depressive and anxiety symptoms were assessed using the Hospital Anxiety & Depression Scale (HADS). The associations of depression and anxiety with severity of histological features of NAFLD were analysed using multiple logistic (or ordinal logistic) regression models with and without adjusting for confounding factors. RESULT: Subclinical and clinical depression was noted in 53% and 14% of patients respectively. Subclinical and clinical anxiety was noted in 45% and 25% of patients respectively. After adjusting for confounders, depression was significantly associated with more severe hepatocyte ballooning in a dose-dependent manner (likelihood ratio test, P = 0.0201); adjusted cumulative odds ratio (COR) of subclinical and clinical depression for having a higher grade of hepatocyte ballooning were 2.1 [95% CI, 1.0, 4.4] and 3.6 [95% CI, 1.4, 8.8]. CONCLUSIONS: In patients with NAFLD, depression was associated with more severe hepatocyte ballooning. Further investigation exploring pathobiological mechanisms underlying the observed associations and potential effects of antidepressant pharmacotherapy on NAFLD liver histology is warranted.

Authors
Youssef, NA; Abdelmalek, MF; Binks, M; Guy, CD; Omenetti, A; Smith, AD; Diehl, AME; Suzuki, A
MLA Citation
Youssef, NA, Abdelmalek, MF, Binks, M, Guy, CD, Omenetti, A, Smith, AD, Diehl, AME, and Suzuki, A. "Associations of depression, anxiety and antidepressants with histological severity of nonalcoholic fatty liver disease." Liver Int 33.7 (August 2013): 1062-1070.
PMID
23560860
Source
pubmed
Published In
Liver International
Volume
33
Issue
7
Publish Date
2013
Start Page
1062
End Page
1070
DOI
10.1111/liv.12165

Environmental ToxinLinked Nonalcoholic Steatohepatitis and Hepatic Metabolic Reprogramming in Obese Mice

Authors
Seth, RK; Kumar, A; Das, S; Kadiiska, MB; Michelotti, G; Diehl, AM; Chatterjee, S
MLA Citation
Seth, RK, Kumar, A, Das, S, Kadiiska, MB, Michelotti, G, Diehl, AM, and Chatterjee, S. "Environmental ToxinLinked Nonalcoholic Steatohepatitis and Hepatic Metabolic Reprogramming in Obese Mice." TOXICOLOGICAL SCIENCES 134.2 (August 2013): 291-303.
PMID
23640861
Source
wos-lite
Published In
Toxicological Sciences (Elsevier)
Volume
134
Issue
2
Publish Date
2013
Start Page
291
End Page
303
DOI
10.1093/toxsci/kft104

Smoothened is a master regulator of adult liver repair.

When regenerative processes cannot keep pace with cell death, functional epithelia are replaced by scar. Scarring is characterized by both excessive accumulation of fibrous matrix and persistent outgrowth of cell types that accumulate transiently during successful wound healing, including myofibroblasts (MFs) and progenitors. This suggests that signaling that normally directs these cells to repair injured epithelia is deregulated. To evaluate this possibility, we examined liver repair during different types of liver injury after Smoothened (SMO), an obligate intermediate in the Hedgehog (Hh) signaling pathway, was conditionally deleted in cells expressing the MF-associated gene, αSMA. Surprisingly, blocking canonical Hh signaling in MFs not only inhibited liver fibrosis but also prevented accumulation of liver progenitors. Hh-sensitive, hepatic stellate cells (HSCs) were identified as the source of both MFs and progenitors by lineage-tracing studies in 3 other strains of mice, coupled with analysis of highly pure HSC preparations using flow cytometry, immunofluorescence confocal microscopy, RT-PCR, and in situ hybridization. The results identify SMO as a master regulator of hepatic epithelial regeneration based on its ability to promote mesenchymal-to-epithelial transitions in a subpopulation of HSC-derived MFs with features of multipotent progenitors.

Authors
Michelotti, GA; Xie, G; Swiderska, M; Choi, SS; Karaca, G; Krüger, L; Premont, R; Yang, L; Syn, W-K; Metzger, D; Diehl, AM
MLA Citation
Michelotti, GA, Xie, G, Swiderska, M, Choi, SS, Karaca, G, Krüger, L, Premont, R, Yang, L, Syn, W-K, Metzger, D, and Diehl, AM. "Smoothened is a master regulator of adult liver repair." J Clin Invest 123.6 (June 2013): 2380-2394.
PMID
23563311
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
123
Issue
6
Publish Date
2013
Start Page
2380
End Page
2394
DOI
10.1172/JCI66904

Hedgehog pathway and pediatric nonalcoholic fatty liver disease.

UNLABELLED: It is unclear why the histology of pediatric and adult nonalcoholic fatty liver disease (NAFLD) sometimes differs. In adults, severity of portal inflammation and fibrosis correlate with Hedgehog pathway activity. Hedgehog (Hh) signaling regulates organogenesis, but is silent in adult livers until injury reinduces Hh ligand production. During adolescence, liver development is completed and children's livers normally lose cells that produce and/or respond to Hh ligands. We postulated that fatty liver injury interferes with this process by increasing Hh ligand production, and theorized that hepatic responses to Hh ligands might differ among children according to age, gender, and/or puberty status. Using unstained liver biopsy slides from 56 children with NAFLD, we performed immunohistochemistry to assess Hh pathway activation and correlated the results with clinical information obtained at biopsy. Fibrosis stage generally correlated with Hh pathway activity, as demonstrated by the numbers of Hh-ligand-producing cells (P < 0.0001) and Hh-responsive (glioma-associated oncogene 2-positive [Gli2]) cells (P = 0.0013). The numbers of Gli2(+) cells also correlated with portal inflammation grade (P = 0.0012). Two distinct zonal patterns of Hh-ligand production, portal/periportal versus lobular, were observed. Higher portal/periportal Hh-ligand production was associated with male gender. Male gender and prepuberty were also associated with ductular proliferation (P < 0.05), increased numbers of portal Gli2(+) cells (P < 0.017) and portal fibrosis. CONCLUSION: The portal/periportal (progenitor) compartment of prepubescent male livers exhibits high Hh pathway activity. This may explain the unique histologic features of pediatric NAFLD because Hh signaling promotes the fibroductular response.

Authors
Swiderska-Syn, M; Suzuki, A; Guy, CD; Schwimmer, JB; Abdelmalek, MF; Lavine, JE; Diehl, AM
MLA Citation
Swiderska-Syn, M, Suzuki, A, Guy, CD, Schwimmer, JB, Abdelmalek, MF, Lavine, JE, and Diehl, AM. "Hedgehog pathway and pediatric nonalcoholic fatty liver disease." Hepatology 57.5 (May 2013): 1814-1825.
PMID
23300059
Source
pubmed
Published In
Hepatology
Volume
57
Issue
5
Publish Date
2013
Start Page
1814
End Page
1825
DOI
10.1002/hep.26230

Underlying potential: cellular and molecular determinants of adult liver repair.

The liver has a unique and extraordinary capacity for regeneration, even in adult organisms. This regenerative potential has traditionally been attributed to the replicative capabilities of mature hepatocytes and cholangiocytes, though emerging evidence suggests that other resident liver cell types such as progenitors, liver sinusoidal endothelial cells, and hepatic stellate cells respond to liver injury and contribute to repair. These other cells types are also associated with liver scarring, dysfunction, and carcinogenesis, which suggests that appropriate regulation of these cells is a major determinant of response to liver injury. The Reviews in this series explore possible contributions of liver progenitor cells, liver sinusoidal endothelial cells, and hepatic stellate cells to liver homeostasis and repair and highlight how these processes can go awry in chronic liver injury, fibrosis, and liver cancer.

Authors
Diehl, AM; Chute, J
MLA Citation
Diehl, AM, and Chute, J. "Underlying potential: cellular and molecular determinants of adult liver repair." J Clin Invest 123.5 (May 2013): 1858-1860. (Review)
PMID
23635782
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
123
Issue
5
Publish Date
2013
Start Page
1858
End Page
1860
DOI
10.1172/JCI69966

Genetic signatures in choline and 1-carbon metabolism are associated with the severity of hepatic steatosis.

Choline metabolism is important for very low-density lipoprotein secretion, making this nutritional pathway an important contributor to hepatic lipid balance. The purpose of this study was to assess whether the cumulative effects of multiple single nucleotide polymorphisms (SNPs) across genes of choline/1-carbon metabolism and functionally related pathways increase susceptibility to developing hepatic steatosis. In biopsy-characterized cases of nonalcoholic fatty liver disease and controls, we assessed 260 SNPs across 21 genes in choline/1-carbon metabolism. When SNPs were examined individually, using logistic regression, we only identified a single SNP (PNPLA3 rs738409) that was significantly associated with severity of hepatic steatosis after adjusting for confounders and multiple comparisons (P=0.02). However, when groupings of SNPs in similar metabolic pathways were defined using unsupervised hierarchical clustering, we identified groups of subjects with shared SNP signatures that were significantly correlated with steatosis burden (P=0.0002). The lowest and highest steatosis clusters could also be differentiated by ethnicity. However, unique SNP patterns defined steatosis burden irrespective of ethnicity. Our results suggest that analysis of SNP patterns in genes of choline/1-carbon metabolism may be useful for prediction of severity of steatosis in specific subsets of people, and the metabolic inefficiencies caused by these SNPs should be examined further.

Authors
Corbin, KD; Abdelmalek, MF; Spencer, MD; da Costa, K-A; Galanko, JA; Sha, W; Suzuki, A; Guy, CD; Cardona, DM; Torquati, A; Diehl, AM; Zeisel, SH
MLA Citation
Corbin, KD, Abdelmalek, MF, Spencer, MD, da Costa, K-A, Galanko, JA, Sha, W, Suzuki, A, Guy, CD, Cardona, DM, Torquati, A, Diehl, AM, and Zeisel, SH. "Genetic signatures in choline and 1-carbon metabolism are associated with the severity of hepatic steatosis." FASEB J 27.4 (April 2013): 1674-1689.
PMID
23292069
Source
pubmed
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
27
Issue
4
Publish Date
2013
Start Page
1674
End Page
1689
DOI
10.1096/fj.12-219097

PRAZOSIN AN ALPHA1 ADRENOCEPTOR ANTAGONIST PROTECTS LIVER FROM ACETAMINOPHEN INDUCED ACUTE LIVER INJURY AND EXPANDS THE PROGENITOR CELL POPULATION

Authors
Soeda, J; Mouralidarane, A; Ray, S; Diehl, AM; Oben, JA
MLA Citation
Soeda, J, Mouralidarane, A, Ray, S, Diehl, AM, and Oben, JA. "PRAZOSIN AN ALPHA1 ADRENOCEPTOR ANTAGONIST PROTECTS LIVER FROM ACETAMINOPHEN INDUCED ACUTE LIVER INJURY AND EXPANDS THE PROGENITOR CELL POPULATION." April 2013.
Source
wos-lite
Published In
Journal of Hepatology
Volume
58
Publish Date
2013
Start Page
S131
End Page
S131

IL28B rs12979860 is not associated with histologic features of NAFLD in a cohort of Caucasian North American patients.

Authors
Garrett, ME; Abdelmalek, MF; Ashley-Koch, A; Hauser, MA; Moylan, CA; Pang, H; Diehl, AM; Tillmann, HL
MLA Citation
Garrett, ME, Abdelmalek, MF, Ashley-Koch, A, Hauser, MA, Moylan, CA, Pang, H, Diehl, AM, and Tillmann, HL. "IL28B rs12979860 is not associated with histologic features of NAFLD in a cohort of Caucasian North American patients." J Hepatol 58.2 (February 2013): 402-403. (Letter)
PMID
23063570
Source
pubmed
Published In
Journal of Hepatology
Volume
58
Issue
2
Publish Date
2013
Start Page
402
End Page
403
DOI
10.1016/j.jhep.2012.09.035

Hedgehog signalling regulates liver sinusoidal endothelial cell capillarisation.

OBJECTIVE: Vascular remodelling during liver damage involves loss of healthy liver sinusoidal endothelial cell (LSEC) phenotype via capillarisation. Hedgehog (Hh) signalling regulates vascular development and increases during liver injury. This study therefore examined its role in capillarisation. DESIGN: Primary LSEC were cultured for 5 days to induce capillarisation. Pharmacological, antibody-mediated and genetic approaches were used to manipulate Hh signalling. Effects on mRNA and protein expression of Hh-regulated genes and capillarisation markers were evaluated by quantitative reverse transcription PCR and immunoblot. Changes in LSEC function were assessed by migration and tube forming assay, and gain/loss of fenestrae was examined by electron microscopy. Mice with acute or chronic liver injury were treated with Hh inhibitors; effects on capillarisation were assessed by immunohistochemistry. RESULTS: Freshly isolated LSEC expressed Hh ligands, Hh receptors and Hh ligand antagonist Hhip. Capillarisation was accompanied by repression of Hhip and increased expression of Hh-regulated genes. Treatment with Hh agonist further induced expression of Hh ligands and Hh-regulated genes, and upregulated capillarisation-associated genes; whereas Hh signalling antagonist or Hh ligand neutralising antibody each repressed expression of Hh target genes and capillarisation markers. LSEC isolated from Smo(loxP/loxP) transgenic mice that had been infected with adenovirus expressing Cre-recombinase to delete Smoothened showed over 75% knockdown of Smoothened. During culture, Smoothened-deficient LSEC had inhibited Hh signalling, less induction of capillarisation-associated genes and retention of fenestrae. In mice with injured livers, inhibiting Hh signalling prevented capillarisation. CONCLUSIONS: LSEC produce and respond to Hh ligands, and use Hh signalling to regulate complex phenotypic changes that occur during capillarisation.

Authors
Xie, G; Choi, SS; Syn, W-K; Michelotti, GA; Swiderska, M; Karaca, G; Chan, IS; Chen, Y; Diehl, AM
MLA Citation
Xie, G, Choi, SS, Syn, W-K, Michelotti, GA, Swiderska, M, Karaca, G, Chan, IS, Chen, Y, and Diehl, AM. "Hedgehog signalling regulates liver sinusoidal endothelial cell capillarisation." Gut 62.2 (February 2013): 299-309.
PMID
22362915
Source
pubmed
Published In
Gut
Volume
62
Issue
2
Publish Date
2013
Start Page
299
End Page
309
DOI
10.1136/gutjnl-2011-301494

Macrophage-derived Hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni.

BACKGROUND: Schistosomiasis mansoni is a major cause of portal fibrosis and portal hypertension. The Hedgehog pathway regulates fibrogenic repair in some types of liver injury. AIMS: Determine if Hedgehog pathway activation occurs during fibrosis progression in schistosomiasis and to determine if macrophage-related mechanisms are involved. METHODS: Immunohistochemistry was used to characterize the cells that generate and respond to Hedgehog ligands in 28 liver biopsies from patients with different grades of schistosomiasis fibrosis staged by ultrasound. Cultured macrophages (RAW264.7 and primary rat Kupffer cells) and primary rat liver sinusoidal endothelial cells (LSEC) were treated with schistosome egg antigen (SEA) and evaluated using qRT-PCR. Inhibition of the Hedgehog pathway was used to investigate its role in alternative activation of macrophages (M2) and vascular tube formation. RESULTS: Patients with schistosomiasis expressed more ligands (Shh and Ihh) and target genes (Patched and Gli2) than healthy individuals. Activated LSEC and myofibroblasts were Hedgehog responsive [Gli2(+)] and accumulated in parallel with fibrosis stage (P < 0.05). Double IHC for Ihh/CD68 showed that Ihh(+) cells were macrophages. In vitro studies demonstrated that SEA-stimulated macrophages to express Ihh and Shh mRNA (P < 0.05). Conditioned media from such macrophages induced luciferase production by Shh-LightII cells (P < 0.001) and Hedgehog inhibitors blocked this effect (P < 0.001). SEA-treated macrophages also up-regulated their own expression of M2 markers, and Hh pathway inhibitors abrogated this response (P < 0.01). Inhibition of the Hedgehog pathway in LSEC blocked SEA-induced migration and tube formation. CONCLUSION: SEA stimulates liver macrophages to produce Hh ligands, which promote alternative activation of macrophages, fibrogenesis and vascular remodelling in schistosomiasis.

Authors
Pereira, TA; Xie, G; Choi, SS; Syn, W-K; Voieta, I; Lu, J; Chan, IS; Swiderska, M; Amaral, KB; Antunes, CM; Secor, WE; Witek, RP; Lambertucci, JR; Pereira, FL; Diehl, AM
MLA Citation
Pereira, TA, Xie, G, Choi, SS, Syn, W-K, Voieta, I, Lu, J, Chan, IS, Swiderska, M, Amaral, KB, Antunes, CM, Secor, WE, Witek, RP, Lambertucci, JR, Pereira, FL, and Diehl, AM. "Macrophage-derived Hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni." Liver Int 33.1 (January 2013): 149-161.
PMID
23121638
Source
pubmed
Published In
Liver International
Volume
33
Issue
1
Publish Date
2013
Start Page
149
End Page
161
DOI
10.1111/liv.12016

The benefits of restraint: a pivotal role for IL-13 in hepatic glucose homeostasis.

In response to feeding, insulin promotes the uptake of sugar in peripheral tissues and suppresses the production of sugar, a process called gluconeogenesis, in the liver. Recent research has shown that chronic inflammation promotes insulin resistance, and in turn, chronically high glucose levels can drive inflammation. In this issue of the JCI, Stanya et al. investigate the connection between inflammation and glucose homeostasis by analyzing the effect of the antiinflammatory cytokine IL-13. Their results suggest that IL-13 plays an unexpected role in the regulation of glucose homeostasis by modulating gluconeogenesis and may be a useful therapeutic target for treatment of diabetes and metabolic syndrome.

Authors
Machado, MV; Yang, Y; Diehl, AM
MLA Citation
Machado, MV, Yang, Y, and Diehl, AM. "The benefits of restraint: a pivotal role for IL-13 in hepatic glucose homeostasis." J Clin Invest 123.1 (January 2013): 115-117.
PMID
23257364
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
123
Issue
1
Publish Date
2013
Start Page
115
End Page
117
DOI
10.1172/JCI67238

IL28B rs12979860 is not associated with histologic features of NAFLD in a cohort of Caucasian North American patients

Authors
Garrett, ME; Abdelmalek, MF; Ashley-Koch, A; Hauser, MA; Moylan, CA; Pang, H; Diehl, AM; Tillmann, HL
MLA Citation
Garrett, ME, Abdelmalek, MF, Ashley-Koch, A, Hauser, MA, Moylan, CA, Pang, H, Diehl, AM, and Tillmann, HL. "IL28B rs12979860 is not associated with histologic features of NAFLD in a cohort of Caucasian North American patients." Journal of Hepatology 58.2 (2013): 402-403.
Source
scival
Published In
Journal of Hepatology
Volume
58
Issue
2
Publish Date
2013
Start Page
402
End Page
403
DOI
10.1016/j.jhep.2012.09.035

Hedgehog signalling regulates liver sinusoidal endothelial cell capillarisation

Objective: Vascular remodelling during liver damage involves loss of healthy liver sinusoidal endothelial cell (LSEC) phenotype via capillarisation. Hedgehog (Hh) signalling regulates vascular development and increases during liver injury. This study therefore examined its role in capillarisation. Design: Primary LSEC were cultured for 5 days to induce capillarisation. Pharmacological, antibody-mediated and genetic approaches were used to manipulate Hh signalling. Effects on mRNA and protein expression of Hh-regulated genes and capillarisation markers were evaluated by quantitative reverse transcription PCR and immunoblot. Changes in LSEC function were assessed by migration and tube forming assay, and gain/loss of fenestrae was examined by electron microscopy. Mice with acute or chronic liver injury were treated with Hh inhibitors; effects on capillarisation were assessed by immunohistochemistry. Results: Freshly isolated LSEC expressed Hh ligands, Hh receptors and Hh ligand antagonist Hhip. Capillarisation was accompanied by repression of Hhip and increased expression of Hh-regulated genes. Treatment with Hh agonist further induced expression of Hh ligands and Hh-regulated genes, and upregulated capillarisation-associated genes; whereas Hh signalling antagonist or Hh ligand neutralising antibody each repressed expression of Hh target genes and capillarisation markers. LSEC isolated from SmoloxP/loxP transgenic mice that had been infected with adenovirus expressing Cre-recombinase to delete Smoothened showed over 75% knockdown of Smoothened. During culture, Smoothened-deficient LSEC had inhibited Hh signalling, less induction of capillarisation-associated genes and retention of fenestrae. In mice with injured livers, inhibiting Hh signalling prevented capillarisation. Conclusions: LSEC produce and respond to Hh ligands, and use Hh signalling to regulate complex phenotypic changes that occur during capillarisation.

Authors
Xie, G; Choi, SS; Syn, W-K; Michelotti, GA; Swiderska, M; Karaca, G; Chan, IS; Chen, Y; Diehl, AM
MLA Citation
Xie, G, Choi, SS, Syn, W-K, Michelotti, GA, Swiderska, M, Karaca, G, Chan, IS, Chen, Y, and Diehl, AM. "Hedgehog signalling regulates liver sinusoidal endothelial cell capillarisation." Gut 62.2 (2013): 299-309.
Source
scival
Published In
Gut
Volume
62
Issue
2
Publish Date
2013
Start Page
299
End Page
309
DOI
10.1136/gutjnl-2011-301494

Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis

Background & Aims: Progression from steatosis to steatohepatitic lesions is hypothesized to require a second hit. These lesions have been associated with increased oxidative stress, often ascribed to high levels of leptin and other proinflammatory mediators. Here we have examined the role of leptin in inducing oxidative stress and Kupffer cell activation in CCl4-mediated steatohepatitic lesions of obese mice. Methods: Male C57BL/6 mice fed with a high-fat diet (60% kcal) at 16 weeks were administered CCl4 to induce steatohepatitic lesions. Approaches included use of immuno-spin trapping for measuring free radical stress, gene-deficient mice for leptin, p47 phox, iNOS and adoptive transfer of leptin primed macrophages in vivo. Results: Diet-induced obese (DIO) mice, treated with CCl4 increased serum leptin levels. Oxidative stress was significantly elevated in the DIO mouse liver, but not in ob/ob mice, or in DIO mice treated with leptin antibody. In ob/ob mice, leptin supplementation restored markers of free radical generation. Markers of free radical formation were significantly decreased by the peroxynitrite decomposition catalyst FeTPPS, the iNOS inhibitor 1400W, the NADPH oxidase inhibitor apocynin, or in iNOS or p47 phox-deficient mice. These results correlated with the decreased expression of TNF-alpha and MCP-1. Kupffer cell depletion eliminated oxidative stress and inflammation, whereas in macrophage-depleted mice, the adoptive transfer of leptin-primed macrophages significantly restored inflammation. Conclusions: These results, for the first time, suggest that leptin action in macrophages of the steatotic liver, through induction of iNOS and NADPH oxidase, causes peroxynitrite-mediated oxidative stress thus activating Kupffer cells. © 2012 European Association for the Study of the Liver.

Authors
Chatterjee, S; Ganini, D; Tokar, EJ; Kumar, A; Das, S; Corbett, J; Kadiiska, MB; Waalkes, MP; Diehl, AM; Mason, RP
MLA Citation
Chatterjee, S, Ganini, D, Tokar, EJ, Kumar, A, Das, S, Corbett, J, Kadiiska, MB, Waalkes, MP, Diehl, AM, and Mason, RP. "Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis." Journal of Hepatology (2013).
PMID
23207144
Source
scival
Published In
Journal of Hepatology
Publish Date
2013
DOI
10.1016/j.jhep.2012.11.035

Hedgehog pathway and pediatric nonalcoholic fatty liver disease

It is unclear why the histology of pediatric and adult nonalcoholic fatty liver disease (NAFLD) sometimes differs. In adults, severity of portal inflammation and fibrosis correlate with Hedgehog pathway activity. Hedgehog (Hh) signaling regulates organogenesis, but is silent in adult livers until injury reinduces Hh ligand production. During adolescence, liver development is completed and children's livers normally lose cells that produce and/or respond to Hh ligands. We postulated that fatty liver injury interferes with this process by increasing Hh ligand production, and theorized that hepatic responses to Hh ligands might differ among children according to age, gender, and/or puberty status. Using unstained liver biopsy slides from 56 children with NAFLD, we performed immunohistochemistry to assess Hh pathway activation and correlated the results with clinical information obtained at biopsy. Fibrosis stage generally correlated with Hh pathway activity, as demonstrated by the numbers of Hh-ligand-producing cells (P < 0.0001) and Hh-responsive (glioma-associated oncogene 2-positive [Gli2]) cells (P = 0.0013). The numbers of Gli2(+) cells also correlated with portal inflammation grade (P = 0.0012). Two distinct zonal patterns of Hh-ligand production, portal/periportal versus lobular, were observed. Higher portal/periportal Hh-ligand production was associated with male gender. Male gender and prepuberty were also associated with ductular proliferation (P < 0.05), increased numbers of portal Gli2(+) cells (P < 0.017) and portal fibrosis. Conclusion:: The portal/periportal (progenitor) compartment of prepubescent male livers exhibits high Hh pathway activity. This may explain the unique histologic features of pediatric NAFLD because Hh signaling promotes the fibroductular response. (HEPATOLOGY 2013) Copyright © 2013 American Association for the Study of Liver Diseases.

Authors
Swiderska-Syn, M; Suzuki, A; Guy, CD; Schwimmer, JB; Abdelmalek, MF; Lavine, JE; Diehl, AM
MLA Citation
Swiderska-Syn, M, Suzuki, A, Guy, CD, Schwimmer, JB, Abdelmalek, MF, Lavine, JE, and Diehl, AM. "Hedgehog pathway and pediatric nonalcoholic fatty liver disease." Hepatology 57.5 (2013): 1814-1825.
Source
scival
Published In
Hepatology
Volume
57
Issue
5
Publish Date
2013
Start Page
1814
End Page
1825
DOI
10.1002/hep.26230

Obese Humans With Nonalcoholic Fatty Liver Disease Display Alterations in Fecal Microbiota and Volatile Organic Compounds

Authors
Boursier, J; Rawls, JF; Diehl, AM
MLA Citation
Boursier, J, Rawls, JF, and Diehl, AM. "Obese Humans With Nonalcoholic Fatty Liver Disease Display Alterations in Fecal Microbiota and Volatile Organic Compounds." Clinical Gastroenterology and Hepatology 11.7 (2013): 876-878.
PMID
23628504
Source
scival
Published In
Clinical Gastroenterology and Hepatology
Volume
11
Issue
7
Publish Date
2013
Start Page
876
End Page
878
DOI
10.1016/j.cgh.2013.04.016

Associations of depression, anxiety and antidepressants with histological severity of nonalcoholic fatty liver disease

Background: Depression and anxiety are common in patients with nonalcoholic fatty liver disease (NAFLD). However, their associations with histological severity of NAFLD are unknown. Aim: This study examined the association(s) of depression, anxiety and antidepressant pharmacotherapy with severity of histological features in patients with NAFLD. Methods: We analysed 567 patients with biopsy-proven NAFLD enrolled in the Duke NAFLD Clinical Database. Depressive and anxiety symptoms were assessed using the Hospital Anxiety & Depression Scale (HADS). The associations of depression and anxiety with severity of histological features of NAFLD were analysed using multiple logistic (or ordinal logistic) regression models with and without adjusting for confounding factors. Result: Subclinical and clinical depression was noted in 53% and 14% of patients respectively. Subclinical and clinical anxiety was noted in 45% and 25% of patients respectively. After adjusting for confounders, depression was significantly associated with more severe hepatocyte ballooning in a dose-dependent manner (likelihood ratio test, P = 0.0201); adjusted cumulative odds ratio (COR) of subclinical and clinical depression for having a higher grade of hepatocyte ballooning were 2.1 [95% CI, 1.0, 4.4] and 3.6 [95% CI, 1.4, 8.8]. Conclusions: In patients with NAFLD, depression was associated with more severe hepatocyte ballooning. Further investigation exploring pathobiological mechanisms underlying the observed associations and potential effects of antidepressant pharmacotherapy on NAFLD liver histology is warranted. © 2013 John Wiley & Sons A/S.

Authors
Youssef, NA; Abdelmalek, MF; Binks, M; Guy, CD; Omenetti, A; Smith, AD; Diehl, AME; Suzuki, A
MLA Citation
Youssef, NA, Abdelmalek, MF, Binks, M, Guy, CD, Omenetti, A, Smith, AD, Diehl, AME, and Suzuki, A. "Associations of depression, anxiety and antidepressants with histological severity of nonalcoholic fatty liver disease." Liver International 33.7 (2013): 1062-1070.
Source
scival
Published In
Liver International
Volume
33
Issue
7
Publish Date
2013
Start Page
1062
End Page
1070
DOI
10.1111/liv.12165

Potential role of Hedgehog signaling and microRNA-29 in liver fibrosis of IKKβ-deficient mouse

Recent studies have reported that NF-κB mediated down-regulation of miRNA-29 and lower expression of miRNA-29 promoted the deposition of collagens in fibrotic liver. Our previous research demonstrated that the increased Hedgehog (Hh) signaling, a key regulator for hepatic fibrogenesis, induced the severe hepatic fibrosis in the livers with impaired NF-κB signaling. These findings led us to investigate the effect of Hh and miRNA-29 on the hepatic fibrosis under dysregulated NF-κB signaling. In this study, we used IKKβF/F and IKKβ-deficient IKKβΔHEP mouse model with a defective NF-κB signaling pathway, and assessed the expression of the miRNA-29 family (miRNA-29a, miRNA-29b, and miRNA-29c), Hh, and proliferation of MF-HSCs in liver from IKKβF/F mice and IKKβΔHEP mice both before and after MCDE treatment. The activation of NF-κB was significantly increased in MCDE diet-fed IKKβF/F mice compared to IKKβΔHEP mice. Expression of miRNA-29 family was greater in MCDE diet-fed IKKβΔHEP mice than IKKβF/F mice, demonstrating that the impaired NF-κB pathway was unable to suppress the expression of miRNA-29s after injury. However, expression of the Hh signaling pathway was greatly enhanced, and activation of Hh promoted the accumulation of MF-HSCs with impaired NF-κB, eventually increasing fibrogenesis in the damaged liver of IKKβΔHEP mice. Therefore, these results demonstrated that Hh signaling regulates the proliferation of MF-HSCs irrespective of the action of miRNA-29, eventually contributing hepatic fibrosis, when the NF-κB pathway is disrupted. © 2013 Springer Science+Business Media Dordrecht.

Authors
Hyun, J; Choi, SS; Diehl, AM; Jung, Y
MLA Citation
Hyun, J, Choi, SS, Diehl, AM, and Jung, Y. "Potential role of Hedgehog signaling and microRNA-29 in liver fibrosis of IKKβ-deficient mouse." Journal of Molecular Histology (2013): 1-10.
PMID
23949847
Source
scival
Published In
Journal of Molecular Histology
Publish Date
2013
Start Page
1
End Page
10
DOI
10.1007/s10735-013-9532-5

Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis

Background & Aims: Progression from steatosis to steatohepatitic lesions is hypothesized to require a second hit. These lesions have been associated with increased oxidative stress, often ascribed to high levels of leptin and other proinflammatory mediators. Here we have examined the role of leptin in inducing oxidative stress and Kupffer cell activation in CCl 4-mediated steatohepatitic lesions of obese mice. Methods: Male C57BL/6 mice fed with a high-fat diet (60% kcal) at 16 weeks were administered CCl4 to induce steatohepatitic lesions. Approaches included use of immuno-spin trapping for measuring free radical stress, gene-deficient mice for leptin, p47 phox, iNOS and adoptive transfer of leptin primed macrophages in vivo. Results: Diet-induced obese (DIO) mice, treated with CCl4 increased serum leptin levels. Oxidative stress was significantly elevated in the DIO mouse liver, but not in ob/ob mice, or in DIO mice treated with leptin antibody. In ob/ob mice, leptin supplementation restored markers of free radical generation. Markers of free radical formation were significantly decreased by the peroxynitrite decomposition catalyst FeTPPS, the iNOS inhibitor 1400W, the NADPH oxidase inhibitor apocynin, or in iNOS or p47 phox-deficient mice. These results correlated with the decreased expression of TNF-alpha and MCP-1. Kupffer cell depletion eliminated oxidative stress and inflammation, whereas in macrophage-depleted mice, the adoptive transfer of leptin-primed macrophages significantly restored inflammation. Conclusions: These results, for the first time, suggest that leptin action in macrophages of the steatotic liver, through induction of iNOS and NADPH oxidase, causes peroxynitrite-mediated oxidative stress thus activating Kupffer cells. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Authors
Chatterjee, S; Ganini, D; Tokar, EJ; Kumar, A; Das, S; Corbett, J; Kadiiska, MB; Waalkes, MP; Diehl, AM; Mason, RP
MLA Citation
Chatterjee, S, Ganini, D, Tokar, EJ, Kumar, A, Das, S, Corbett, J, Kadiiska, MB, Waalkes, MP, Diehl, AM, and Mason, RP. "Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis." Journal of Hepatology 58.4 (2013): 778-784.
Source
scival
Published In
Journal of Hepatology
Volume
58
Issue
4
Publish Date
2013
Start Page
778
End Page
784
DOI
10.1016/j.jhep.2012.11.035

STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib

There have been major advances in defining the immunological events associated with fibrosis in various chronic liver diseases. We have taken advantage of this data to focus on the mechanisms of action of a unique multi-kinase inhibitor, coined sorafenib, on CCl4-induced murine liver fibrosis, including the effects of this agent in models of both acute and chronic CCl4-mediated pathology. Importantly, sorafenib significantly attenuated chronic liver injury and fibrosis, including reduction in liver inflammation and histopathology as well as decreased expression of liver fibrosis-related genes, including α-smooth muscle actin, collagen, matrix metalloproteinases and the tissue inhibitor of metalloproteinase-1. Furthermore, sorafenib treatment resulted in translocation of cytoplasmic STAT3 to the nucleus in its active form. Based on this observation, we used hepatocyte-specific STAT3 knockout (STAT3Hep-/-) mice to demonstrate that hepatic STAT3 was critical for sorafenib-mediated protection against liver fibrosis, and that the upregulation of STAT3 phosphorylation was dependent on Kupffer cell-derived IL-6. In conclusion, these data reflect the clinical potential of the multi-kinase inhibitor sorafenib for the prevention of fibrosis as well as the treatment of established liver fibrosis and illustrate the immunological mechanisms that underlie the protective effects of sorafenib. © 2013 Elsevier Ltd. All rights reserved.

Authors
Deng, Y-R; Ma, H-D; Tsuneyama, K; Yang, W; Wang, Y-H; Lu, F-T; Liu, C-H; Liu, P; He, X-S; Diehl, AM; al, E
MLA Citation
Deng, Y-R, Ma, H-D, Tsuneyama, K, Yang, W, Wang, Y-H, Lu, F-T, Liu, C-H, Liu, P, He, X-S, Diehl, AM, and al, E. "STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib." Journal of Autoimmunity (2013).
PMID
23948302
Source
scival
Published In
Journal of Autoimmunity
Publish Date
2013
DOI
10.1016/j.jaut.2013.07.008

Paracrine Hedgehog signaling drives metabolic changes in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) typically develops in cirrhosis, a condition characterized by Hedgehog (Hh) pathway activation and accumulation of Hh-responsive myofibroblasts. Although Hh signaling generally regulates stromal-epithelial interactions that support epithelial viability, the role of Hh-dependent myofibroblasts in hepatocarcinogenesis is unknown. Here, we used human HCC samples, a mouse HCC model, and hepatoma cell/myofibroblast cocultures to examine the hypothesis that Hh signaling modulates myofibroblasts' metabolism to generate fuels for neighboring malignant hepatocytes. The results identify a novel paracrine mechanism whereby malignant hepatocytes produce Hh ligands to stimulate glycolysis in neighboring myofibroblasts, resulting in release of myofibroblast-derived lactate that the malignant hepatocytes use as an energy source. This discovery reveals new diagnostic and therapeutic targets that might be exploited to improve the outcomes of cirrhotic patients with HCCs.

Authors
Chan, IS; Guy, CD; Chen, Y; Lu, J; Swiderska-Syn, M; Michelotti, GA; Karaca, G; Xie, G; Krüger, L; Syn, W-K; Anderson, BR; Pereira, TA; Choi, SS; Baldwin, AS; Diehl, AM
MLA Citation
Chan, IS, Guy, CD, Chen, Y, Lu, J, Swiderska-Syn, M, Michelotti, GA, Karaca, G, Xie, G, Krüger, L, Syn, W-K, Anderson, BR, Pereira, TA, Choi, SS, Baldwin, AS, and Diehl, AM. "Paracrine Hedgehog signaling drives metabolic changes in hepatocellular carcinoma." Cancer Res 72.24 (December 15, 2012): 6344-6350.
PMID
23066040
Source
pubmed
Published In
Cancer Research
Volume
72
Issue
24
Publish Date
2012
Start Page
6344
End Page
6350
DOI
10.1158/0008-5472.CAN-12-1068

Hedgehog controls hepatic stellate cell fate by regulating metabolism.

BACKGROUND & AIMS: The pathogenesis of cirrhosis, a disabling outcome of defective liver repair, involves deregulated accumulation of myofibroblasts derived from quiescent hepatic stellate cells (HSCs), but the mechanisms that control transdifferentiation of HSCs are poorly understood. We investigated whether the Hedgehog (Hh) pathway controls the fate of HSCs by regulating metabolism. METHODS: Microarray, quantitative polymerase chain reaction, and immunoblot analyses were used to identify metabolic genes that were differentially expressed in quiescent vs myofibroblast HSCs. Glycolysis and lactate production were disrupted in HSCs to determine if metabolism influenced transdifferentiation. Hh signaling and hypoxia-inducible factor 1α (HIF1α) activity were altered to identify factors that alter glycolytic activity. Changes in expression of genes that regulate glycolysis were quantified and localized in biopsy samples from patients with cirrhosis and liver samples from mice following administration of CCl(4) or bile duct ligation. Mice were given systemic inhibitors of Hh to determine if they affect glycolytic activity of the hepatic stroma; Hh signaling was also conditionally disrupted in myofibroblasts to determine the effects of glycolytic activity. RESULTS: Transdifferentiation of cultured, quiescent HSCs into myofibroblasts induced glycolysis and caused lactate accumulation. Increased expression of genes that regulate glycolysis required Hh signaling and involved induction of HIF1α. Inhibitors of Hh signaling, HIF1α, glycolysis, or lactate accumulation converted myofibroblasts to quiescent HSCs. In diseased livers of animals and patients, numbers of glycolytic stromal cells were associated with the severity of fibrosis. Conditional disruption of Hh signaling in myofibroblasts reduced numbers of glycolytic myofibroblasts and liver fibrosis in mice; similar effects were observed following administration of pharmacologic inhibitors of Hh. CONCLUSIONS: Hedgehog signaling controls the fate of HSCs by regulating metabolism. These findings might be applied to diagnosis and treatment of patients with cirrhosis.

Authors
Chen, Y; Choi, SS; Michelotti, GA; Chan, IS; Swiderska-Syn, M; Karaca, GF; Xie, G; Moylan, CA; Garibaldi, F; Premont, R; Suliman, HB; Piantadosi, CA; Diehl, AM
MLA Citation
Chen, Y, Choi, SS, Michelotti, GA, Chan, IS, Swiderska-Syn, M, Karaca, GF, Xie, G, Moylan, CA, Garibaldi, F, Premont, R, Suliman, HB, Piantadosi, CA, and Diehl, AM. "Hedgehog controls hepatic stellate cell fate by regulating metabolism." Gastroenterology 143.5 (November 2012): 1319-29.e1-11-.
PMID
22885334
Source
pubmed
Published In
Gastroenterology
Volume
143
Issue
5
Publish Date
2012
Start Page
1319-29.e1-11
DOI
10.1053/j.gastro.2012.07.115

The Association of Serum Thyroid Hormone Levels and Hepatic Gene Expression of Potential Regulators of Intracellular Thyroid Hormone Concentration with Severity of Nonalcoholic Fatty Liver Disease

Authors
Bohinc, B; Suzuki, A; Guy, C; Pang, H; Piercy, D; Feinglos, M; Yen, P; Diehl, AM; Abdelmalek, M
MLA Citation
Bohinc, B, Suzuki, A, Guy, C, Pang, H, Piercy, D, Feinglos, M, Yen, P, Diehl, AM, and Abdelmalek, M. "The Association of Serum Thyroid Hormone Levels and Hepatic Gene Expression of Potential Regulators of Intracellular Thyroid Hormone Concentration with Severity of Nonalcoholic Fatty Liver Disease." AMERICAN JOURNAL OF GASTROENTEROLOGY 107 (October 2012): S193-S193.
Source
wos-lite
Published In
The American Journal of Gastroenterology (Elsevier)
Volume
107
Publish Date
2012
Start Page
S193
End Page
S193

Expression QTL analysis of a gene expression signature which predicts advanced non-alcoholic fatty liver disease

Authors
Garrett, ME; Moylan, CA; Gibson, J; Yang, H; Pang, H; Dellinger, A; Suzuki, A; Tillmann, HL; Guy, CD; Abdelmalek, MF; Murphy, SK; Diehl, AM; Hauser, M; Ashley-Koch, AE
MLA Citation
Garrett, ME, Moylan, CA, Gibson, J, Yang, H, Pang, H, Dellinger, A, Suzuki, A, Tillmann, HL, Guy, CD, Abdelmalek, MF, Murphy, SK, Diehl, AM, Hauser, M, and Ashley-Koch, AE. "Expression QTL analysis of a gene expression signature which predicts advanced non-alcoholic fatty liver disease." October 2012.
Source
wos-lite
Published In
Hepatology
Volume
56
Publish Date
2012
Start Page
267A
End Page
268A

Gender and Menopause Impact Severity of Fibrosis among Patients with Nonalcoholic Steatohepatitis

Authors
Suzuki, A; Pang, H; Guy, CD; Smith, AD; Diehl, AM; Abdelmalek, MF
MLA Citation
Suzuki, A, Pang, H, Guy, CD, Smith, AD, Diehl, AM, and Abdelmalek, MF. "Gender and Menopause Impact Severity of Fibrosis among Patients with Nonalcoholic Steatohepatitis." October 2012.
PMID
24123276
Source
wos-lite
Published In
Hepatology
Volume
56
Publish Date
2012
Start Page
888A
End Page
889A

Impact of Gender and Menopause on Histologic Severity of Inflammation and Injury in patients with Nonalcoholic Fatty Liver Disease

Authors
Suzuki, A; Guy, CD; Pang, H; Smith, AD; Diehl, AM; Abdelmalek, MF
MLA Citation
Suzuki, A, Guy, CD, Pang, H, Smith, AD, Diehl, AM, and Abdelmalek, MF. "Impact of Gender and Menopause on Histologic Severity of Inflammation and Injury in patients with Nonalcoholic Fatty Liver Disease." October 2012.
Source
wos-lite
Published In
Hepatology
Volume
56
Publish Date
2012
Start Page
901A
End Page
901A

Activation Of Hedgehog Pathway In Schistosomiasis Mansoni And Its Relationship With Liver Fibrosis

Authors
Pereira, TA; Gurgel, CA; Schlaepfer-Sales, CB; Voieta, I; Antunes, CM; Andrade, ZA; Pereira, FE; Diehl, AM; Lambertucci, JR
MLA Citation
Pereira, TA, Gurgel, CA, Schlaepfer-Sales, CB, Voieta, I, Antunes, CM, Andrade, ZA, Pereira, FE, Diehl, AM, and Lambertucci, JR. "Activation Of Hedgehog Pathway In Schistosomiasis Mansoni And Its Relationship With Liver Fibrosis." October 2012.
Source
wos-lite
Published In
Hepatology
Volume
56
Publish Date
2012
Start Page
813A
End Page
814A

Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines.

BACKGROUND: Crosstalk between malignant hepatocytes and the surrounding peritumoral stroma is a key modulator of hepatocarcinogenesis and therapeutic resistance. To examine the chemotherapy resistance of these two cellular compartments in vitro, we evaluated a well-established hepatic tumor cell line, HepG2, and an adult hepatic stellate cell line, LX2. The aim was to compare the chemosensitization potential of arsenic trioxide (ATO) in combination with sorafenib or fluorouracil (5-FU), in both hepatic tumor cells and stromal cells. METHODS: Cytotoxicity of ATO, 5-FU, and sorafenib, alone and in combination against HepG2 cells and LX2 cells was measured by an automated high throughput cell-based proliferation assay. Changes in survival and apoptotic signaling pathways were analyzed by flow cytometry and western blot. Gene expression of the 5-FU metabolic enzyme, thymidylate synthase, was analyzed by real time PCR. RESULTS: Both HepG2 and LX2 cell lines were susceptible to single agent sorafenib and ATO at 24 hr (ATO IC(50): 5.3 μM in LX2; 32.7 μM in HepG2; Sorafenib IC(50): 11.8 μM in LX2; 9.9 μM in HepG2). In contrast, 5-FU cytotoxicity required higher concentrations and prolonged (48-72 hr) drug exposure. Concurrent ATO and 5-FU treatment of HepG2 cells was synergistic, leading to increased cytotoxicity due in part to modulation of thymidylate synthase levels by ATO. Concurrent ATO and sorafenib treatment showed a trend towards increased HepG2 cytotoxicity, possibly due to a significant decrease in MAPK activation in comparison to treatment with ATO alone. CONCLUSIONS: ATO differentially sensitizes hepatic tumor cells and adult hepatic stellate cells to 5-FU and sorafenib. Given the importance of both of these cell types in hepatocarcinogenesis, these data have implications for the rational development of anti-cancer therapy combinations for the treatment of hepatocellular carcinoma (HCC).

Authors
Rangwala, F; Williams, KP; Smith, GR; Thomas, Z; Allensworth, JL; Lyerly, HK; Diehl, AM; Morse, MA; Devi, GR
MLA Citation
Rangwala, F, Williams, KP, Smith, GR, Thomas, Z, Allensworth, JL, Lyerly, HK, Diehl, AM, Morse, MA, and Devi, GR. "Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines. (Published online)" BMC Cancer 12 (September 10, 2012): 402-.
PMID
22963400
Source
pubmed
Published In
BMC Cancer
Volume
12
Publish Date
2012
Start Page
402
DOI
10.1186/1471-2407-12-402

NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease.

OBJECTIVE: Immune responses are important in dictating non-alcoholic steatohepatitis (NASH) outcome. We previously reported that upregulation of hedgehog (Hh) and osteopontin (OPN) occurs in NASH, that Hh-regulated accumulation of natural killer T (NKT) cells promotes hepatic stellate cell (HSC) activation, and that cirrhotic livers harbour large numbers of NKT cells. DESIGN: The hypothesis that activated NKT cells drive fibrogenesis during NASH was evaluated by assessing if NKT depletion protects against NASH fibrosis; identifying the NKT-associated fibrogenic factors; and correlating plasma levels of the NKT cell-associated factor OPN with fibrosis severity in mice and humans. RESULTS: When fed methionine-choline-deficient (MCD) diets for 8 weeks, wild type (WT) mice exhibited Hh pathway activation, enhanced OPN expression, and NASH-fibrosis. Ja18-/- and CD1d-/- mice which lack NKT cells had significantly attenuated Hh and OPN expression and dramatically less fibrosis. Liver mononuclear cells (LMNCs) from MCD diet fed WT mice contained activated NKT cells, generated Hh and OPN, and stimulated HSCs to become myofibroblasts; neutralising these factors abrogated the fibrogenic actions of WT LMNCs. LMNCs from NKT-cell-deficient mice were deficient in fibrogenic factors, failing to activate collagen gene expression in HSCs. Human NASH livers with advanced fibrosis contained more OPN and Hh protein than those with early fibrosis. Plasma levels of OPN mirrored hepatic OPN expression and correlated with fibrosis severity. CONCLUSION: Hepatic NKT cells drive production of OPN and Hh ligands that promote fibrogenesis during NASH. Associated increases in plasma levels of OPN may provide a biomarker of NASH fibrosis.

Authors
Syn, W-K; Agboola, KM; Swiderska, M; Michelotti, GA; Liaskou, E; Pang, H; Xie, G; Philips, G; Chan, IS; Karaca, GF; Pereira, TDA; Chen, Y; Mi, Z; Kuo, PC; Choi, SS; Guy, CD; Abdelmalek, MF; Diehl, AM
MLA Citation
Syn, W-K, Agboola, KM, Swiderska, M, Michelotti, GA, Liaskou, E, Pang, H, Xie, G, Philips, G, Chan, IS, Karaca, GF, Pereira, TDA, Chen, Y, Mi, Z, Kuo, PC, Choi, SS, Guy, CD, Abdelmalek, MF, and Diehl, AM. "NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease." Gut 61.9 (September 2012): 1323-1329.
PMID
22427237
Source
pubmed
Published In
Gut
Volume
61
Issue
9
Publish Date
2012
Start Page
1323
End Page
1329
DOI
10.1136/gutjnl-2011-301857

Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes.

UNLABELLED: Fructose consumption predicts increased hepatic fibrosis in those with nonalcoholic fatty liver disease (NAFLD). Because of its ability to lower hepatic adenosine triphosphate (ATP) levels, habitual fructose consumption could result in more hepatic ATP depletion and impaired ATP recovery. The degree of ATP depletion after an intravenous (IV) fructose challenge test in low- versus high-fructose consumers was assessed. We evaluated diabetic adults enrolled in the Action for Health in Diabetes Fatty Liver Ancillary Study (n = 244) for whom dietary fructose consumption estimated by a 130-item food frequency questionnaire and hepatic ATP measured by phosphorus magnetic resonance spectroscopy and uric acid (UA) levels were performed (n = 105). In a subset of participants (n = 25), an IV fructose challenge was utilized to assess change in hepatic ATP content. The relationships between dietary fructose, UA, and hepatic ATP depletion at baseline and after IV fructose challenge were evaluated in low- (<15 g/day) versus high-fructose (≥ 15 g/day) consumers. High dietary fructose consumers had slightly lower baseline hepatic ATP levels and a greater absolute change in hepatic α-ATP/ inorganic phosphate (Pi) ratio (0.08 versus 0.03; P = 0.05) and γ-ATP /Pi ratio after an IV fructose challenge (0.03 versus 0.06; P = 0.06). Patients with high UA (≥ 5.5 mg/dL) showed a lower minimum liver ATP/Pi ratio postfructose challenge (4.5 versus 7.0; P = 0.04). CONCLUSIONS: High-fructose consumption depletes hepatic ATP and impairs recovery from ATP depletion after an IV fructose challenge. Subjects with high UA show a greater nadir in hepatic ATP in response to fructose. Both high dietary fructose intake and elevated UA level may predict more severe hepatic ATP depletion in response to fructose and hence may be risk factors for the development and progression of NAFLD.

Authors
Abdelmalek, MF; Lazo, M; Horska, A; Bonekamp, S; Lipkin, EW; Balasubramanyam, A; Bantle, JP; Johnson, RJ; Diehl, AM; Clark, JM; Fatty Liver Subgroup of Look AHEAD Research Group,
MLA Citation
Abdelmalek, MF, Lazo, M, Horska, A, Bonekamp, S, Lipkin, EW, Balasubramanyam, A, Bantle, JP, Johnson, RJ, Diehl, AM, Clark, JM, and Fatty Liver Subgroup of Look AHEAD Research Group, . "Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes." Hepatology 56.3 (September 2012): 952-960.
PMID
22467259
Source
pubmed
Published In
Hepatology
Volume
56
Issue
3
Publish Date
2012
Start Page
952
End Page
960
DOI
10.1002/hep.25741

Mechanisms of disease progression in NASH: new paradigms.

The incidence of nonalcoholic fatty liver disease is increasing at an astonishing rate in the US population. Although only a small proportion of these patients develop steatohepatitis (NASH), those who do have a greater likelihood of developing end-stage liver disease and complications. Research on liver fibrosis and NASH progression shows that hedgehog (Hh) is reactivated after liver injury to assist in liver repair and regeneration. When the process of tissue repair and regeneration is prolonged or when Hh ligand and related genes are aberrantly regulated and excessive, tissue repair goes awry and NASH progresses to cirrhosis and hepatocellular carcinoma.

Authors
Bohinc, BN; Diehl, AM
MLA Citation
Bohinc, BN, and Diehl, AM. "Mechanisms of disease progression in NASH: new paradigms." Clin Liver Dis 16.3 (August 2012): 549-565. (Review)
PMID
22824480
Source
pubmed
Published In
Clinics in Liver Disease
Volume
16
Issue
3
Publish Date
2012
Start Page
549
End Page
565
DOI
10.1016/j.cld.2012.05.002

Association between puberty and features of nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Physiological changes that occur during puberty might affect pathologic features of nonalcoholic fatty liver disease (NAFLD). We investigated associations between pubertal development and clinical and histopathologic features of NAFLD. METHODS: We studied 186 children (age <18 years, 143 boys) with biopsy-proven NAFLD. The population was divided into 3 groups on the basis of Tanner stage (prepuberty, puberty, and postpuberty). Clinical characteristics and histologic features were compared among groups. Multivariable regression models were used to adjust for potential confounders. RESULTS: After adjusting for other factors, hyperuricemia and low levels of high-density-lipoprotein cholesterol were more prevalent among children who entered puberty with lower levels of quantitative insulin sensitivity check index (P < .05). The degree of steatosis, numbers of Mallory-Denk bodies, and diagnostic categories of NAFLD differed among groups (P < .05). There were potential sex differences in associations between stages of puberty and lobular inflammation, hepatocyte ballooning, and borderline steatohepatitis of zone 3; these were therefore not included in multivariable analyses of the overall population. After adjustment for different sets of confounders, patients at or beyond puberty were less likely to have high-grade steatosis, severe portal inflammation, borderline steatohepatitis (zone 1), or a high stage of fibrosis than patients who had not entered puberty (P < .05). On the contrary, the prevalence of Mallory-Denk body was greater among postpuberty subjects (P = .06). CONCLUSIONS: Steatosis, portal inflammation, and fibrosis are less severe during or after puberty than before puberty among subjects with NAFLD. Postpubescent individuals have a lower prevalence of borderline steatohepatitis of zone 1 but are more likely to have Mallory-Denk bodies. These findings indicate that puberty affects the pathologic features of NAFLD.

Authors
Suzuki, A; Abdelmalek, MF; Schwimmer, JB; Lavine, JE; Scheimann, AO; Unalp-Arida, A; Yates, KP; Sanyal, AJ; Guy, CD; Diehl, AM; Nonalcoholic Steatohepatitis Clinical Research Network,
MLA Citation
Suzuki, A, Abdelmalek, MF, Schwimmer, JB, Lavine, JE, Scheimann, AO, Unalp-Arida, A, Yates, KP, Sanyal, AJ, Guy, CD, Diehl, AM, and Nonalcoholic Steatohepatitis Clinical Research Network, . "Association between puberty and features of nonalcoholic fatty liver disease." Clin Gastroenterol Hepatol 10.7 (July 2012): 786-794.
PMID
22343513
Source
pubmed
Published In
Clinical Gastroenterology and Hepatology
Volume
10
Issue
7
Publish Date
2012
Start Page
786
End Page
794
DOI
10.1016/j.cgh.2012.01.020

OSTEOPONTIN PROMOTES NATURAL KILLER T (NKT) CELL ACCUMULATION IN NONALCOHOLIC STEATOHEPATITIS (NASH)

Authors
Liaskou, E; Claridge, LC; Younis, R; Shah, H; Shaw, J; Oo, YH; Mi, Z; Kuo, PC; Canbay, A; Adams, DH; Diehl, AM; Syn, WK
MLA Citation
Liaskou, E, Claridge, LC, Younis, R, Shah, H, Shaw, J, Oo, YH, Mi, Z, Kuo, PC, Canbay, A, Adams, DH, Diehl, AM, and Syn, WK. "OSTEOPONTIN PROMOTES NATURAL KILLER T (NKT) CELL ACCUMULATION IN NONALCOHOLIC STEATOHEPATITIS (NASH)." GUT 61 (July 2012): A122-A122.
Source
wos-lite
Published In
Gut
Volume
61
Publish Date
2012
Start Page
A122
End Page
A122
DOI
10.1136/gutjnl-2012-302514b.121

Costaining for keratins 8/18 plus ubiquitin improves detection of hepatocyte injury in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease is a global health dilemma. The gold standard for diagnosis is liver biopsy. Ballooned hepatocytes are histologic manifestations of hepatocellular injury and are characteristic of steatohepatitis, the more severe form of nonalcoholic fatty liver disease. Definitive histologic identification of ballooned hepatocytes on routine stains, however, can be difficult. Immunohistochemical evidence for loss of the normal hepatocytic keratin 8/18 can serve as an objective marker of ballooned hepatocytes. We sought to explore the utility of a keratin 8/18 plus ubiquitin double immunohistochemical stain for the histologic evaluation of adult nonalcoholic fatty liver disease. Double immunohistochemical staining for keratin 8/18 and ubiquitin was analyzed using 40 adult human nonalcoholic fatty liver disease core liver biopsies. Ballooned hepatocytes lack keratin 8/18 staining as previously shown by others, but normal-size hepatocytes with keratin loss are approximately 5 times greater in number than keratin-negative ballooned hepatocytes. Keratin-negative ballooned hepatocytes, normal-size hepatocytes with keratin loss, and ubiquitin deposits show a zonal distribution, are positively associated with each other, and are frequently found adjacent to or intermixed with fibrous matrix. All 3 lesions correlate with fibrosis stage and the hematoxylin and eosin diagnosis of steatohepatitis (all P < .05). Compared with hematoxylin and eosin staining, immunohistochemical staining improves the receiver operating characteristics curve for advanced fibrosis (0.77 versus 0.83, 0.89, and 0.89 for keratin-negative ballooned hepatocytes, normal-size hepatocytes with keratin loss, and ubiquitin, respectively) because immunohistochemistry is more sensitive and specific for fibrogenic hepatocellular injury than hematoxylin and eosin staining. Keratin 8/18 plus ubiquitin double immunohistochemical stain improves detection of hepatocyte injury in nonalcoholic fatty liver disease. Thus, it may help differentiate nonalcoholic steatohepatitis from nonalcoholic fatty liver.

Authors
Guy, CD; Suzuki, A; Burchette, JL; Brunt, EM; Abdelmalek, MF; Cardona, D; McCall, SJ; Ünalp, A; Belt, P; Ferrell, LD; Diehl, AM; Nonalcoholic Steatohepatitis Clinical Research Network,
MLA Citation
Guy, CD, Suzuki, A, Burchette, JL, Brunt, EM, Abdelmalek, MF, Cardona, D, McCall, SJ, Ünalp, A, Belt, P, Ferrell, LD, Diehl, AM, and Nonalcoholic Steatohepatitis Clinical Research Network, . "Costaining for keratins 8/18 plus ubiquitin improves detection of hepatocyte injury in nonalcoholic fatty liver disease." Hum Pathol 43.6 (June 2012): 790-800.
PMID
22036053
Source
pubmed
Published In
Human Pathology
Volume
43
Issue
6
Publish Date
2012
Start Page
790
End Page
800
DOI
10.1016/j.humpath.2011.07.007

Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease.

UNLABELLED: The Hedgehog (HH)-signaling pathway mediates several processes that are deregulated in patients with metabolic syndrome (e.g., fat mass regulation, vascular/endothelial remodeling, liver injury and repair, and carcinogenesis). The severity of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome generally correlate. Therefore, we hypothesized that the level of HH-pathway activation would increase in parallel with the severity of liver damage in NAFLD. To assess potential correlations between known histologic and clinical predictors of advanced liver disease and HH-pathway activation, immunohistochemistry was performed on liver biopsies from a large, well-characterized cohort of NAFLD patients (n = 90) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Database 1 study. Increased HH activity (evidenced by accumulation of HH-ligand-producing cells and HH-responsive target cells) strongly correlated with portal inflammation, ballooning, and fibrosis stage (each P < 0.0001), supporting a relationship between HH-pathway activation and liver damage. Pathway activity also correlated significantly with markers of liver repair, including numbers of hepatic progenitors and myofibroblastic cells (both P < 0.03). In addition, various clinical parameters that have been linked to histologically advanced NAFLD, including increased patient age (P < 0.005), body mass index (P < 0.002), waist circumference (P < 0.0007), homeostatic model assessment of insulin resistance (P < 0.0001), and hypertension (P < 0.02), correlated with hepatic HH activity. CONCLUSION: In NAFLD patients, the level of hepatic HH-pathway activity is highly correlated with the severity of liver damage and with metabolic syndrome parameters that are known to be predictive of advanced liver disease. Hence, deregulation of the HH-signaling network may contribute to the pathogenesis and sequelae of liver damage that develops with metabolic syndrome.

Authors
Guy, CD; Suzuki, A; Zdanowicz, M; Abdelmalek, MF; Burchette, J; Unalp, A; Diehl, AM; NASH CRN,
MLA Citation
Guy, CD, Suzuki, A, Zdanowicz, M, Abdelmalek, MF, Burchette, J, Unalp, A, Diehl, AM, and NASH CRN, . "Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease." Hepatology 55.6 (June 2012): 1711-1721.
PMID
22213086
Source
pubmed
Published In
Hepatology
Volume
55
Issue
6
Publish Date
2012
Start Page
1711
End Page
1721
DOI
10.1002/hep.25559

Diabetes and the Liver

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the western world. The syndrome encompasses a spectrum of histopathological changes in the liver ranging from benign fatty infiltration (steatosis) to steatosis with inflammation with or without necrosis (steatohepatitis) to cirrhosis. NAFLD is strongly associated with type 2 diabetes. The complex interaction of insulin resistance, inflammatory cytokines and fibrogenic factors lead to development and progression of NALFD. There is no one diagnostic test for NAFLD. Fatty liver disease is usually diagnosed during evaluation for elevation in liver tests or in the setting of radiological evidence of excess fat deposition in the liver. Liver biopsy is the current gold standard for the diagnosis of fatty liver disease. It also provides an assessment of the extent and severity of hepatocellular injury and fibrosis. There is no established treatment for NAFLD. Targeted therapy antagonizes the mechanisms central to the development of obesity, insulin resistance, intrahepatic oxidative stress and inflammation. The diversity of available treatment modalities (lifestyle modification, medication, surgical intervention) reflects the complex pathogenesis of the disease. © 2012 John Wiley & Sons, Ltd..

Authors
Jones, L; Diehl, AM
MLA Citation
Jones, L, and Diehl, AM. "Diabetes and the Liver." (April 19, 2012): 67-82. (Chapter)
Source
scopus
Publish Date
2012
Start Page
67
End Page
82
DOI
10.1002/9781118405550.ch3

STATINS INDUCE SENESCENCE OF ACTIVATED HSC BY INHIBITION OF THE HEDGEHOG PATHWAY

Authors
Klein, S; Granzow, M; Schierwagen, R; Van der Ven, P; Raskopf, E; Pieper-Fuerst, U; Fuerst, D; Lammert, F; Choi, S; Diehl, AM; Shah, V; Sauerbruch, T; Trebicka, J
MLA Citation
Klein, S, Granzow, M, Schierwagen, R, Van der Ven, P, Raskopf, E, Pieper-Fuerst, U, Fuerst, D, Lammert, F, Choi, S, Diehl, AM, Shah, V, Sauerbruch, T, and Trebicka, J. "STATINS INDUCE SENESCENCE OF ACTIVATED HSC BY INHIBITION OF THE HEDGEHOG PATHWAY." April 2012.
Source
wos-lite
Published In
Journal of Hepatology
Volume
56
Publish Date
2012
Start Page
S152
End Page
S152

Genotype-based hierarchical clustering reveals a panel of polymorphisms in one carbon metabolism that are associated with obesity

Authors
Corbin, KD; Spencer, MD; da Costa, K-A; Sha, W; Abdelmalek, MF; Pan, Y; Suzuki, A; Guy, CD; Cardona, DM; Torquati, A; Diehl, AM; Zeisel, SH
MLA Citation
Corbin, KD, Spencer, MD, da Costa, K-A, Sha, W, Abdelmalek, MF, Pan, Y, Suzuki, A, Guy, CD, Cardona, DM, Torquati, A, Diehl, AM, and Zeisel, SH. "Genotype-based hierarchical clustering reveals a panel of polymorphisms in one carbon metabolism that are associated with obesity." April 2012.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
26
Publish Date
2012

Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis: A pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study

The PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis [NASH]) trial demonstrated that pioglitazone and vitamin E improved liver histology to varying degrees, but the mechanisms are unknown. We conducted a study to examine the changes in adipose tissue insulin resistance (Adipo-IR) during the PIVENS trial and its relationship to histological endpoints. Adipo-IR (fasting nonesterified fatty acids [NEFAs] × fasting insulin) was calculated at baseline and after 16 and 96 weeks of therapy. Compared to placebo, the baseline Adipo-IR was not different in either the vitamin E group (P = 0.34) or the pioglitazone group (P = 0.29). Baseline Adipo-IR was significantly associated with fibrosis score (P = 0.02), but not with other histological features or nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 16 weeks, compared to placebo, the pioglitazone group had a significant reduction in Adipo-IR (-15.7 versus -1.91; P = 0.02), but this effect did not persist at 96 weeks (-3.25 versus -4.28; P = 0.31). Compared to placebo, Adipo-IR in the vitamin E group did not change significantly either after 16 weeks (P = 0.70) or after 96 weeks (P = 0.85). Change in Adipo-IR at week 16 was not associated with changes in any histological parameters at week 96, but improvement in Adipo-IR at week 96 was significantly associated with improvement in ballooning (P = 0.03), fibrosis (P = 0.004), and NAS (P = 0.01). Conclusion: Vitamin E improved liver histology independent of changes in Adipo-IR, and pioglitazone treatment acutely improved Adipo-IR, but this was not sustained. Changes in Adipo-IR were associated with changes in liver histology, including fibrosis. © 2012 American Association for the Study of Liver Diseases.

Authors
Bell, LN; Wang, J; Muralidharan, S; Chalasani, S; Fullenkamp, AM; Wilson, LA; Sanyal, AJ; Kowdley, KV; Neuschwander-Tetri, BA; Brunt, EM; McCullough, AJ; Bass, NM; Diehl, AM; Unalp-Arida, A; Chalasani, N
MLA Citation
Bell, LN, Wang, J, Muralidharan, S, Chalasani, S, Fullenkamp, AM, Wilson, LA, Sanyal, AJ, Kowdley, KV, Neuschwander-Tetri, BA, Brunt, EM, McCullough, AJ, Bass, NM, Diehl, AM, Unalp-Arida, A, and Chalasani, N. "Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis: A pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study." Hepatology 56.4 (2012): 1311-1318.
PMID
22532269
Source
scival
Published In
Hepatology
Volume
56
Issue
4
Publish Date
2012
Start Page
1311
End Page
1318
DOI
10.1002/hep.25805

Erratum: The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the american association for the study of liver diseases, American College of Gastroenterology, and the American Gastroenterological Association (American Journal of Gastroenterology (2012) 107 (811-826) DOI: 10.1038/ajg.2012.128)

Authors
Chalasani, N; Younossi, Z; Lavine, JE; Diehl, AM; Brunt, EM; Cusi, K; Charlton, M; Sanyal, AJ
MLA Citation
Chalasani, N, Younossi, Z, Lavine, JE, Diehl, AM, Brunt, EM, Cusi, K, Charlton, M, and Sanyal, AJ. "Erratum: The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the american association for the study of liver diseases, American College of Gastroenterology, and the American Gastroenterological Association (American Journal of Gastroenterology (2012) 107 (811-826) DOI: 10.1038/ajg.2012.128)." American Journal of Gastroenterology 107.10 (2012): 1598--.
Source
scival
Published In
The American Journal of Gastroenterology (Elsevier)
Volume
107
Issue
10
Publish Date
2012
Start Page
1598-
DOI
10.1038/ajg.2012.217

Reply:

Authors
Diehl, AM
MLA Citation
Diehl, AM. "Reply:." Hepatology 56.4 (2012): 1588--.
PMID
24333511
Source
scival
Published In
Hepatology
Volume
56
Issue
4
Publish Date
2012
Start Page
1588-
DOI
10.1002/hep.25728

NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease

Objective: Immune responses are important in dictating non-alcoholic steatohepatitis (NASH) outcome. We previously reported that upregulation of hedgehog (Hh) and osteopontin (OPN) occurs in NASH, that Hh-regulated accumulation of natural killer T (NKT) cells promotes hepatic stellate cell (HSC) activation, and that cirrhotic livers harbour large numbers of NKT cells. Design: The hypothesis that activated NKT cells drive fibrogenesis during NASH was evaluated by assessing if NKT depletion protects against NASH fibrosis; identifying the NKT-associated fibrogenic factors; and correlating plasma levels of the NKT cell-associated factor OPN with fibrosis severity in mice and humans. Results: When fed methionine-choline-deficient (MCD) diets for 8 weeks, wild type (WT) mice exhibited Hh pathway activation, enhanced OPN expression, and NASH-fibrosis. Ja18-/- and CD1d-/- mice which lack NKT cells had significantly attenuated Hh and OPN expression and dramatically less fibrosis. Liver mononuclear cells (LMNCs) from MCD diet fed WT mice contained activated NKT cells, generated Hh and OPN, and stimulated HSCs to become myofibroblasts; neutralising these factors abrogated the fibrogenic actions of WT LMNCs. LMNCs from NKT-cell-deficient mice were deficient in fibrogenic factors, failing to activate collagen gene expression in HSCs. Human NASH livers with advanced fibrosis contained more OPN and Hh protein than those with early fibrosis. Plasma levels of OPN mirrored hepatic OPN expression and correlated with fibrosis severity. Conclusion: Hepatic NKT cells drive production of OPN and Hh ligands that promote fibrogenesis during NASH. Associated increases in plasma levels of OPN may provide a biomarker of NASH fibrosis. Copyright Article author (or their employer) 2012.

Authors
Syn, W-K; Agboola, KM; Swiderska, M; Michelotti, GA; Liaskou, E; Pang, H; Xie, G; Philips, G; Chan, IS; Karaca, GF; Pereira, TDA; Chen, Y; Mi, Z; Kuo, PC; Choi, SS; Guy, CD; Abdelmalek, MF; Diehl, AM
MLA Citation
Syn, W-K, Agboola, KM, Swiderska, M, Michelotti, GA, Liaskou, E, Pang, H, Xie, G, Philips, G, Chan, IS, Karaca, GF, Pereira, TDA, Chen, Y, Mi, Z, Kuo, PC, Choi, SS, Guy, CD, Abdelmalek, MF, and Diehl, AM. "NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease." Gut (2012).
Source
scival
Published In
Gut
Publish Date
2012
DOI
10.1136/gutjnl-2011-301857

Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein

The hepatitis B virus (HBV) encoded X protein (HBx) contributes centrally to the pathogenesis of hepatocellular carcinoma (HCC). Aberrant activation of the Hedgehog (Hh) pathway has been linked to many tumor types including HCC. Thus, experiments were designed to test the hypothesis that HBx promotes HCC via activation of Hh signaling. HBx expression correlated with an upregulation of Hh markers in human liver cancer cell lines, in liver samples from HBV infected patients with HCC, and in the livers of HBx transgenic mice (HBxTg) that develop hepatitis, steatosis, and dysplasia, culminating in the appearance of HCC. The findings in human samples provide clinical validation for the in vitro results and those in the HBxTg. Blockade of Hh signaling inhibited HBx stimulation of cell migration, anchorage-independent growth, tumor development in HBxTg, and xenograft growth in nude mice. Results suggest that the ability of HBx to promote cancer is at least partially dependent upon the activation of the Hh pathway. This study provides biologic evidence for the role of Hh signaling in the pathogenesis of HBV-mediated HCC and suggests cause and effect for the first time. The observation that inhibition of Hh signaling partially blocked the ability of HBx to promote growth and migration in vitro and tumorigenesis in two animal models implies that Hh signaling may represent an "oncogene addiction" pathway for HBV-associated HCC. This work could be central to designing specific treatments that target early development and progression of HBx-mediated HCC. ©2012 AACR.

Authors
Arzumanyan, A; Sambandam, V; Clayton, MM; Choi, SS; Xie, G; Diehl, AM; Yu, D-Y; Feitelson, MA
MLA Citation
Arzumanyan, A, Sambandam, V, Clayton, MM, Choi, SS, Xie, G, Diehl, AM, Yu, D-Y, and Feitelson, MA. "Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein." Cancer Research 72.22 (2012): 5912-5920.
PMID
22986746
Source
scival
Published In
Cancer Research
Volume
72
Issue
22
Publish Date
2012
Start Page
5912
End Page
5920
DOI
10.1158/0008-5472.CAN-12-2329

After goodbye? Dead hepatocytes as a biomarker for fibrosis and steatohepatitis

Authors
Choi, S; Diehl, AM
MLA Citation
Choi, S, and Diehl, AM. "After goodbye? Dead hepatocytes as a biomarker for fibrosis and steatohepatitis." Hepatology 55.2 (2012): 333-335.
PMID
22183709
Source
scival
Published In
Hepatology
Volume
55
Issue
2
Publish Date
2012
Start Page
333
End Page
335
DOI
10.1002/hep.25540

The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

Authors
Chalasani, N; Younossi, Z; Lavine, JE; Diehl, AM; Brunt, EM; Cusi, K; Charlton, M; Sanyal, AJ
MLA Citation
Chalasani, N, Younossi, Z, Lavine, JE, Diehl, AM, Brunt, EM, Cusi, K, Charlton, M, and Sanyal, AJ. "The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association." American Journal of Gastroenterology 107.6 (2012): 811-826.
PMID
22641309
Source
scival
Published In
The American Journal of Gastroenterology (Elsevier)
Volume
107
Issue
6
Publish Date
2012
Start Page
811
End Page
826
DOI
10.1038/ajg.2012.128

The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology

Authors
Chalasani, N; Younossi, Z; Lavine, JE; Diehl, AM; Brunt, EM; Cusi, K; Charlton, M; Sanyal, AJ
MLA Citation
Chalasani, N, Younossi, Z, Lavine, JE, Diehl, AM, Brunt, EM, Cusi, K, Charlton, M, and Sanyal, AJ. "The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology." Gastroenterology 142.7 (2012): 1592-1609.
PMID
22656328
Source
scival
Published In
Gastroenterology
Volume
142
Issue
7
Publish Date
2012
Start Page
1592
End Page
1609
DOI
10.1053/j.gastro.2012.04.001

The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

Authors
Chalasani, N; Younossi, Z; Lavine, JE; Diehl, AM; Brunt, EM; Cusi, K; Charlton, M; Sanyal, AJ
MLA Citation
Chalasani, N, Younossi, Z, Lavine, JE, Diehl, AM, Brunt, EM, Cusi, K, Charlton, M, and Sanyal, AJ. "The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association." Hepatology 55.6 (2012): 2005-2023.
PMID
22488764
Source
scival
Published In
Hepatology
Volume
55
Issue
6
Publish Date
2012
Start Page
2005
End Page
2023
DOI
10.1002/hep.25762

Neighborhood watch orchestrates liver regeneration

Authors
Diehl, AM
MLA Citation
Diehl, AM. "Neighborhood watch orchestrates liver regeneration." Nature Medicine 18.4 (2012): 497-499.
PMID
22481408
Source
scival
Published In
Nature Medicine
Volume
18
Issue
4
Publish Date
2012
Start Page
497
End Page
499
DOI
10.1038/nm.2719

Choline intake in a large cohort of patients with nonalcoholic fatty liver disease

Background: There is significant histologic and biochemical overlap between nonalcoholic fatty liver disease (NAFLD) and steatohepatitis associated with choline deficiency. Objective: We sought to determine whether subjects with biopsyproven NAFLD and evidence of an inadequate intake of choline had more severe histologic features. Design: We performed a cross-sectional analysis of 664 subjects enrolled in the multicenter, prospective Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) with baseline data on diet composition (from a recall-based food-frequency questionnaire) within 6 mo of a liver biopsy. Food questionnaires were analyzed with proprietary software to estimate daily intakes of choline. Liver biopsies were centrally read, and consensus was scored with the NASH CRN-developed scoring system. Because choline needs vary by age, sex, and menopausal status, participants were segregated into corresponding categories (children 9-13 y old, males ≥14 y old, premenopausal women ≥19 y old, and postmenopausal women) on the basis of the Institute of Medicine's definition of adequate intake (AI) for choline. Deficient intake was defined as <50% AI. Results: Postmenopausal women with deficient choline intake had worse fibrosis (P = 0.002) once factors associated with NAFLD (age, race-ethnicity, obesity, elevated triglycerides, diabetes, alcohol use, and steroid use) were considered in multiple ordinal logistic regression models. Choline intake was not identified as a contributor to disease severity in children, men, or premenopausal women. Conclusion: Decreased choline intake is significantly associated with increased fibrosis in postmenopausal women with NAFLD. The Pioglitazone vs Vitamin E vs Placebo for Treatment of Non- Diabetic Patients With Nonalcoholic Steatohepatitis trial was registered at clinicaltrials.gov as NCT00063622, and the Treatment of Nonalcoholic Fatty Liver Disease in Children trial was registered at clinicaltrials.gov as NCT00063635. © 2012 American Society for Nutrition.

Authors
Guerrerio, AL; Colvin, RM; Schwartz, AK; Molleston, JP; Murray, KF; Diehl, A; Mohan, P; Schwimmer, JB; Lavine, JE; Torbenson, MS; Scheimann, AO
MLA Citation
Guerrerio, AL, Colvin, RM, Schwartz, AK, Molleston, JP, Murray, KF, Diehl, A, Mohan, P, Schwimmer, JB, Lavine, JE, Torbenson, MS, and Scheimann, AO. "Choline intake in a large cohort of patients with nonalcoholic fatty liver disease." American Journal of Clinical Nutrition 95.4 (2012): 892-900.
PMID
22338037
Source
scival
Published In
American Journal of Clinical Nutrition
Volume
95
Issue
4
Publish Date
2012
Start Page
892
End Page
900
DOI
10.3945/ajcn.111.020156

Lower serum hepcidin and greater parenchymal iron in nonalcoholic fatty liver disease patients with C282Y HFE mutations

Hepcidin regulation is linked to both iron and inflammatory signals and may influence iron loading in nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the relationships among HFE genotype, serum hepcidin level, hepatic iron deposition, and histology in nonalcoholic fatty liver disease (NAFLD). Single-nucleotide polymorphism genotyping for C282Y (rs1800562) and H63D (rs1799945) HFE mutations was performed in 786 adult subjects in the NASH Clinical Research Network (CRN). Clinical, histologic, and laboratory data were compared using nonparametric statistics and multivariate logistic regression. NAFLD patients with C282Y, but not H63D mutations, had lower median serum hepcidin levels (57 versus 65 ng/mL; P = 0.01) and higher mean hepatocellular (HC) iron grades (0.59 versus 0.28; P < 0.001), compared to wild-type (WT) subjects. Subjects with hepatic iron deposition had higher serum hepcidin levels than subjects without iron for all HFE genotypes (P < 0.0001). Hepcidin levels were highest among patients with mixed HC/reticuloendothelial system cell (RES) iron deposition. H63D mutations were associated with higher steatosis grades and NAFLD activity scores (odds ratio [OR], ≥1.4; 95% confidence interval [CI]: >1.0, ≤2.5; P ≤ 0.041), compared to WT, but not with either HC or RES iron. NAFLD patients with C282Y mutations had less ballooning or NASH (OR, ≤0.62; 95% CI: >0.39, <0.94; P ≤ 0.024), compared to WT subjects. Conclusions: The presence of C282Y mutations in patients with NAFLD is associated with greater HC iron deposition and decreased serum hepcidin levels, and there is a positive relationship between hepatic iron stores and serum hepcidin level across all HFE genotypes. These data suggest that body iron stores are the major determinant of hepcidin regulation in NAFLD, regardless of HFE genotype. A potential role for H63D mutations in NAFLD pathogenesis is possible through iron-independent mechanisms. © 2012 American Association for the Study of Liver Diseases.

Authors
Nelson, JE; Brunt, EM; Kowdley, KV; Abrams, SH; Fairly, LA; McCullough, AJ; Brandt, P; Bringman, D; Dasarathy, S; Dasarathy, J; Hawkins, C; Liu, Y-C; Rogers, N; Stager, M; Whitwell, J; McCullough, AJ; Dasarathy, S; Pagadala, M; Sargent, R; Yerian, L; Zein, C; Merriman, R; Nguyen, A; Mohan, P; Nair, K; DeVore, S; Kohli, R; Lake, K; Xanthakos, S; Cosme, Y; Lavine, JE; Mencin, A; Ovchinsky, N; Abdelmalek, MF; Buie, S; Diehl, AM; Gottfried, M; Guy, C; Hanna, M; Kigongo, C; Killenberg, P; Kwan, S et al.
MLA Citation
Nelson, JE, Brunt, EM, Kowdley, KV, Abrams, SH, Fairly, LA, McCullough, AJ, Brandt, P, Bringman, D, Dasarathy, S, Dasarathy, J, Hawkins, C, Liu, Y-C, Rogers, N, Stager, M, Whitwell, J, McCullough, AJ, Dasarathy, S, Pagadala, M, Sargent, R, Yerian, L, Zein, C, Merriman, R, Nguyen, A, Mohan, P, Nair, K, DeVore, S, Kohli, R, Lake, K, Xanthakos, S, Cosme, Y, Lavine, JE, Mencin, A, Ovchinsky, N, Abdelmalek, MF, Buie, S, Diehl, AM, Gottfried, M, Guy, C, Hanna, M, Kigongo, C, Killenberg, P, and Kwan, S et al. "Lower serum hepcidin and greater parenchymal iron in nonalcoholic fatty liver disease patients with C282Y HFE mutations." Hepatology 56.5 (2012): 1730-1740.
PMID
22611049
Source
scival
Published In
Hepatology
Volume
56
Issue
5
Publish Date
2012
Start Page
1730
End Page
1740
DOI
10.1002/hep.25856

Alcoholic liver disease

Authors
Jou, JH; Diehl, AM
MLA Citation
Jou, JH, and Diehl, AM. "Alcoholic liver disease." Handbook of Liver Disease (2012): 95-105.
Source
scival
Published In
Handbook of Liver Disease
Publish Date
2012
Start Page
95
End Page
105
DOI
10.1016/B978-1-4377-1725-9.10006-1

Leptin is Key To Macrophage-Dependent Free Radical Formation in Ccl(4)-Induced Exacerbation of Steatohepatitis of Obesity

Authors
Chatterjee, S; Tokar, EJ; Kadiiska, M; Waalkes, M; Diehl, AM; Mason, RP
MLA Citation
Chatterjee, S, Tokar, EJ, Kadiiska, M, Waalkes, M, Diehl, AM, and Mason, RP. "Leptin is Key To Macrophage-Dependent Free Radical Formation in Ccl(4)-Induced Exacerbation of Steatohepatitis of Obesity." November 1, 2011.
Source
wos-lite
Published In
Free Radical Biology & Medicine
Volume
51
Publish Date
2011
Start Page
S26
End Page
S27
DOI
10.1016/j.freeradbiomed.2011.10.061

Up-regulation of Hedgehog pathway is associated with cellular permissiveness for hepatitis C virus replication.

UNLABELLED: Studies of the hepatitis C virus (HCV) life-cycle rely heavily on Huh7.5 cells, but the reasons why these cells are exceptionally permissive for HCV replication are not clear. Based on recent clinical observations, we hypothesized that the Hedgehog (Hh) pathway, which has not been previously associated with HCV replication, may be involved in the Huh7.5 phenotype of increased permissiveness. We tested this hypothesis by comparing levels of a variety of Hh-related cellular markers in Huh7.5 cells with the parental Huh7 cells, which are far less permissive. Here we demonstrate that Huh7.5 cells, when compared with Huh7 cells, have substantially decreased expression of epithelial markers, increased levels of mesenchymal markers, and markedly up-regulated Hh pathway activity: Shh, >100-fold, Gli1, >30-fold, Ptc, 2-fold. In Huh7.5 cells, we found that cyclopamine, an Hh pathway antagonist, reduced HCV RNA levels by 50% compared with vehicle and inactive isomer controls. Moreover, in Huh7 cells treatment with recombinant Shh ligand and SAG, both Hh pathway agonists, stimulated HCV replication by 2-fold and 4-fold, respectively. These effects were observed with both viral infections and a subgenomic replicon. Finally, we demonstrated that GDC-0449 decreased HCV RNA levels in a dose-response manner. CONCLUSION: We have identified a relationship between HCV and Hh signaling where up-regulated pathway activity during infection promotes an environment conducive to replication. Given that Hh activity is very low in most hepatocytes, these findings may serve to further shift the model of HCV liver infection from modest widespread replication in hepatocytes to one where a subset of cells support high-level replication. These findings also introduce Hh pathway inhibitors as potential anti-HCV therapeutics.

Authors
Choi, SS; Bradrick, S; Qiang, G; Mostafavi, A; Chaturvedi, G; Weinman, SA; Diehl, AM; Jhaveri, R
MLA Citation
Choi, SS, Bradrick, S, Qiang, G, Mostafavi, A, Chaturvedi, G, Weinman, SA, Diehl, AM, and Jhaveri, R. "Up-regulation of Hedgehog pathway is associated with cellular permissiveness for hepatitis C virus replication." Hepatology 54.5 (November 2011): 1580-1590.
PMID
21793033
Source
pubmed
Published In
Hepatology
Volume
54
Issue
5
Publish Date
2011
Start Page
1580
End Page
1590
DOI
10.1002/hep.24576

Retraction for Garman et al: A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities.

Authors
Garman, KS; Acharya, CR; Edelman, E; Grade, M; Gaedcke, J; Sud, S; Barry, W; Diehl, AM; Provenzale, D; Ginsburg, GS; Ghadimi, BM; Ried, T; Nevins, JR; Mukherjee, S; Hsu, D; Potti, A
MLA Citation
Garman, KS, Acharya, CR, Edelman, E, Grade, M, Gaedcke, J, Sud, S, Barry, W, Diehl, AM, Provenzale, D, Ginsburg, GS, Ghadimi, BM, Ried, T, Nevins, JR, Mukherjee, S, Hsu, D, and Potti, A. "Retraction for Garman et al: A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities." Proc Natl Acad Sci U S A 108.42 (October 18, 2011): 17569-.
PMID
21969600
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
108
Issue
42
Publish Date
2011
Start Page
17569
DOI
10.1073/pnas.1115170108

HEDGEHOG PATHWAY INHIBITION BY GDC-0449 CAUSES REGRESSION OF HEPATOCELLULAR CARCINOMAS AND IMPROVES LIVER FIBROSIS IN MDR2-DEFICIENT MICE

Authors
Chan, IS; Philips, GM; Zdanowicz, M; Teaberry, V; Karaca, G; Rangwala, F; Guy, CD; Moylan, CA; Venkatraman, T; Feuerlein, S; Syn, W-K; Jung, Y; Witek, RP; Michelotti, GA; Choi, SS; Merkle, EM; Lascola, C; Diehl, AM
MLA Citation
Chan, IS, Philips, GM, Zdanowicz, M, Teaberry, V, Karaca, G, Rangwala, F, Guy, CD, Moylan, CA, Venkatraman, T, Feuerlein, S, Syn, W-K, Jung, Y, Witek, RP, Michelotti, GA, Choi, SS, Merkle, EM, Lascola, C, and Diehl, AM. "HEDGEHOG PATHWAY INHIBITION BY GDC-0449 CAUSES REGRESSION OF HEPATOCELLULAR CARCINOMAS AND IMPROVES LIVER FIBROSIS IN MDR2-DEFICIENT MICE." October 2011.
Source
wos-lite
Published In
Hepatology
Volume
54
Publish Date
2011
Start Page
1278A
End Page
1278A

TRANSITION OF QUIESCENT STELLATE CELLS INTO MYOFIBROBLASTS REQUIRES HEDGEHOG-MEDIATED INDUCTION OF GLYCOLYSIS

Authors
Chen, Y; Choi, SS; Michelotti, GA; Moylan, CA; Karaca, G; Zdanowicz, M; Xie, G; Kruger, L; Diehl, AM
MLA Citation
Chen, Y, Choi, SS, Michelotti, GA, Moylan, CA, Karaca, G, Zdanowicz, M, Xie, G, Kruger, L, and Diehl, AM. "TRANSITION OF QUIESCENT STELLATE CELLS INTO MYOFIBROBLASTS REQUIRES HEDGEHOG-MEDIATED INDUCTION OF GLYCOLYSIS." October 2011.
Source
wos-lite
Published In
Hepatology
Volume
54
Publish Date
2011
Start Page
422A
End Page
422A

ABROGATION OF CANONICAL HEDGEHOG ACTIVITY DECREASES HEPATIC FIBROSIS

Authors
Michelotti, GA; Choi, SS; Zdanowicz, M; Karaca, G; Premont, RT; Diehl, AM
MLA Citation
Michelotti, GA, Choi, SS, Zdanowicz, M, Karaca, G, Premont, RT, and Diehl, AM. "ABROGATION OF CANONICAL HEDGEHOG ACTIVITY DECREASES HEPATIC FIBROSIS." October 2011.
Source
wos-lite
Published In
Hepatology
Volume
54
Publish Date
2011
Start Page
434A
End Page
435A

AUTOCRINE ACTIVATION OF THE HEDGEHOG PATHWAY DURING LIVER SINUSOIDAL ENDOTHELIAL CELL CAPILLARIZATION

Authors
Xie, G; Choi, SS; Syn, W-K; Michelotti, GA; Zdanowicz, M; Karaca, G; Chen, Y; Diehl, AM
MLA Citation
Xie, G, Choi, SS, Syn, W-K, Michelotti, GA, Zdanowicz, M, Karaca, G, Chen, Y, and Diehl, AM. "AUTOCRINE ACTIVATION OF THE HEDGEHOG PATHWAY DURING LIVER SINUSOIDAL ENDOTHELIAL CELL CAPILLARIZATION." October 2011.
Source
wos-lite
Published In
Hepatology
Volume
54
Publish Date
2011
Start Page
757A
End Page
757A

HEDGEHOG PATHWAY INHIBITION INDUCES HCC TUMOR NECROSIS BY REPRESSING EXPRESSION OF ANGIOPOIETIN-2 AND ITS COGNATE RECEPTOR, TIE-2

Authors
Philips, GM; Chan, IS; Choi, SS; Xie, G; Michelotti, GA; Zdanowicz, M; Teaberry, V; Rangwala, F; Guy, CD; Karaca, G; Venkatraman, T; Feuerlein, S; Moylan, CA; Syn, W-K; Jung, Y; Witek, RP; Merkle, EM; Lascola, C; Diehl, AM
MLA Citation
Philips, GM, Chan, IS, Choi, SS, Xie, G, Michelotti, GA, Zdanowicz, M, Teaberry, V, Rangwala, F, Guy, CD, Karaca, G, Venkatraman, T, Feuerlein, S, Moylan, CA, Syn, W-K, Jung, Y, Witek, RP, Merkle, EM, Lascola, C, and Diehl, AM. "HEDGEHOG PATHWAY INHIBITION INDUCES HCC TUMOR NECROSIS BY REPRESSING EXPRESSION OF ANGIOPOIETIN-2 AND ITS COGNATE RECEPTOR, TIE-2." October 2011.
Source
wos-lite
Published In
Hepatology
Volume
54
Publish Date
2011
Start Page
1280A
End Page
1280A

HEDGEHOG PATHWAY ACTIVATION OCCURS IN PULMONARY MICROVASCULATURE DURING EXPERIMENTAL HEPATOPULMONARY SYNDROME (HPS)

Authors
Philips, GM; Zdanowicz, M; Michelotti, GA; Choi, SS; Karaca, G; Chan, IS; Diehl, AM
MLA Citation
Philips, GM, Zdanowicz, M, Michelotti, GA, Choi, SS, Karaca, G, Chan, IS, and Diehl, AM. "HEDGEHOG PATHWAY ACTIVATION OCCURS IN PULMONARY MICROVASCULATURE DURING EXPERIMENTAL HEPATOPULMONARY SYNDROME (HPS)." October 2011.
Source
wos-lite
Published In
Hepatology
Volume
54
Publish Date
2011
Start Page
1235A
End Page
1235A

DOSE DEPENDENT ASSOCIATION OF FRUCTOSE CONSUMPTION WITH HYPERURICEMIA AND INSULIN RESISTANCE IN CHILDREN WITH NAFLD

Authors
Shah, KK; Suzuki, A; Schwimmer, JB; Unalp, A; Guy, CD; Molleston, JP; Whitington, PF; Johnson, R; Diehl, AM; Abdelmalek, MF
MLA Citation
Shah, KK, Suzuki, A, Schwimmer, JB, Unalp, A, Guy, CD, Molleston, JP, Whitington, PF, Johnson, R, Diehl, AM, and Abdelmalek, MF. "DOSE DEPENDENT ASSOCIATION OF FRUCTOSE CONSUMPTION WITH HYPERURICEMIA AND INSULIN RESISTANCE IN CHILDREN WITH NAFLD." October 2011.
Source
wos-lite
Published In
Hepatology
Volume
54
Publish Date
2011
Start Page
1116A
End Page
1116A

P89 Osteopontin promotes lymphocyte recruitment in steatohepatitis

Authors
Liaskou, E; Claridge, LC; Shah, H; Oo, Y; Shaw, J; Mi, Z; Kuo, PC; Canbay, A; Diehl, AM; Adams, DH; Syn, W-K
MLA Citation
Liaskou, E, Claridge, LC, Shah, H, Oo, Y, Shaw, J, Mi, Z, Kuo, PC, Canbay, A, Diehl, AM, Adams, DH, and Syn, W-K. "P89 Osteopontin promotes lymphocyte recruitment in steatohepatitis." Gut 60.Suppl 2 (September 1, 2011): A41-A41.
Source
crossref
Published In
Gut
Volume
60
Issue
Suppl 2
Publish Date
2011
Start Page
A41
End Page
A41
DOI
10.1136/gutjnl-2011-300857a.89

Noninvasive evaluation of hepatic fibrosis using acoustic radiation force-based shear stiffness in patients with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease in developed countries, may progress to nonalcoholic steatohepatitis (NASH) in a minority of people. Those with NASH are at increased risk for cirrhosis and hepatocellular carcinoma. The potential risk and economic burden of utilizing liver biopsy to stage NAFLD in an overwhelmingly large at-risk population are enormous; thus, the discovery of sensitive, inexpensive, and reliable noninvasive diagnostic modalities is essential for population-based screening. METHODS: Acoustic Radiation Force Impulse (ARFI) shear wave imaging, a noninvasive method of assessing tissue stiffness, was used to evaluate liver fibrosis in 172 patients diagnosed with NAFLD. Liver shear stiffness measures in three different imaging locations were reconstructed and compared to the histologic features of NAFLD and AST-to-platelet ratio indices (APRI). RESULTS: Reconstructed shear stiffnesses were not associated with ballooned hepatocytes (p=0.11), inflammation (p=0.69), nor imaging location (p=0.11). Using a predictive shear stiffness threshold of 4.24kPa, shear stiffness distinguished low (fibrosis stage 0-2) from high (fibrosis stage 3-4) fibrosis stages with a sensitivity of 90% and a specificity of 90% (AUC of 0.90). Shear stiffness had a mild correlation with APRI (R(2)=0.22). BMI>40kg/m(2) was not a limiting factor for ARFI imaging, and no correlation was noted between BMI and shear stiffness (R(2)=0.05). CONCLUSIONS: ARFI imaging is a promising imaging modality for assessing the presence or absence of advanced fibrosis in patients with obesity-related liver disease.

Authors
Palmeri, ML; Wang, MH; Rouze, NC; Abdelmalek, MF; Guy, CD; Moser, B; Diehl, AM; Nightingale, KR
MLA Citation
Palmeri, ML, Wang, MH, Rouze, NC, Abdelmalek, MF, Guy, CD, Moser, B, Diehl, AM, and Nightingale, KR. "Noninvasive evaluation of hepatic fibrosis using acoustic radiation force-based shear stiffness in patients with nonalcoholic fatty liver disease." J Hepatol 55.3 (September 2011): 666-672.
PMID
21256907
Source
pubmed
Published In
Journal of Hepatology
Volume
55
Issue
3
Publish Date
2011
Start Page
666
End Page
672
DOI
10.1016/j.jhep.2010.12.019

Increased production of sonic hedgehog by ballooned hepatocytes.

Ballooned hepatocytes distinguish non-alcoholic steatohepatitis (NASH) from steatosis. Such cells contain dilated endoplasmic reticulum and ubiquitin aggregates, characteristics of endoplasmic reticulum stress. Hepatocyte ballooning increases the risk for fibrosis in NASH, suggesting that ballooned hepatocytes release pro-fibrogenic factors. Hedgehog ligands function as pro-fibrogenic factors in liver diseases, but mechanisms for hedgehog ligand production remain poorly understood. We evaluated the hypothesis that endoplasmic reticulum stress induces hepatocyte production of hedgehog ligands that provide paracrine pro-fibrogenic signals to neighbouring cells. In livers from NASH patients, keratin 8/18 and ubiquitin staining demonstrated enlarged, keratin 8/18-negative/ubiquitin-positive hepatocytes (ballooned hepatocytes) that were positive for Sonic hedgehog. In order to model endoplasmic reticulum stress in vitro, primary mouse hepatocytes were treated with tunicamycin. Compared to vehicle, tunicamycin significantly increased Sonic hedgehog and Indian hedgehog expression. Furthermore, conditioned medium from tunicamycin-treated hepatocytes increased Gli-luciferase reporter activity 14-fold more than conditioned medium from vehicle-treated hepatocytes. Cyclopamine (hedgehog signalling inhibitor) abrogated the effect of conditioned medium from tunicamycin-treated hepatocytes, verifying that soluble hepatocyte-derived factors activate hedgehog signalling. Ballooned hepatocytes in NASH patients did not express the hedgehog target gene, Gli2, α-smooth muscle actin or vimentin, but were surrounded by Gli2-positive stromal cells expressing these myofibroblast markers. Trichrome staining demonstrated the accumulation of ballooned hepatocytes in areas of matrix deposition, and numbers of Sonic hedgehog-positive hepatocytes correlated with the degree of ballooning and fibrosis stage. Hepatocytes undergoing endoplasmic reticiulum stress generate hedgehog ligands which act as paracrine pro-fibrogenic factors for hedgehog-responsive stromal cells. These results help to explain why fibrosis stage correlates with hepatocyte ballooning in NASH.

Authors
Rangwala, F; Guy, CD; Lu, J; Suzuki, A; Burchette, JL; Abdelmalek, MF; Chen, W; Diehl, AM
MLA Citation
Rangwala, F, Guy, CD, Lu, J, Suzuki, A, Burchette, JL, Abdelmalek, MF, Chen, W, and Diehl, AM. "Increased production of sonic hedgehog by ballooned hepatocytes." J Pathol 224.3 (July 2011): 401-410.
PMID
21547909
Source
pubmed
Published In
The Journal of Pathology
Volume
224
Issue
3
Publish Date
2011
Start Page
401
End Page
410
DOI
10.1002/path.2888

Hedgehog signaling in cholangiocytes.

PURPOSE OF REVIEW: Cells lining the biliary tree are targets of injury, but also orchestrate liver repair. The latter involves autocrine/paracrine signaling that enhances the viability and growth of residual ductular cells and promotes accumulation of inflammatory and myofibroblastic cells. The mechanisms mediating this so-called 'ductular reaction' need to be better understood to improve injury outcomes. Studies are revealing that ductular cells produce and respond to hedgehog (Hh) ligands, developmental morphogens that control progenitor cell fate and tissue construction during embryogenesis. Because this has potential implications for liver repair, this review will summarize current knowledge about Hh signaling and cholangiocytes. RECENT FINDINGS: Diverse types of liver injury stimulate cholangiocytes to generate Hh ligands, and cholangiocyte-derived Hh ligands interact with receptors on cholangiocytes and neighboring cells to modulate virtually every aspect of the ductular reaction to injury. Excessive Hh signaling promotes dysfunctional repair and results in chronic hepatic inflammation, fibrogenesis, and carcinogenesis. SUMMARY: The Hh pathway is part of the complex signaling network that orchestrates liver repair. How other pathways and posttranscriptional mechanisms modulate Hh signaling in ductular cells remains unclear. Further research in this area may identify novel therapeutic targets for the treatment of cholangiopathies and cholangiocarcinoma.

Authors
Omenetti, A; Diehl, AM
MLA Citation
Omenetti, A, and Diehl, AM. "Hedgehog signaling in cholangiocytes." Curr Opin Gastroenterol 27.3 (May 2011): 268-275. (Review)
PMID
21423008
Source
pubmed
Published In
Current Opinion in Gastroenterology
Volume
27
Issue
3
Publish Date
2011
Start Page
268
End Page
275
DOI
10.1097/MOG.0b013e32834550b4

Hedgehog activity, epithelial-mesenchymal transitions, and biliary dysmorphogenesis in biliary atresia.

UNLABELLED: Biliary atresia (BA) is notable for marked ductular reaction and rapid development of fibrosis. Activation of the Hedgehog (Hh) pathway promotes the expansion of populations of immature epithelial cells that coexpress mesenchymal markers and may be profibrogenic. We examined the hypothesis that in BA excessive Hh activation impedes ductular morphogenesis and enhances fibrogenesis by promoting accumulation of immature ductular cells with a mesenchymal phenotype. Livers and remnant extrahepatic ducts from BA patients were evaluated by quantitative reverse-transcription polymerase chain reaction (QRT-PCR) and immunostaining for Hh ligands, target genes, and markers of mesenchymal cells or ductular progenitors. Findings were compared to children with genetic cholestatic disease, age-matched deceased donor controls, and adult controls. Ductular cells isolated from adult rats with and without bile duct ligation were incubated with Hh ligand-enriched medium ± Hh-neutralizing antibody to determine direct effects of Hh ligands on epithelial to mesenchymal transition (EMT) marker expression. Livers from pediatric controls showed greater innate Hh activation than adult controls. In children with BA, both intra- and extrahepatic ductular cells demonstrated striking up-regulation of Hh ligand production and increased expression of Hh target genes. Excessive accumulation of Hh-producing cells and Hh-responsive cells also occurred in other infantile cholestatic diseases. Further analysis of the BA samples demonstrated that immature ductular cells with a mesenchymal phenotype were Hh-responsive. Treating immature ductular cells with Hh ligand-enriched medium induced mesenchymal genes; neutralizing Hh ligands inhibited this. CONCLUSION: BA is characterized by excessive Hh pathway activity, which stimulates biliary EMT and may contribute to biliary dysmorphogenesis. Other cholestatic diseases show similar activation, suggesting that this is a common response to cholestatic injury in infancy.

Authors
Omenetti, A; Bass, LM; Anders, RA; Clemente, MG; Francis, H; Guy, CD; McCall, S; Choi, SS; Alpini, G; Schwarz, KB; Diehl, AM; Whitington, PF
MLA Citation
Omenetti, A, Bass, LM, Anders, RA, Clemente, MG, Francis, H, Guy, CD, McCall, S, Choi, SS, Alpini, G, Schwarz, KB, Diehl, AM, and Whitington, PF. "Hedgehog activity, epithelial-mesenchymal transitions, and biliary dysmorphogenesis in biliary atresia." Hepatology 53.4 (April 2011): 1246-1258.
PMID
21480329
Source
pubmed
Published In
Hepatology
Volume
53
Issue
4
Publish Date
2011
Start Page
1246
End Page
1258
DOI
10.1002/hep.24156

Single nucleotide polymorphisms affecting phosphatidylcholine transport are associated with obesity

Authors
Corbin, KD; da Costa, K-A; Sha, W; Abdelmalek, MF; Diehl, AM; Zeisel, SH
MLA Citation
Corbin, KD, da Costa, K-A, Sha, W, Abdelmalek, MF, Diehl, AM, and Zeisel, SH. "Single nucleotide polymorphisms affecting phosphatidylcholine transport are associated with obesity." April 2011.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
25
Publish Date
2011

Hedgehog signaling in the liver.

Reactivation of Hedgehog (Hh), a morphogenic signaling pathway that controls progenitor cell fate and tissue construction during embryogenesis occurs during many types of liver injury in adult. The net effects of activating the Hedgehog pathway include expansion of liver progenitor populations to promote liver regeneration, but also hepatic accumulation of inflammatory cells, liver fibrogenesis, and vascular remodeling. All of these latter responses are known to be involved in the pathogenesis of cirrhosis. In addition, Hh signaling may play a role in primary liver cancers, such as cholangiocarcinoma and hepatocellular carcinoma. Study of Hedgehog signaling in liver cells is in its infancy. Additional research in this area is justified given growing experimental and clinical data supporting a role for the pathway in regulating outcomes of liver injury.

Authors
Omenetti, A; Choi, S; Michelotti, G; Diehl, AM
MLA Citation
Omenetti, A, Choi, S, Michelotti, G, and Diehl, AM. "Hedgehog signaling in the liver." J Hepatol 54.2 (February 2011): 366-373. (Review)
PMID
21093090
Source
pubmed
Published In
Journal of Hepatology
Volume
54
Issue
2
Publish Date
2011
Start Page
366
End Page
373
DOI
10.1016/j.jhep.2010.10.003

Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults.

Paracrine signaling between cholangiocytes and stromal cells regulates biliary remodeling. Cholangiocytes have neuroepithelial characteristics and serotonin receptor agonists inhibit their growth, but whether they are capable of serotonin biosynthesis is unknown. We hypothesized that cholangiocytes synthesize serotonin and that cross talk between liver myofibroblasts (MF) and cholangiocytes regulates this process to influence biliary remodeling. Transwell cultures of cholangiocytes ± MF, and tryptophan hydroxylase-2 knockin (TPH2KI) mice with an inactivating mutation of the neuronal tryptophan hydroxylase (TPH) isoform, TPH2, were evaluated. Results in the cell culture models confirm that cholangiocytes have serotonin receptors and demonstrate for the first time that these cells express TPH2 and produce serotonin, which autoinhibits their growth but stimulates MF production of TGF-β(1). Increased TGF-β(1), in turn, counteracts autocrine inhibition of cholangiocyte growth by repressing cholangiocyte TPH2 expression. Studies of TPH2KI mice confirm that TPH2-mediated production of serotonin plays an important role in remodeling damaged bile ducts because mice with decreased TPH2 function have reduced biliary serotonin levels and exhibit excessive cholangiocyte proliferation, accumulation of aberrant ductules and liver progenitors, and increased liver fibrosis after bile duct ligation. This new evidence that cholangiocytes express the so-called neuronal isoform of TPH, synthesize serotonin de novo, and deploy serotonin as an autocrine/paracrine signal to regulate regeneration of the biliary tree complements earlier work that revealed that passive release of serotonin from platelets stimulates hepatocyte proliferation. Given the prevalent use of serotonin-modulating drugs, these findings have potentially important implications for recovery from various types of liver damage.

Authors
Omenetti, A; Yang, L; Gainetdinov, RR; Guy, CD; Choi, SS; Chen, W; Caron, MG; Diehl, AM
MLA Citation
Omenetti, A, Yang, L, Gainetdinov, RR, Guy, CD, Choi, SS, Chen, W, Caron, MG, and Diehl, AM. "Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults." Am J Physiol Gastrointest Liver Physiol 300.2 (February 2011): G303-G315.
PMID
21071507
Source
pubmed
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
300
Issue
2
Publish Date
2011
Start Page
G303
End Page
G315
DOI
10.1152/ajpgi.00368.2010

The role of Hedgehog signaling in fibrogenic liver repair.

Repair of adult liver, like many tissues, involves the coordinated response of a number of different cell types. In adult livers, fibroblastic cells, ductular cells, inflammatory cells, and progenitor cells contribute to this process. Our studies demonstrate that the fates of such cells are dictated, at least in part, by Hedgehog, a fetal morphogenic pathway that was once thought to be active mainly during embryogenesis. Studies of injured adult human and rodent livers demonstrate that injury-related activation of the Hedgehog pathway modulates several important aspects of repair, including the growth of hepatic progenitor populations, hepatic accumulation of myofibroblasts, repair-related inflammatory responses, vascular remodeling, liver fibrosis and hepatocarcinogenesis. These findings identify the Hedgehog pathway as a potentially important target for biomarker development and therapeutic manipulation, and emphasize the need for further research to advance knowledge about how this pathway is regulated by and interacts with other signals that regulate adult liver repair.

Authors
Choi, SS; Omenetti, A; Syn, W-K; Diehl, AM
MLA Citation
Choi, SS, Omenetti, A, Syn, W-K, and Diehl, AM. "The role of Hedgehog signaling in fibrogenic liver repair." Int J Biochem Cell Biol 43.2 (February 2011): 238-244. (Review)
PMID
21056686
Source
pubmed
Published In
The International Journal of Biochemistry and Cell Biology
Volume
43
Issue
2
Publish Date
2011
Start Page
238
End Page
244
DOI
10.1016/j.biocel.2010.10.015

A Novel Immunohiostochemical Staining Pattern for Keratin 8/18 Plus Ubiquitin in Nonalcoholic Fatty Liver Disease Is Associated with Increased Disease Severity and Advanced Fibrosis

Authors
Guy, CD; Suzuki, A; Burchette, JL; Brunt, EM; Abelmalek, MF; Cardona, D; McCall, SJ; Unlap, A; Belt, P; Wilson, L; Ferrell, LD; Diehl, AM
MLA Citation
Guy, CD, Suzuki, A, Burchette, JL, Brunt, EM, Abelmalek, MF, Cardona, D, McCall, SJ, Unlap, A, Belt, P, Wilson, L, Ferrell, LD, and Diehl, AM. "A Novel Immunohiostochemical Staining Pattern for Keratin 8/18 Plus Ubiquitin in Nonalcoholic Fatty Liver Disease Is Associated with Increased Disease Severity and Advanced Fibrosis." February 2011.
Source
wos-lite
Published In
Laboratory Investigation
Volume
91
Publish Date
2011
Start Page
361A
End Page
361A

A Novel Immunohiostochemical Staining Pattern for Keratin 8/18 Plus Ubiquitin in Nonalcoholic Fatty Liver Disease Is Associated with Increased Disease Severity and Advanced Fibrosis

Authors
Guy, CD; Suzuki, A; Burchette, JL; Brunt, EM; Abelmalek, MF; Cardona, D; McCall, SJ; Unlap, A; Belt, P; Wilson, L; Ferrell, LD; Diehl, AM
MLA Citation
Guy, CD, Suzuki, A, Burchette, JL, Brunt, EM, Abelmalek, MF, Cardona, D, McCall, SJ, Unlap, A, Belt, P, Wilson, L, Ferrell, LD, and Diehl, AM. "A Novel Immunohiostochemical Staining Pattern for Keratin 8/18 Plus Ubiquitin in Nonalcoholic Fatty Liver Disease Is Associated with Increased Disease Severity and Advanced Fibrosis." February 2011.
Source
wos-lite
Published In
Modern Pathology
Volume
24
Publish Date
2011
Start Page
361A
End Page
361A

Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis.

UNLABELLED: Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis. Recently, we showed that NASH-related cirrhosis is associated with Hedgehog (Hh) pathway activation. The gene encoding osteopontin (OPN), a profibrogenic extracellular matrix protein and cytokine, is a direct transcriptional target of the Hh pathway. Thus, we hypothesize that Hh signaling induces OPN to promote liver fibrosis in NASH. Hepatic OPN expression and liver fibrosis were analyzed in wild-type (WT) mice, Patched-deficient (Ptc(+/-) ) (overly active Hh signaling) mice, and OPN-deficient mice before and after feeding methionine and choline-deficient (MCD) diets to induce NASH-related fibrosis. Hepatic OPN was also quantified in human NASH and nondiseased livers. Hh signaling was manipulated in cultured liver cells to assess direct effects on OPN expression, and hepatic stellate cells (HSCs) were cultured in medium with different OPN activities to determine effects on HSC phenotype. When fed MCD diets, Ptc(+/-) mice expressed more OPN and developed worse liver fibrosis (P < 0.05) than WT mice, whereas OPN-deficient mice exhibited reduced fibrosis (P < 0.05). In NASH patients, OPN was significantly up-regulated and correlated with Hh pathway activity and fibrosis stage. During NASH, ductular cells strongly expressed OPN. In cultured HSCs, SAG (an Hh agonist) up-regulated, whereas cyclopamine (an Hh antagonist) repressed OPN expression (P < 0.005). Cholangiocyte-derived OPN and recombinant OPN promoted fibrogenic responses in HSCs (P < 0.05); neutralizing OPN with RNA aptamers attenuated this (P < 0.05). CONCLUSION: OPN is Hh-regulated and directly promotes profibrogenic responses. OPN induction correlates with Hh pathway activity and fibrosis stage. Therefore, OPN inhibition may be beneficial in NASH.

Authors
Syn, W-K; Choi, SS; Liaskou, E; Karaca, GF; Agboola, KM; Oo, YH; Mi, Z; Pereira, TA; Zdanowicz, M; Malladi, P; Chen, Y; Moylan, C; Jung, Y; Bhattacharya, SD; Teaberry, V; Omenetti, A; Abdelmalek, MF; Guy, CD; Adams, DH; Kuo, PC; Michelotti, GA; Whitington, PF; Diehl, AM
MLA Citation
Syn, W-K, Choi, SS, Liaskou, E, Karaca, GF, Agboola, KM, Oo, YH, Mi, Z, Pereira, TA, Zdanowicz, M, Malladi, P, Chen, Y, Moylan, C, Jung, Y, Bhattacharya, SD, Teaberry, V, Omenetti, A, Abdelmalek, MF, Guy, CD, Adams, DH, Kuo, PC, Michelotti, GA, Whitington, PF, and Diehl, AM. "Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis." Hepatology 53.1 (January 2011): 106-115.
PMID
20967826
Source
pubmed
Published In
Hepatology
Volume
53
Issue
1
Publish Date
2011
Start Page
106
End Page
115
DOI
10.1002/hep.23998

Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer.

OBJECTIVE: Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3) develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC) emerges spontaneously in such mice by 50-60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2(-/-) mice to investigate the hypothesis that activation of the hedgehog (Hh) signaling pathway promotes development of both liver fibrosis and HCC. METHODS: Hepatic injury and fibrosis, Hh pathway activation, and liver progenitor populations were compared in Mdr2(-/-) mice and age-matched wild type controls. A dose finding experiment with the Hh signaling antagonist GDC-0449 was performed to optimize Hh pathway inhibition. Mice were then treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging. RESULTS: Unlike controls, Mdr2(-/-) mice consistently expressed Hh ligands and progressively accumulated Hh-responsive liver myofibroblasts and progenitors with age. Treatment of aged Mdr2-deficient mice with GDC-0449 significantly inhibited hepatic Hh activity, decreased liver myofibroblasts and progenitors, reduced liver fibrosis, promoted regression of intra-hepatic HCCs, and decreased the number of metastatic HCC without increasing mortality. CONCLUSIONS: Hh pathway activation promotes liver fibrosis and hepatocarcinogenesis, and inhibiting Hh signaling safely reverses both processes even when fibrosis and HCC are advanced.

Authors
Philips, GM; Chan, IS; Swiderska, M; Schroder, VT; Guy, C; Karaca, GF; Moylan, C; Venkatraman, T; Feuerlein, S; Syn, W-K; Jung, Y; Witek, RP; Choi, S; Michelotti, GA; Rangwala, F; Merkle, E; Lascola, C; Diehl, AM
MLA Citation
Philips, GM, Chan, IS, Swiderska, M, Schroder, VT, Guy, C, Karaca, GF, Moylan, C, Venkatraman, T, Feuerlein, S, Syn, W-K, Jung, Y, Witek, RP, Choi, S, Michelotti, GA, Rangwala, F, Merkle, E, Lascola, C, and Diehl, AM. "Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer." PLoS One 6.9 (2011): e23943-.
Website
http://hdl.handle.net/10161/11084
PMID
21912653
Source
pubmed
Published In
PloS one
Volume
6
Issue
9
Publish Date
2011
Start Page
e23943
DOI
10.1371/journal.pone.0023943

A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities (Proceedings of the National Academy of Sciences of the United States of America (2008) 105, 49, (19432-19437) DOI: 10.1073/pnas.0806674105)

Authors
Garman, KS; Acharya, CR; Edelman, E; Grade, M; Gaedcke, J; Sud, S; Barry, W; Diehl, AM; Provenzale, D; Ginsburg, GS; Ghadimi, BM; Ried, T; Nevins, JR; Mukherjee, S; Hsu, D; Potti, A
MLA Citation
Garman, KS, Acharya, CR, Edelman, E, Grade, M, Gaedcke, J, Sud, S, Barry, W, Diehl, AM, Provenzale, D, Ginsburg, GS, Ghadimi, BM, Ried, T, Nevins, JR, Mukherjee, S, Hsu, D, and Potti, A. "A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities (Proceedings of the National Academy of Sciences of the United States of America (2008) 105, 49, (19432-19437) DOI: 10.1073/pnas.0806674105)." Proceedings of the National Academy of Sciences of the United States of America 108.42 (2011): 17569--.
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
108
Issue
42
Publish Date
2011
Start Page
17569-
DOI
10.1073/pnas.1115170108

NAFLD and extrahepatic cancers: Have a look at the colon

Authors
Tilg, H; Diehl, AM
MLA Citation
Tilg, H, and Diehl, AM. "NAFLD and extrahepatic cancers: Have a look at the colon." Gut 60.6 (2011): 745-746.
PMID
21454382
Source
scival
Published In
Gut
Volume
60
Issue
6
Publish Date
2011
Start Page
745
End Page
746
DOI
10.1136/gut.2011.239392

Pathogenesis of alcohol-induced liver disease: Classical concepts and recent advances

Alcoholic liver disease (ALD) is a primary consequence of heavy and prolonged drinking. ALD contributes to the bulk of liver disease burden worldwide. Progression of ALD is a multifactorial and multistep process that includes many genetic and environmental risk factors. The molecular pathogenesis of ALD involves alcohol metabolism and secondary mechanisms such as oxidative stress, endotoxin, cytokines and immune regulators. The histopathological manifestation of ALD occurs as an outcome of complex but controlled interactions between hepatic cell types. Hepatic stellate cells (HSCs) are the key drivers of fibrogenesis, but transformation of hepatocytes to myofibroblastoids also implicate parenchymal cells as playing an active role in hepatic fibrogenesis. Recent discoveries indicate that lipogenesis during the early stages of ALD is a risk for advancement to cirrhosis. Other recently identified novel molecules and physiological/cell signaling pathways include fibrinolysis, osteopontin, transforming growth factor-β-SMAD and hedgehog signaling, and involvement of novel cytokines in hepatic fibrogenesis. The observation that ALD and non-alcoholic steatohepatitis share common pathways and genetic polymorphisms suggests operation of parallel pathogenic mechanisms. Future research involving genomics, epigenomics, deep sequencing and non-coding regulatory elements holds promise to identify novel diagnostic and therapeutic targets for ALD. There is also a need for adequate animal models to study pathogenic mechanisms at the molecular level and targeted therapy. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Authors
Seth, D; Haber, PS; Syn, W-K; Diehl, AM; Day, CP
MLA Citation
Seth, D, Haber, PS, Syn, W-K, Diehl, AM, and Day, CP. "Pathogenesis of alcohol-induced liver disease: Classical concepts and recent advances." Journal of Gastroenterology and Hepatology (Australia) 26.7 (2011): 1089-1105.
PMID
21545524
Source
scival
Published In
Journal of Gastroenterology and Hepatology
Volume
26
Issue
7
Publish Date
2011
Start Page
1089
End Page
1105
DOI
10.1111/j.1440-1746.2011.06756.x

Physical activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liver disease

Objectives:Factors that determine disease severity in nonalcoholic fatty liver disease (NAFLD) are unclear, but exercise is a recommended treatment. We evaluated the association between physical activity intensity and histological severity of NAFLD.Methods:We conducted a retrospective analysis of adults with biopsy-proven NAFLD enrolled in the NASH CRN (Nonalcoholic Steatohepatitis Clinical Research Network). Using self-reported time spent in physical activity, we classified participants as inactive or as meeting the US guidelines for either moderate or vigorous exercise. Histology was reviewed by a central pathology committee. Frequency and odds of steatohepatitis (NASH) and advanced fibrosis were compared between subjects who either met or did not meet exercise recommendations, and by the total amount of exercise per week.Results:A total of 813 adults (males302, females511) with NAFLD were included, with a mean age of 48 years. Neither moderate-intensity exercise nor total exercise per week was associated with NASH or stage of fibrosis. Meeting vigorous recommendations was associated with a decreased adjusted odds of having NASH (odds ratio (OR): 0.65 (0.43-0.98)). Doubling the recommended time spent in vigorous exercise, as is suggested for achieving additional health benefits, was associated with a decreased adjusted odds of advanced fibrosis (OR: 0.53 (0.29-0.97)).Conclusions: These data support an association of vigorous but not moderate or total exercise with the severity of NAFLD. Optimal doses of exercise by duration and intensity for the prevention or treatment of NASH have not been established; however, intensity may be more important than duration or total volume. © 2011 by the American College of Gastroenterology.

Authors
Kistler, KD; Brunt, EM; Clark, JM; Diehl, AM; Sallis, JF; Schwimmer, JB
MLA Citation
Kistler, KD, Brunt, EM, Clark, JM, Diehl, AM, Sallis, JF, and Schwimmer, JB. "Physical activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liver disease." American Journal of Gastroenterology 106.3 (2011): 460-468.
PMID
21206486
Source
scival
Published In
The American Journal of Gastroenterology (Elsevier)
Volume
106
Issue
3
Publish Date
2011
Start Page
460
End Page
468
DOI
10.1038/ajg.2010.488

Cancer stem cells: repair gone awry?

Because cell turnover occurs in all adult organs, stem/progenitor cells within the stem-cell niche of each tissue must be appropriately mobilized and differentiated to maintain normal organ structure and function. Tissue injury increases the demands on this process, and thus may unmask defective regulation of pathways, such as Hedgehog (Hh), that modulate progenitor cell fate. Hh pathway dysregulation has been demonstrated in many types of cancer, including pancreatic and liver cancers, in which defective Hh signaling has been linked to outgrowth of Hh-responsive cancer stem-initiating cells and stromal elements. Hence, the Hh pathway might be a therapeutic target in such tumors.

Authors
Rangwala, F; Omenetti, A; Diehl, AM
MLA Citation
Rangwala, F, Omenetti, A, and Diehl, AM. "Cancer stem cells: repair gone awry?." J Oncol 2011 (2011): 465343-.
PMID
21188169
Source
pubmed
Published In
Journal of Oncology
Volume
2011
Publish Date
2011
Start Page
465343
DOI
10.1155/2011/465343

Microarchitecture of the liver: A Jigsaw puzzle

Authors
Rojkind, M; Philips, G; Diehl, AM
MLA Citation
Rojkind, M, Philips, G, and Diehl, AM. "Microarchitecture of the liver: A Jigsaw puzzle." Journal of Hepatology 54.1 (2011): 187-188.
PMID
20951459
Source
scival
Published In
Journal of Hepatology
Volume
54
Issue
1
Publish Date
2011
Start Page
187
End Page
188
DOI
10.1016/j.jhep.2010.09.004

Sonic hedgehog pathway

The Hedgehog (Hh) Pathway, originally identified in Drosophila, [1-4] is a highly conserved signaling pathway which orchestrates multiple, disparate aspects of embryogenesis, development and tissue remodeling in a wide spectrum of systems [5-8] . This is usually accomplished by autocrine/paracrine signaling and aims to control the size and localization of Hh-responsive cell populations in response to local/long distance signals [7, 9]. Hh pathway activation typically enhances the growth and viability of Hh-responsive cells, whereas abrogating Hh signal transduction usually triggers apoptosis in such cells, unless other locally available differentiating factors expedite cellular differentiation to a more mature phenotype that no longer requires Hh viability signals [5, 9] . Thus, up-/down-regulation of the Hh pathway provides a selective growth advantage for cell types that are capable of responding to Hh ligands, when compared to neighboring cells that lack Hh receptors. This leads to-expansion/contraction, respectively, of Hh-responsive cells, thereby, orchestrating the cellular composition of several tissues [5-7, 9]. © 2010 Springer-Verlag Berlin Heidelberg.

Authors
Omenetti, A; Diehl, AM
MLA Citation
Omenetti, A, and Diehl, AM. "Sonic hedgehog pathway." (December 1, 2010): 393-401. (Chapter)
Source
scopus
Publish Date
2010
Start Page
393
End Page
401
DOI
10.1007/978-3-642-00150-5_26

Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma.

Hedgehog (Hh) pathway activation promotes many processes that occur during fibrogenic liver repair. Whether the Hh pathway modulates the outcomes of virally mediated liver injury has never been examined. Gene-profiling studies of human hepatocellular carcinomas (HCCs) demonstrate Hh pathway activation in HCCs related to chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Because most HCCs develop in cirrhotic livers, we hypothesized that Hh pathway activation occurs during fibrogenic repair of liver damage due to chronic viral hepatitis, and that Hh-responsive cells mediate disease progression and hepatocarciongenesis in chronic viral hepatitis. Immunohistochemistry and qRT-PCR analysis were used to analyze Hh pathway activation and identify Hh-responsive cell types in liver biopsies from 45 patients with chronic HBV or HCV. Hh signaling was then manipulated in cultured liver cells to directly assess the impact of Hh activity in relevant cell types. We found increased hepatic expression of Hh ligands in all patients with chronic viral hepatitis, and demonstrated that infection with HCV stimulated cultured hepatocytes to produce Hh ligands. The major cell populations that expanded during cirrhosis and HCC (ie, liver myofibroblasts, activated endothelial cells, and progenitors expressing markers of tumor stem/initiating cells) were Hh responsive, and higher levels of Hh pathway activity associated with cirrhosis and HCC. Inhibiting pathway activity in Hh-responsive target cells reduced fibrogenesis, angiogenesis, and growth. In conclusion, HBV/HCV infection increases hepatocyte production of Hh ligands and expands the types of Hh-responsive cells that promote liver fibrosis and cancer.

Authors
Pereira, TDA; Witek, RP; Syn, W-K; Choi, SS; Bradrick, S; Karaca, GF; Agboola, KM; Jung, Y; Omenetti, A; Moylan, CA; Yang, L; Fernandez-Zapico, ME; Jhaveri, R; Shah, VH; Pereira, FE; Diehl, AM
MLA Citation
Pereira, TDA, Witek, RP, Syn, W-K, Choi, SS, Bradrick, S, Karaca, GF, Agboola, KM, Jung, Y, Omenetti, A, Moylan, CA, Yang, L, Fernandez-Zapico, ME, Jhaveri, R, Shah, VH, Pereira, FE, and Diehl, AM. "Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma." Lab Invest 90.12 (December 2010): 1690-1703.
Website
http://hdl.handle.net/10161/11085
PMID
20697376
Source
pubmed
Published In
Laboratory Investigation
Volume
90
Issue
12
Publish Date
2010
Start Page
1690
End Page
1703
DOI
10.1038/labinvest.2010.147

Regional anthropometric measures and hepatic fibrosis in patients with nonalcoholic Fatty liver disease.

BACKGROUND & AIMS: In overnourished individuals, impaired peripheral fat storage (ie, reduced fat mass in extremities) can increase delivery of surplus calories to the organs other than peripheral adipose tissues, including the liver (ie, lipid overload), and facilitate disease progression in patients with nonalcoholic fatty liver disease (NAFLD). We investigated whether peripheral and/or abdominal adipose depot size correlates with stage of hepatic fibrosis in patients with NAFLD in sex- and/or menopausal stage-specific manners. METHODS: We performed a cross-sectional analysis of 537 adult patients with NAFLD. Peripheral adipose depot size was defined as the sum of z-scores of 2 anthropometric parameters (middle upper arm circumference and hip circumference, relative to total body size) and expressed as extremity size. Abdominal adipose depot size was defined as waist circumference. Peripheral and abdominal adipose depot sizes were associated with fibrosis stage(s) (F0-F4) using multivariable analyses separately for men and pre- and post-menopausal women. RESULTS: After adjusting for caloric intake and energy expenditure during physical activity (MET; hours/week), peripheral and/or abdominal adipose depot sizes were differentially associated with fibrosis stages in men and pre- and post-menopausal women. Men with smaller extremity size, premenopausal women with larger extremity size, and postmenopausal women with larger abdominal size were more likely to have higher stages of fibrosis. CONCLUSIONS: In patients with NAFLD, regional anthropometric measures are associated with fibrosis severity in a sex- and menopausal stage-specific manner. Unlike premenopausal women, men with NAFLD who have small peripheral adipose depots are at an increased risk of having advanced fibrosis.

Authors
Suzuki, A; Abdelmalek, MF; Unalp-Arida, A; Yates, K; Sanyal, A; Guy, C; Diehl, AM
MLA Citation
Suzuki, A, Abdelmalek, MF, Unalp-Arida, A, Yates, K, Sanyal, A, Guy, C, and Diehl, AM. "Regional anthropometric measures and hepatic fibrosis in patients with nonalcoholic Fatty liver disease." Clin Gastroenterol Hepatol 8.12 (December 2010): 1062-1069.
PMID
20728571
Source
pubmed
Published In
Clinical Gastroenterology and Hepatology
Volume
8
Issue
12
Publish Date
2010
Start Page
1062
End Page
1069
DOI
10.1016/j.cgh.2010.08.005

Leptin promotes the myofibroblastic phenotype in hepatic stellate cells by activating the hedgehog pathway.

Trans-differentiation of quiescent hepatic stellate cells (Q-HSCs), which exhibit epithelial and adipocytic features, into myofibroblastic-HSC (MF-HSCs) is a key event in liver fibrosis. Culture models demonstrated that Hedgehog (Hh) pathway activation is required for transition of epithelioid/adipocytic Q-HSCs into MF-HSCs. Hh signaling inhibits adiposity and promotes epithelial-to-mesenchymal transitions (EMTs). Leptin (anti-adipogenic, pro-EMT factor) promotes HSC trans-differentiation and liver fibrosis, suggesting that the pathways may interact to modulate cell fate. This study aimed to determine whether leptin activates Hh signaling and whether this is required for the fibrogenic effects of leptin. Cultures of primary HSCs from lean and fa/fa rats with an inherited ObRb defect were examined. Inhibitors of PI3K/Akt, JAK/STAT, and Hh signaling were used to delineate how ObRb activation influenced Hh signaling and HSC trans-differentiation. Fibrogenesis was compared in wild type and db/db mice (impaired ObRb function) to assess the profibrotic role of leptin. The results demonstrate that leptin-ObR interactions activate Hh signaling with the latter necessary to promote trans-differentiation. Leptin-related increases in Hh signaling required ObR induction of PI3K/Akt, which was sufficient for leptin to repress the epithelioid/adipocytic program. Leptin-mediated induction of JAK/STAT was required for mesenchymal gene expression. Leptin-ObRb interactions were not necessary for HSC trans-differentiation to occur in vitro or in vivo but are important because liver fibrogenesis was attenuated in db/db mice. These findings reveal that leptin activates Hh signaling to alter gene expression programs that control cell fate and have important implications for liver fibrosis and other leptin-regulated processes involving EMTs, including development, obesity, and cancer metastasis.

Authors
Choi, SS; Syn, W-K; Karaca, GF; Omenetti, A; Moylan, CA; Witek, RP; Agboola, KM; Jung, Y; Michelotti, GA; Diehl, AM
MLA Citation
Choi, SS, Syn, W-K, Karaca, GF, Omenetti, A, Moylan, CA, Witek, RP, Agboola, KM, Jung, Y, Michelotti, GA, and Diehl, AM. "Leptin promotes the myofibroblastic phenotype in hepatic stellate cells by activating the hedgehog pathway." J Biol Chem 285.47 (November 19, 2010): 36551-36560.
PMID
20843817
Source
pubmed
Published In
The Journal of biological chemistry
Volume
285
Issue
47
Publish Date
2010
Start Page
36551
End Page
36560
DOI
10.1074/jbc.M110.168542

MYOFIBROBLAST-DERIVED TGF beta PROMOTES BILIARY TREE GROWTH DURING CHOLESTATIC LIVER INJURY BY SUPPRESSING ANGIOPOIETIN 1/TIE2/TRYPTOPHAN HYDROXYLASE 2 AXIS AND SEROTONIN SECRETION IN NEIGHBORING CHOLANGIOCYTES

Authors
Omenetti, A; Yang, L; Gainetdinov, RR; Guy, CD; Choi, SS; Chen, W; Caron, MG; Diehl, AM
MLA Citation
Omenetti, A, Yang, L, Gainetdinov, RR, Guy, CD, Choi, SS, Chen, W, Caron, MG, and Diehl, AM. "MYOFIBROBLAST-DERIVED TGF beta PROMOTES BILIARY TREE GROWTH DURING CHOLESTATIC LIVER INJURY BY SUPPRESSING ANGIOPOIETIN 1/TIE2/TRYPTOPHAN HYDROXYLASE 2 AXIS AND SEROTONIN SECRETION IN NEIGHBORING CHOLANGIOCYTES." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
407A
End Page
408A

INCREASED PRODUCTION OF SONIC HEDGEHOG BY BALLOONED HEPATOCYTES: IMPLICATIONS FOR FIBROSIS PROGRESSION IN NASH

Authors
Rangwala, F; Guy, CD; Jiuyi, L; Chen, W; Diehl, AM
MLA Citation
Rangwala, F, Guy, CD, Jiuyi, L, Chen, W, and Diehl, AM. "INCREASED PRODUCTION OF SONIC HEDGEHOG BY BALLOONED HEPATOCYTES: IMPLICATIONS FOR FIBROSIS PROGRESSION IN NASH." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
352A
End Page
352A

CO-CULTURE OF LIVER EPITHELIAL CELLS STABLY TRANSFECTED WITH HEPATITIS B VIRUS X PROTEIN PROMOTES MYOFIBROBLASTIC ACTIVATION AND ACCUMULATION VIA A HEDGEHOG-MEDIATED PROCESS IN RAT HEPATIC STELLATE CELLS

Authors
Choi, SS; Pereira, TA; Syn, W-K; Agboola, KM; Moylan, CA; Omenetti, A; Karaca, GF; Rangwala, F; Jhaveri, R; Diehl, AM
MLA Citation
Choi, SS, Pereira, TA, Syn, W-K, Agboola, KM, Moylan, CA, Omenetti, A, Karaca, GF, Rangwala, F, Jhaveri, R, and Diehl, AM. "CO-CULTURE OF LIVER EPITHELIAL CELLS STABLY TRANSFECTED WITH HEPATITIS B VIRUS X PROTEIN PROMOTES MYOFIBROBLASTIC ACTIVATION AND ACCUMULATION VIA A HEDGEHOG-MEDIATED PROCESS IN RAT HEPATIC STELLATE CELLS." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
977A
End Page
978A

MACROPHAGE-DERIVED HEDGEHOG LIGANDS PROMOTES FIBROGENIC RESPONSES IN SCHISTOSOMIASIS MANSONI

Authors
Pereira, TA; Syn, W-K; Voieta, I; Jiuyi, L; Choi, SS; Witek, RP; Agboola, KM; Karaca, GF; Antunes, CM; Secor, WE; Andrade, ZA; Lambertucci, JR; Pereira, FE; Diehl, AM
MLA Citation
Pereira, TA, Syn, W-K, Voieta, I, Jiuyi, L, Choi, SS, Witek, RP, Agboola, KM, Karaca, GF, Antunes, CM, Secor, WE, Andrade, ZA, Lambertucci, JR, Pereira, FE, and Diehl, AM. "MACROPHAGE-DERIVED HEDGEHOG LIGANDS PROMOTES FIBROGENIC RESPONSES IN SCHISTOSOMIASIS MANSONI." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
611A
End Page
612A

NR4A NUCLEAR ORPHAN RECEPTORS ARE NOVEL REGULATORS OF HEPATIC FIBROSIS

Authors
Choi, SS; Syn, W-K; Smith, MP; Diehl, AM; Michelotti, GA
MLA Citation
Choi, SS, Syn, W-K, Smith, MP, Diehl, AM, and Michelotti, GA. "NR4A NUCLEAR ORPHAN RECEPTORS ARE NOVEL REGULATORS OF HEPATIC FIBROSIS." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
606A
End Page
607A

DEFECTIVE LIVER REGENERATION AFTER PARTIAL HEPATECTOMY IN MICE LACKING FIBROBLAST GROWTH FACTOR INDUCIBLE 14

Authors
Karaca, GF; Chen, Y; Syn, W-K; Ochoa, B; Choi, SS; Jakubowski, A; Diehl, AM
MLA Citation
Karaca, GF, Chen, Y, Syn, W-K, Ochoa, B, Choi, SS, Jakubowski, A, and Diehl, AM. "DEFECTIVE LIVER REGENERATION AFTER PARTIAL HEPATECTOMY IN MICE LACKING FIBROBLAST GROWTH FACTOR INDUCIBLE 14." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
969A
End Page
970A

HEDGEHOG PATHWAY DRIVES THE ACQUISITION OF MESENCHYMAL MARKERS IN DUCTULAR CELLS OF PATIENTS WITH BILIARY ATRESIA

Authors
Omenetti, A; Bass, LM; Anders, RA; Clemente, MG; Francis, H; Guy, CD; Choi, SS; Alpini, G; Schwarz, KB; Whitington, PF; Diehl, AM
MLA Citation
Omenetti, A, Bass, LM, Anders, RA, Clemente, MG, Francis, H, Guy, CD, Choi, SS, Alpini, G, Schwarz, KB, Whitington, PF, and Diehl, AM. "HEDGEHOG PATHWAY DRIVES THE ACQUISITION OF MESENCHYMAL MARKERS IN DUCTULAR CELLS OF PATIENTS WITH BILIARY ATRESIA." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
1022A
End Page
1023A

Statin Therapy Decreases Risk of Hepatic Steatosis and Lobular Inflammation in Patients with Nonalcoholic Fatty Liver Disease

Authors
Abdelmalek, M; Suzuki, A; Guy, C; Smith, A; Adeyefa, B; Pan, Y; Smith, M; Diehl, AM
MLA Citation
Abdelmalek, M, Suzuki, A, Guy, C, Smith, A, Adeyefa, B, Pan, Y, Smith, M, and Diehl, AM. "Statin Therapy Decreases Risk of Hepatic Steatosis and Lobular Inflammation in Patients with Nonalcoholic Fatty Liver Disease." October 2010.
Source
wos-lite
Published In
The American Journal of Gastroenterology (Elsevier)
Volume
105
Publish Date
2010
Start Page
S116
End Page
S116

CHANGES IN ALT AND VITAMIN E LEVELS AND HISTOLOGICAL RESPONSE IN PATIENTS WITH NASH TREATED WITH VITAMIN E IN THE PIVENS TRIAL

Authors
Neuschwander-Tetri, BA; Sanyal, AJ; Chalasani, NP; Kowdley, KV; McCullough, AJ; Diehl, AM; Bass, NM; Lavine, JE; Loomba, R; Brunt, EM; Kleiner, DE; Donithan, M; Van Natta, M; Tonascia, J; Unalp, A; Clark, JM; Robuck, PR
MLA Citation
Neuschwander-Tetri, BA, Sanyal, AJ, Chalasani, NP, Kowdley, KV, McCullough, AJ, Diehl, AM, Bass, NM, Lavine, JE, Loomba, R, Brunt, EM, Kleiner, DE, Donithan, M, Van Natta, M, Tonascia, J, Unalp, A, Clark, JM, and Robuck, PR. "CHANGES IN ALT AND VITAMIN E LEVELS AND HISTOLOGICAL RESPONSE IN PATIENTS WITH NASH TREATED WITH VITAMIN E IN THE PIVENS TRIAL." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
620A
End Page
621A

HEDGEHOG PATHWAY INHIBITOR IS A SAFE AND EFFECTIVE TREATMENT FOR HEPATOCELLULAR CARCINOMA IN MDR2-/- MICE WITH CHRONIC LIVER DISEASE

Authors
Schroder, VT; Rangwala, F; Syn, W-K; Guy, CD; Karaca, GF; Diehl, AM
MLA Citation
Schroder, VT, Rangwala, F, Syn, W-K, Guy, CD, Karaca, GF, and Diehl, AM. "HEDGEHOG PATHWAY INHIBITOR IS A SAFE AND EFFECTIVE TREATMENT FOR HEPATOCELLULAR CARCINOMA IN MDR2-/- MICE WITH CHRONIC LIVER DISEASE." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
1146A
End Page
1146A

DEPRESSION AND ANXIETY SCORES ARE INDEPENDENTLY ASSOCIATED WITH HISTOLOGIC SEVERITY IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE

Authors
Suzuki, A; Binks, M; Omenetti, A; Guy, CD; Pryor, AD; Pan, Y; Smith, MM; Diehl, AM; Abdelmalek, MF
MLA Citation
Suzuki, A, Binks, M, Omenetti, A, Guy, CD, Pryor, AD, Pan, Y, Smith, MM, Diehl, AM, and Abdelmalek, MF. "DEPRESSION AND ANXIETY SCORES ARE INDEPENDENTLY ASSOCIATED WITH HISTOLOGIC SEVERITY IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
626A
End Page
626A

OSTEOPONTIN PROMOTES NONALCOHOLIC FATTY LIVER DISEASE PROGRESSION

Authors
Syn, W-K; Choi, SS; Liaskou, E; Karaca, GF; Oo, YH; Pereira, TA; Bhattacharya, SD; Moylan, CA; Agboola, KM; Omenetti, A; Schroder, VT; Mi, Z; Guy, CD; Abdelmalek, MF; Potti, A; Kuo, PC; Michelotti, GA; Adams, DH; Diehl, AM
MLA Citation
Syn, W-K, Choi, SS, Liaskou, E, Karaca, GF, Oo, YH, Pereira, TA, Bhattacharya, SD, Moylan, CA, Agboola, KM, Omenetti, A, Schroder, VT, Mi, Z, Guy, CD, Abdelmalek, MF, Potti, A, Kuo, PC, Michelotti, GA, Adams, DH, and Diehl, AM. "OSTEOPONTIN PROMOTES NONALCOHOLIC FATTY LIVER DISEASE PROGRESSION." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
350A
End Page
351A

FRUCTOKINASE POLYMORPHISMS IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE ARE ASSOCIATED WITH DECREASED URIC ACID AND THE PRESENCE OF HEPATIC FIBROSIS

Authors
Abdelmalek, MF; Suzuki, A; Schmidt, S; Rimmler, J; Unalp, A; Guy, CD; Johnson, R; Hauser, MA; Diehl, AM
MLA Citation
Abdelmalek, MF, Suzuki, A, Schmidt, S, Rimmler, J, Unalp, A, Guy, CD, Johnson, R, Hauser, MA, and Diehl, AM. "FRUCTOKINASE POLYMORPHISMS IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE ARE ASSOCIATED WITH DECREASED URIC ACID AND THE PRESENCE OF HEPATIC FIBROSIS." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
644A
End Page
645A

CONSERVED GENE EXPRESSION PATTERNS IN MYOFIBROBLASTIC MURINE AND HUMAN HEPATIC STELLATE CELLS AND NAFLD PATIENTS WITH LIVER FIBROSIS COMPATIBLE WITH EPITHELIAL-TO-MESENCHYMAL LIKE TRANSITION

Authors
Moylan, CA; Choi, SS; Dellinger, A; Pang, H; Abdelmalek, MF; Hampton, D; Chen, Y; Omenetti, A; Suzuki, A; Tillmann, HL; Acharya, CR; Potti, A; Hauser, MA; Diehl, AM
MLA Citation
Moylan, CA, Choi, SS, Dellinger, A, Pang, H, Abdelmalek, MF, Hampton, D, Chen, Y, Omenetti, A, Suzuki, A, Tillmann, HL, Acharya, CR, Potti, A, Hauser, MA, and Diehl, AM. "CONSERVED GENE EXPRESSION PATTERNS IN MYOFIBROBLASTIC MURINE AND HUMAN HEPATIC STELLATE CELLS AND NAFLD PATIENTS WITH LIVER FIBROSIS COMPATIBLE WITH EPITHELIAL-TO-MESENCHYMAL LIKE TRANSITION." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
1286A
End Page
1287A

SIGNALS FROM THE FIBROTIC LIVER IN PATIENTS WITH NAFLD MAY PROMOTE DIABETES AND OBESITY

Authors
Moylan, CA; Abdelmalek, MF; Pang, H; Dellinger, A; Choi, SS; Omenetti, A; Chen, Y; Hampton, D; Syn, W-K; Suzuki, A; Tillmann, HL; Acharya, CR; Potti, A; Hauser, MA; Diehl, AM
MLA Citation
Moylan, CA, Abdelmalek, MF, Pang, H, Dellinger, A, Choi, SS, Omenetti, A, Chen, Y, Hampton, D, Syn, W-K, Suzuki, A, Tillmann, HL, Acharya, CR, Potti, A, Hauser, MA, and Diehl, AM. "SIGNALS FROM THE FIBROTIC LIVER IN PATIENTS WITH NAFLD MAY PROMOTE DIABETES AND OBESITY." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
1049A
End Page
1050A

OBSTRUCTIVE SLEEP APNEA WORSENS HEPATIC INFLAMMATION AND FIBROSIS IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE

Authors
Piercy, DL; Suzuki, A; Feng, J; Pan, Y; Guy, CD; Diehl, AM; Chiang, AA; Abdelmalek, MF
MLA Citation
Piercy, DL, Suzuki, A, Feng, J, Pan, Y, Guy, CD, Diehl, AM, Chiang, AA, and Abdelmalek, MF. "OBSTRUCTIVE SLEEP APNEA WORSENS HEPATIC INFLAMMATION AND FIBROSIS IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE." October 2010.
Source
wos-lite
Published In
Hepatology
Volume
52
Issue
4
Publish Date
2010
Start Page
631A
End Page
631A

HEDGEHOG PATHWAY ACTIVATION AND PATHOGENESIS OF CIRRHOSIS IN ALCOHOLIC AND NONALCOHOLIC FATTY LIVER DISEASE

Authors
Diehl, AM
MLA Citation
Diehl, AM. "HEDGEHOG PATHWAY ACTIVATION AND PATHOGENESIS OF CIRRHOSIS IN ALCOHOLIC AND NONALCOHOLIC FATTY LIVER DISEASE." August 10, 2010.
Source
wos-lite
Published In
Alcoholism: Clinical and Experimental Research
Volume
34
Issue
8
Publish Date
2010
Start Page
59A
End Page
59A

Activation of Rac1 promotes hedgehog-mediated acquisition of the myofibroblastic phenotype in rat and human hepatic stellate cells.

Hepatic accumulation of myofibroblastic hepatic stellate cells (MF-HSCs) is pivotal in the pathogenesis of cirrhosis. Two events are necessary for MF-HSCs to accumulate in damaged livers: transition of resident, quiescent hepatic stellate cells (Q-HSCs) to MF-HSCs and expansion of MF-HSC numbers through increased proliferation and/or reduced apoptosis. In this study, we identified two novel mediators of MF-HSC accumulation: Ras-related C3 botulinum toxin substrate 1 (Rac1) and Hedgehog (Hh). It is unclear whether Rac1 and Hh interact to regulate the accumulation of MF-HSCs. We evaluated the hypothesis that Rac1 promotes activation of the Hh pathway, thereby stimulating signals that promote transition of Q-HSCs into MF-HSCs and enhance the viability of MF-HSCs. Using both in vitro and in vivo model systems, Rac1 activity was manipulated through adenoviral vector-mediated delivery of constitutively active or dominant-negative rac1. Rac1-transgenic mice with targeted myofibroblast expression of a mutated human rac1 transgene that produces constitutively active Rac1 were also examined. Results in all models demonstrated that activating Rac1 in HSC enhanced Hh signaling, promoted acquisition/maintenance of the MF-HSC phenotype, increased MF-HSC viability, and exacerbated fibrogenesis. Conversely, inhibiting Rac1 with dominant-negative rac1 reversed these effects in all systems examined. Pharmacologic manipulation of Hh signaling demonstrated that profibrogenic actions of Rac1 were mediated by its ability to activate Hh pathway-dependent mechanisms that stimulated myofibroblastic transition of HSCs and enhanced MF-HSC viability.These findings demonstrate that interactions between Rac1 and the Hh pathway control the size of MF-HSC populations and have important implications for the pathogenesis of cirrhosis.

Authors
Choi, SS; Witek, RP; Yang, L; Omenetti, A; Syn, W-K; Moylan, CA; Jung, Y; Karaca, GF; Teaberry, VS; Pereira, TA; Wang, J; Ren, X-R; Diehl, AM
MLA Citation
Choi, SS, Witek, RP, Yang, L, Omenetti, A, Syn, W-K, Moylan, CA, Jung, Y, Karaca, GF, Teaberry, VS, Pereira, TA, Wang, J, Ren, X-R, and Diehl, AM. "Activation of Rac1 promotes hedgehog-mediated acquisition of the myofibroblastic phenotype in rat and human hepatic stellate cells." Hepatology (Baltimore, Md.) 52.1 (July 2010): 278-290.
PMID
20578145
Source
epmc
Published In
Hepatology
Volume
52
Issue
1
Publish Date
2010
Start Page
278
End Page
290
DOI
10.1002/hep.23649

Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease.

UNLABELLED: Liver inflammation is greater in nonalcoholic steatohepatitis (NASH) than steatosis, suggesting that immune responses contribute to nonalcoholic fatty liver disease (NAFLD) progression. Livers normally contain many natural killer T (NKT) cells that produce factors that modulate inflammatory and fibrogenic responses. Such cells are relatively depleted in steatosis, but their status in more advanced NAFLD is uncertain. We hypothesized that NKT cells accumulate and promote fibrosis progression in NASH. We aimed to determine if livers become enriched with NKT cells during NASH-related fibrosis; identify responsible mechanisms; and assess if NKT cells stimulate fibrogenesis. NKT cells were analyzed in wildtype mice and Patched-deficient (Ptc(+/-)) mice with an overly active Hedgehog (Hh) pathway, before and after feeding methionine choline-deficient (MCD) diets to induce NASH-related fibrosis. Effects of NKT cell-derived factors on hepatic stellate cells (HSC) were examined and fibrogenesis was evaluated in CD1d-deficient mice that lack NKT cells. NKT cells were quantified in human cirrhotic and nondiseased livers. During NASH-related fibrogenesis in wildtype mice, Hh pathway activation occurred, leading to induction of factors that promoted NKT cell recruitment, retention, and viability, plus liver enrichment with NKT cells. Ptc(+/-) mice accumulated more NKT cells and developed worse liver fibrosis; CD1d-deficient mice that lack NKT cells were protected from fibrosis. NKT cell-conditioned medium stimulated HSC to become myofibroblastic. Liver explants were 2-fold enriched with NKT cells in patients with non-NASH cirrhosis, and 4-fold enriched in patients with NASH cirrhosis. CONCLUSION: Hh pathway activation leads to hepatic enrichment with NKT cells that contribute to fibrosis progression in NASH.

Authors
Syn, W-K; Oo, YH; Pereira, TA; Karaca, GF; Jung, Y; Omenetti, A; Witek, RP; Choi, SS; Guy, CD; Fearing, CM; Teaberry, V; Pereira, FEL; Adams, DH; Diehl, AM
MLA Citation
Syn, W-K, Oo, YH, Pereira, TA, Karaca, GF, Jung, Y, Omenetti, A, Witek, RP, Choi, SS, Guy, CD, Fearing, CM, Teaberry, V, Pereira, FEL, Adams, DH, and Diehl, AM. "Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease." Hepatology 51.6 (June 2010): 1998-2007.
PMID
20512988
Source
pubmed
Published In
Hepatology
Volume
51
Issue
6
Publish Date
2010
Start Page
1998
End Page
2007
DOI
10.1002/hep.23599

Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease.

UNLABELLED: The rising incidence of obesity and diabetes coincides with a marked increase in fructose consumption. Fructose consumption is higher in individuals with nonalcoholic fatty liver disease (NAFLD) than in age-matched and body mass index (BMI)-matched controls. Because fructose elicits metabolic perturbations that may be hepatotoxic, we investigated the relationship between fructose consumption and disease severity in NAFLD. We studied 427 adults enrolled in the NASH Clinical Research Network for whom Block food questionnaire data were collected within 3 months of a liver biopsy. Fructose consumption was estimated based on reporting (frequency x amount) of Kool-aid, fruit juices, and nondietary soda intake, expressed as servings per week, and classified into none, minimum to moderate (<7 servings/week), and daily (> or =7 servings/week). The association of fructose intake with metabolic and histological features of NAFLD was analyzed using multiple linear and ordinal logistic regression analyses with and without controlling for other confounding factors. Increased fructose consumption was univariately associated with decreased age (P < 0.0001), male sex (P < 0.0001), hypertriglyceridemia (P < 0.04), low high-density lipoprotein (HDL) cholesterol (<0.0001), decreased serum glucose (P < 0.001), increased calorie intake (P < 0.0001), and hyperuricemia (P < 0.0001). After controlling for age, sex, BMI, and total calorie intake, daily fructose consumption was associated with lower steatosis grade and higher fibrosis stage (P < 0.05 for each). In older adults (age > or = 48 years), daily fructose consumption was associated with increased hepatic inflammation (P < 0.05) and hepatocyte ballooning (P = 0.05). CONCLUSION: In patients with NAFLD, daily fructose ingestion is associated with reduced hepatic steatosis but increased fibrosis. These results identify a readily modifiable environmental risk factor that may ameliorate disease progression in patients with NAFLD.

Authors
Abdelmalek, MF; Suzuki, A; Guy, C; Unalp-Arida, A; Colvin, R; Johnson, RJ; Diehl, AM; Nonalcoholic Steatohepatitis Clinical Research Network,
MLA Citation
Abdelmalek, MF, Suzuki, A, Guy, C, Unalp-Arida, A, Colvin, R, Johnson, RJ, Diehl, AM, and Nonalcoholic Steatohepatitis Clinical Research Network, . "Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease." Hepatology 51.6 (June 2010): 1961-1971.
PMID
20301112
Source
pubmed
Published In
Hepatology
Volume
51
Issue
6
Publish Date
2010
Start Page
1961
End Page
1971
DOI
10.1002/hep.23535

Hedgehog signaling is critical for normal liver regeneration after partial hepatectomy in mice.

Distinct mechanisms are believed to regulate growth of the liver during fetal development and after injury in adults, because the former relies on progenitors and the latter generally involves replication of mature hepatocytes. However, chronic liver injury in adults increases production of Hedgehog (Hh) ligands, developmental morphogens that control progenitor cell fate and orchestrate various aspects of tissue construction during embryogenesis. This raises the possibility that similar Hh-dependent mechanisms also might regulate adult liver regeneration. The current analysis of murine liver regeneration after 70% partial hepatectomy (PH), an established model of adult liver regeneration, demonstrated that PH induced production of Hh ligands and activated Hh signaling in liver cells. Treatment with a specific Hh signaling inhibitor interfered with several key components of normal liver regeneration, significantly inhibiting progenitor responses, matrix remodeling, proliferation of hepatocytes and ductular cells, and restoration of liver mass. These global inhibitory effects on liver regeneration dramatically reduced survival after PH.Mechanisms that mediate liver organogenesis, such as Hh pathway activation, are retained and promote reconstruction of adult livers after injury.

Authors
Ochoa, B; Syn, W-K; Delgado, I; Karaca, GF; Jung, Y; Wang, J; Zubiaga, AM; Fresnedo, O; Omenetti, A; Zdanowicz, M; Choi, SS; Diehl, AM
MLA Citation
Ochoa, B, Syn, W-K, Delgado, I, Karaca, GF, Jung, Y, Wang, J, Zubiaga, AM, Fresnedo, O, Omenetti, A, Zdanowicz, M, Choi, SS, and Diehl, AM. "Hedgehog signaling is critical for normal liver regeneration after partial hepatectomy in mice." Hepatology (Baltimore, Md.) 51.5 (May 2010): 1712-1723.
PMID
20432255
Source
epmc
Published In
Hepatology
Volume
51
Issue
5
Publish Date
2010
Start Page
1712
End Page
1723
DOI
10.1002/hep.23525

Signals from dying hepatocytes trigger growth of liver progenitors.

OBJECTIVE: The death rate of mature hepatocytes is chronically increased in various liver diseases, triggering responses that prevent liver atrophy, but often cause fibrosis. Mice with targeted disruption of inhibitor kappa B kinase (Ikk) in hepatocytes (HEP mice) provide a model to investigate this process because inhibiting Ikk-nuclear factor-kappaB (NF-kappaB) signalling in hepatocytes increases their apoptosis. METHODS: Cell proliferation, apoptosis, progenitors, fibrosis and production of Hedgehog (Hh) ligands (progenitor and myofibroblast growth factors) were compared in HEP and control mice before and after feeding methionine choline-deficient ethionine-supplemented (MCDE) diets. Ikkbeta was deleted from primary hepatocytes to determine the effects on Hh ligand production; Hh signalling was inhibited directly in progenitors to determine the effects on viability. Liver sections from patients were examined to assess relationships between hepatocyte production of Hh ligands, accumulation of myofibroblastic cells and liver fibrosis. RESULTS: Disrupting the Ikk-NF-kappaB pathway in hepatocytes inhibited their proliferation but induced their production of Hh ligands. The latter provided viability signals for progenitors and myofibroblasts, enhancing accumulation of these cell types and causing fibrogenesis. Findings in the mouse models were recapitulated in diseased human livers. CONCLUSION: Dying mature hepatocytes produce Hh ligands which promote the compensatory outgrowth of progenitors and myofibroblasts. These results help to explain why diseases that chronically increase hepatocyte death promote cirrhosis.

Authors
Jung, Y; Witek, RP; Syn, W-K; Choi, SS; Omenetti, A; Premont, R; Guy, CD; Diehl, AM
MLA Citation
Jung, Y, Witek, RP, Syn, W-K, Choi, SS, Omenetti, A, Premont, R, Guy, CD, and Diehl, AM. "Signals from dying hepatocytes trigger growth of liver progenitors." Gut 59.5 (May 2010): 655-665.
PMID
20427400
Source
pubmed
Published In
Gut
Volume
59
Issue
5
Publish Date
2010
Start Page
655
End Page
665
DOI
10.1136/gut.2009.204354

Epithelial-mesenchymal transitions and hepatocarcinogenesis.

Epithelial-mesenchymal transitions (EMTs) are believed to play a role in invasion and metastasis of many types of tumors. In this issue of the JCI, Chen et al. show that a gene that has been associated with aggressive biology in hepatocellular carcinomas initiates a molecular cascade that results in EMT.

Authors
Jou, J; Diehl, AM
MLA Citation
Jou, J, and Diehl, AM. "Epithelial-mesenchymal transitions and hepatocarcinogenesis." J Clin Invest 120.4 (April 2010): 1031-1034.
Website
http://hdl.handle.net/10161/4329
PMID
20335655
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
120
Issue
4
Publish Date
2010
Start Page
1031
End Page
1034
DOI
10.1172/JCI42615

Hepatic complications of obesity.

Obesity is associated with a spectrum of chronic liver disease. Because obesity increases the risk for advanced forms of liver disease (ie, cirrhosis and liver cancer), the obesity epidemic is emerging as a major factor underlying the burden of liver disease in the United States and many other countries. This article reviews mechanisms that mediate the pathogenesis of obesity-related liver disease, summarizes clinical evidence that demonstrates obesity-related liver disease can be life-threatening, and discusses whether or not treatments for obesity or related comorbidities impact liver disease outcomes.

Authors
Diehl, AM
MLA Citation
Diehl, AM. "Hepatic complications of obesity." Gastroenterol Clin North Am 39.1 (March 2010): 57-68. (Review)
PMID
20202579
Source
pubmed
Published In
Gastroenterology Clinics of North America
Volume
39
Issue
1
Publish Date
2010
Start Page
57
End Page
68
DOI
10.1016/j.gtc.2009.12.001

Serum aminotransferase changes with significant weight loss: sex and age effects.

In obese subjects, the liver may be differentially affected by significant weight loss depending on as yet unknown factors. We explored clinical factors associated with serum alanine aminotransferase (ALT) changes during significant weight loss in a residential weight loss program. Clinical data from 362 adults who received a comprehensive weight loss intervention (ie, diets, physical fitness, and behavioral modification) in the program were analyzed. Serum ALT was used as a surrogate marker of liver injury. The ALT changes during the program were calculated to create study outcome categories (improvement, no change, or deterioration of ALT during significant weight loss). Variables of demography, lifestyle, and comorbidities at baseline, and total/rate of weight change during the program were explored for associations with the ALT change categories using multiple logistic regression models. Variation by sex was apparent among predictors of ALT deterioration; men with rapid weight loss and women with higher initial body mass index were more likely to experience ALT deterioration, whereas men with prior alcohol consumption were less likely to experience ALT deterioration even after adjusting for baseline ALT (Ps < .03). Variation by age was apparent among predictors of ALT improvement; younger patients with current smoking and older patients with rapid weight loss, diabetes or impaired fasting glucose, or sleep apnea or who followed a reduced-carbohydrate diet were less likely to experience ALT improvement (Ps < .05). A number of clinical factors influence ALT changes during weight loss in sex- and age-specific manners. The patterns that we detected may have pathophysiologic significance beyond the practical implications of our findings in clinical practice related to underlying changes in fat metabolism.

Authors
Suzuki, A; Binks, M; Sha, R; Wachholtz, A; Eisenson, H; Diehl, AM
MLA Citation
Suzuki, A, Binks, M, Sha, R, Wachholtz, A, Eisenson, H, and Diehl, AM. "Serum aminotransferase changes with significant weight loss: sex and age effects." Metabolism 59.2 (February 2010): 177-185.
PMID
19765777
Source
pubmed
Published In
Metabolism: clinical and experimental
Volume
59
Issue
2
Publish Date
2010
Start Page
177
End Page
185
DOI
10.1016/j.metabol.2009.06.030

Paradoxical Effects of Smo Proto-Oncogene Overexpression in Hepatocytes

Authors
Sicklick, JK; Wang, J; Huang, J; Chen, W; Diehl, AM
MLA Citation
Sicklick, JK, Wang, J, Huang, J, Chen, W, and Diehl, AM. "Paradoxical Effects of Smo Proto-Oncogene Overexpression in Hepatocytes." February 2010.
Source
wos-lite
Published In
Annals of Surgical Oncology
Volume
17
Publish Date
2010
Start Page
S23
End Page
S24

Effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetes

OBJECTIVE - Weight loss through lifestyle changes is recommended for nonalcoholic fatty liver disease (NAFLD). However, its efficacy in patients with type 2 diabetes is unproven. RESEARCH DESIGN AND METHODS - Look AHEAD (Action for Health in Diabetes) is a 16-center clinical trial with 5,145 overweight or obese adults with type 2 diabetes, who were randomly assigned to an intensive lifestyle intervention (ILI) to induce a minimum weight loss of 7% or a control group who received diabetes support and education (DSE). In the Fatty Liver Ancillary Study, 96 participants completed proton magnetic resonance spectroscopy to quantify hepatic steatosis and tests to exclude other causes of liver disease at baseline and 12 months. We defined steatosis >5.5% as NAFLD. RESULTS - Participants were 49% women and 68% white. The mean age was 61 years, mean BMI was 35 kg/m2, mean steatosis was 8.0%, and mean aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were 20.5 and 24.2 units/l, respectively. After 12 months, participants assigned to ILI (n = 46) lost more weight (-8.5 vs. -0.05%; P < 0.01) than those assigned to DSE and had a greater decline in steatosis (-50.8 vs.-22.8%; P = 0.04) and in A1C (-0.7 vs.-0.2%; P = 0.04). There were no significant 12-month changes in AST or ALT levels. At 12 months, 26% of DSE participants and 3% (1 of 31) of ILI participants without NAFLD at baseline developed NAFLD (P < 0.05). CONCLUSIONS - A 12-month intensive lifestyle intervention in patients with type 2 diabetes reduces steatosis and incident NAFLD. © 2010 by the American Diabetes Association.

Authors
Lazo, M; Solga, SF; Horska, A; Bonekamp, S; Diehl, AM; Brancati, FL; Wagenknecht, LE; Pi-Sunyer, FX; Kahn, SE; Clark, JM
MLA Citation
Lazo, M, Solga, SF, Horska, A, Bonekamp, S, Diehl, AM, Brancati, FL, Wagenknecht, LE, Pi-Sunyer, FX, Kahn, SE, and Clark, JM. "Effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetes." Diabetes Care 33.10 (2010): 2156-2163.
PMID
20664019
Source
scival
Published In
Diabetes Care
Volume
33
Issue
10
Publish Date
2010
Start Page
2156
End Page
2163
DOI
10.2337/dc10-0856

Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease

The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) was formed to conduct multicenter studies on the etiology, contributing factors, natural history, and treatment of nonalcoholic steatohepatitis (NASH). The aim of this study was to determine the associations of readily available demographic, clinical, and laboratory variables with the diagnosis of NASH and its key histological features, and determine the ability of these variables to predict the severity of nonalcoholic fatty liver disease (NAFLD). A total of 1266 adults were enrolled in NASH CRN studies between October 2004 and February 2008, of whom 1101 had available liver histology. The median age was 50 years; 82% were white and 12% Hispanic. The median body mass index was 33 kg/m 2; 49% had hypertension and 31% had type 2 diabetes. On liver biopsy, 57% were judged to have definite NASH and 31% bridging fibrosis or cirrhosis. Using data from the 698 patients with liver biopsies within 6 months of clinical data, patients with definite NASH were more likely to be female and have diabetes, higher levels of aspartate and alanine aminotransferases, alkaline phosphatase, gamma glutamyl transpeptidase, and homeostasis model assessment of insulin resistance (HOMA-IR). Progressive models for predicting histological diagnoses performed modestly for predicting steatohepatitis or ballooning (area under receiver operating characteristic curves [AUROC] ranged from 0.70-0.79), and better for advanced fibrosis (AUROC 0.73-0.85). Conclusion: Readily available clinical and laboratory variables can predict advanced fibrosis in adults with NAFLD, but additional information is needed to reliably predict the presence and severity of NASH. Prospective studies of this well-characterized population and associated tissue bank samples offer a unique opportunity to better understand the cause and natural history of NAFLD and develop more precise means for noninvasive diagnosis. Copyright © 2010 by the American Association for the Study of Liver Diseases.

Authors
Neuschwander-Tetri, BA; Clark, JM; Bass, NM; Natta, MLV; Unalp-Arida, A; Tonascia, J; Zein, CO; Brunt, EM; Kleiner, DE; McCullough, AJ; Sanyal, AJ; Diehl, AM; Lavine, JE; Chalasani, N; Kowdley, KV
MLA Citation
Neuschwander-Tetri, BA, Clark, JM, Bass, NM, Natta, MLV, Unalp-Arida, A, Tonascia, J, Zein, CO, Brunt, EM, Kleiner, DE, McCullough, AJ, Sanyal, AJ, Diehl, AM, Lavine, JE, Chalasani, N, and Kowdley, KV. "Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease." Hepatology 52.3 (2010): 913-924.
PMID
20648476
Source
scival
Published In
Hepatology
Volume
52
Issue
3
Publish Date
2010
Start Page
913
End Page
924
DOI
10.1002/hep.23784

Non-alcoholic steatohepatitis pathogenesis: role of repair in regulating the disease progression.

BACKGROUND: Increased hepatocyte apoptosis distinguishes non-alcoholic steatohepatitis (NASH) from non-alcoholic fatty liver disease (NAFLD). Therefore, we postulated that outcomes of NASH depended upon whether or not hepatic regenerative responses could keep pace with the increased rate of hepatocyte death. METHODS: To investigate mechanisms that the liver deploys to compensate for increased hepatocyte apoptosis, we studied a transgenic mouse model in which hepatocyte vulnerability to apoptosis was increased due to disruption of NF-kappaB survival signaling. RESULTS: We learned that hepatocyte death is coupled to the expansion of cell types that are involved in liver repair, including progenitors and myofibroblasts, and discovered that the outgrowth of these cell types occurs, at least in part, because dying hepatocytes produce Hedgehog morphogens that enhance the growth of progenitor and myofibroblast populations. The clinical significance of this discovery is supported by evidence that the degree of Hedgehog pathway activation also parallels the severity of liver fibrosis in patients with NASH, a disease in which hepatocyte apoptotic activity has been strongly linked to fibrosis progression. CONCLUSION: The data generated by studying a mouse model of chronic hepatocyte apoptosis, as well as NASH, a common human liver disease that is characterized by increased rates of hepatocyte apoptosis, are very similar. Both strongly support the concept that repair responses play an important role in controlling the outcomes of NASH.

Authors
Jung, Y; Diehl, AM
MLA Citation
Jung, Y, and Diehl, AM. "Non-alcoholic steatohepatitis pathogenesis: role of repair in regulating the disease progression." Dig Dis 28.1 (2010): 225-228.
PMID
20460916
Source
pubmed
Published In
Digestive diseases (Basel, Switzerland)
Volume
28
Issue
1
Publish Date
2010
Start Page
225
End Page
228
DOI
10.1159/000282092

Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis

Background: Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease. Methods: We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance. Results: Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P = 0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P = 0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P = 0.005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P = 0.02 for vitamin E and P = 0.004 for pioglitazone) but not with improvement in fibrosis scores (P = 0.24 for vitamin E and P = 0.12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. Conclusions: Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT00063622.) Copyright © 2010 Massachusetts Medical Society.

Authors
Sanyal, AJ; Chalasani, N; Kowdley, KV; McCullough, A; Diehl, AM; Bass, NM; Neuschwander-Tetri, BA; Lavine, JE; Tonascia, J; Unalp, A; Natta, MV; Clark, J; Brunt, EM; Kleiner, DE; Hoofnagle, JH; Robuck, PR
MLA Citation
Sanyal, AJ, Chalasani, N, Kowdley, KV, McCullough, A, Diehl, AM, Bass, NM, Neuschwander-Tetri, BA, Lavine, JE, Tonascia, J, Unalp, A, Natta, MV, Clark, J, Brunt, EM, Kleiner, DE, Hoofnagle, JH, and Robuck, PR. "Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis." New England Journal of Medicine 362.18 (2010): 1675-1685.
PMID
20427778
Source
scival
Published In
The New England journal of medicine
Volume
362
Issue
18
Publish Date
2010
Start Page
1675
End Page
1685
DOI
10.1056/NEJMoa0907929

Genetic susceptibility to hepatic steatosis

Authors
Diehl, AM
MLA Citation
Diehl, AM. "Genetic susceptibility to hepatic steatosis." New England Journal of Medicine 362.12 (2010): 1142-1143.
PMID
20335592
Source
scival
Published In
The New England journal of medicine
Volume
362
Issue
12
Publish Date
2010
Start Page
1142
End Page
1143
DOI
10.1056/NEJMe1000206

Domain 3 of hepatitis C virus core protein is sufficient for intracellular lipid accumulation.

BACKGROUND: Hepatitis C virus (HCV) is a major cause of liver disease worldwide, with steatosis, or "fatty liver," being a frequent histologic finding. In previous work, we identified sequence polymorphisms within domain 3 (d3) of genotype 3 HCV core protein that correlated with steatosis and in vitro lipid accumulation. In this study, we investigated the sufficiency of d3 to promote lipid accumulation, the role of HCV genotype in d3 lipid accumulation, and the subcellular distribution of d3. METHODS: Stable cell lines expressing green fluorescent protein (GFP) fusions with isolates of HCV genotype 3 core steatosis-associated d3 (d3S), non-steatosis-associated d3 (d3NS), and genotype 1 d3 (d3G1) were analyzed by means of immunofluorescence, oil red O (ORO) staining, and triglyceride quantitation. RESULTS: Cells that expressed d3S had statistically significantly more ORO than did cells expressing d3NS or d3G1 (P=.02 and <.001, respectively), as well as higher triglyceride levels P =.03 and .003, respectively). Immunofluorescence analysis showed that d3 does not colocalize to lipid droplets but partially colocalizes to the Golgi apparatus. CONCLUSIONS: Our results suggest that HCV core d3 is sufficient to mediate the accumulation of lipid by means of a mechanism that is independent of domains 1 and 2. Our results also suggest that altered lipid trafficking may be involved.

Authors
Jhaveri, R; Qiang, G; Diehl, AM
MLA Citation
Jhaveri, R, Qiang, G, and Diehl, AM. "Domain 3 of hepatitis C virus core protein is sufficient for intracellular lipid accumulation." J Infect Dis 200.11 (December 1, 2009): 1781-1788.
PMID
19852667
Source
pubmed
Published In
Journal of Infectious Diseases
Volume
200
Issue
11
Publish Date
2009
Start Page
1781
End Page
1788
DOI
10.1086/648094

Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis.

Myofibroblastic hepatic stellate cells (MF-HSC) are derived from quiescent hepatic stellate cells (Q-HSC). Q-HSC express certain epithelial cell markers and have been reported to form junctional complexes similar to epithelial cells. We have shown that Hedgehog (Hh) signaling plays a key role in HSC growth. Because Hh ligands regulate epithelial-to-mesenchymal transition (EMT), we determined whether Q-HSC express EMT markers and then assessed whether these markers change as Q-HSC transition into MF-HSC and whether the process is modulated by Hh signaling. Q-HSC were isolated from healthy livers and cultured to promote myofibroblastic transition. Changes in mRNA and protein expression of epithelial and mesenchymal markers, Hh ligands, and target genes were monitored in HSC treated with and without cyclopamine (an Hh inhibitor). Studies were repeated in primary human HSC and clonally derived HSC from a cirrhotic rat. Q-HSC activation in vitro (culture) and in vivo (CCl(4)-induced cirrhosis) resulted in decreased expression of Hh-interacting protein (Hhip, an Hh antagonist), the EMT inhibitors bone morphogenic protein (BMP-7) and inhibitor of differentiation (Id2), the adherens junction component E-cadherin, and epithelial keratins 7 and 19 and increased expression of Gli2 (an Hh target gene) and mesenchymal markers, including the mesenchyme-associated transcription factors Lhx2 and Msx2, the myofibroblast marker alpha-smooth muscle actin, and matrix molecules such as collagen. Cyclopamine reverted myofibroblastic transition, reducing mesenchymal gene expression while increasing epithelial markers in rodent and human HSC. We conclude that Hh signaling plays a key role in transition of Q-HSC into MF-HSC. Our findings suggest that Q-HSC are capable of transitioning between epithelial and mesenchymal fates.

Authors
Choi, SS; Omenetti, A; Witek, RP; Moylan, CA; Syn, W-K; Jung, Y; Yang, L; Sudan, DL; Sicklick, JK; Michelotti, GA; Rojkind, M; Diehl, AM
MLA Citation
Choi, SS, Omenetti, A, Witek, RP, Moylan, CA, Syn, W-K, Jung, Y, Yang, L, Sudan, DL, Sicklick, JK, Michelotti, GA, Rojkind, M, and Diehl, AM. "Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis." Am J Physiol Gastrointest Liver Physiol 297.6 (December 2009): G1093-G1106.
PMID
19815628
Source
pubmed
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
297
Issue
6
Publish Date
2009
Start Page
G1093
End Page
G1106
DOI
10.1152/ajpgi.00292.2009

Epithelial-to-mesenchymal transitions in the liver.

The outcome of liver injury is dictated by the effectiveness of repair. Successful repair (i.e., regeneration) results in replacement of dead epithelial cells with healthy epithelial cells, and reconstructs normal hepatic structure and function. Liver regeneration is known to involve replication of surviving mature hepatocytes and bile duct cells. This review discusses recent evidence for other mechanisms that might also replace dead hepatic epithelial cells and repair liver damage, particularly during chronic injury. According to this theory, certain epithelial cells in developing livers and/or injured adult livers undergo epithelial-to-mesenchymal transition (EMT) and move into the hepatic mesenchyme where they exhibit fibroblastic features. Some of these epithelia-derived mesenchymal cells, however, may be capable of undergoing subsequent mesenchymal-to-epithelial transition (MET), reverting to epithelial cells that ultimately become hepatocytes or cholangiocytes. Although these concepts remain to be proven, the theory predicts that the balance between EMT and MET modulates the outcome of chronic liver injury. When EMT activity outstrips MET, repair is mainly fibrogenic, causing liver fibrosis. Conversely, predominance of MET favors more normal liver regeneration. In this review, we summarize evidence that certain resident liver cells are capable of EMTs in vitro and during chronic liver injury.

Authors
Choi, SS; Diehl, AM
MLA Citation
Choi, SS, and Diehl, AM. "Epithelial-to-mesenchymal transitions in the liver." Hepatology 50.6 (December 2009): 2007-2013. (Review)
PMID
19824076
Source
pubmed
Published In
Hepatology
Volume
50
Issue
6
Publish Date
2009
Start Page
2007
End Page
2013
DOI
10.1002/hep.23196

Apoptosis and cytokines in non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD), one of the commonest causes of chronic liver disease in the United States, represents several overlapping clinicopathological states, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Although dysregulated lipid accumulation occurs across the spectrum of NAFLD, features of liver cell injury, such as hepatocyte ballooning, cytoskeletal changes (Mallory-Denk bodies), and hepatocyte apoptosis, occur predominantly in NASH and distinguish NASH from simple steatosis. Indeed, NASH is a more serious form of liver damage because cirrhosis and hepatocellular carcinoma are potential outcomes of NASH. Meanwhile, cirrhosis and hepatocellular carcinoma rarely occur in individuals with simple steatosis. Hepatic injury and apoptosis that occur in adults are often dysregulated and accompanied by the accumulation of immune cells, which produce cytokines and growth factors that drive chronic inflammation and may result in fibrosis. This article summarizes the process of apoptosis and roles of putative cytokines in progressive NAFLD.

Authors
Syn, W-K; Choi, SS; Diehl, AM
MLA Citation
Syn, W-K, Choi, SS, and Diehl, AM. "Apoptosis and cytokines in non-alcoholic steatohepatitis." Clin Liver Dis 13.4 (November 2009): 565-580.
PMID
19818305
Source
pubmed
Published In
Clinics in Liver Disease
Volume
13
Issue
4
Publish Date
2009
Start Page
565
End Page
580
DOI
10.1016/j.cld.2009.07.003

Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis.

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) is a potentially progressive liver disease that culminates in cirrhosis. Cirrhosis occurs more often in individuals with nonalcoholic steatohepatitis (NASH) than in those with steatosis (nonalcoholic fatty liver [NAFL]). The difference between NAFL and NASH is the extent of hepatocyte apoptosis, which is more extensive in NASH. Because phagocytosis of apoptotic cells activates hepatic stellate cells (HSCs), we examined the hypothesis that a pan-caspase inhibitor, VX-166, would reduce progression of fibrosis in a mouse model of NASH. Male db/db mice were fed methionine/choline-deficient (MCD) diets to induce NASH and liver fibrosis. Mice were gavaged once daily with either the pan-caspase inhibitor VX-166 (6 mg/kg/d; Vertex, Abingdon, UK) or vehicle only and sacrificed at 4 or 8 weeks. Treatment with an MCD diet increased alanine aminotransferase (ALT), caspase-3 activity, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells, NASH, and fibrosis. Treatment of MCD-fed mice with VX-166 decreased active caspase-3, TUNEL-positive cells, and triglyceride content (P < 0.05). However, ALT levels were similar in VX-166-treated mice and vehicle-treated controls. Histological findings also confirmed that both groups had comparable liver injury (NAFLD activity score >or=6). Nevertheless, VX-166-treated MCD-fed mice demonstrated decreased alpha-smooth muscle actin expression (4 weeks, P < 0.05; 8 weeks, P < 0.005) and had reduced hepatic levels of collagen 1alpha1 messenger RNA (8 weeks, P < 0.05). Hydroxyproline content and Sirius red staining of VX-166-treated livers confirmed decreases in fibrosis. CONCLUSION: Inhibiting hepatic apoptosis suppresses the development of fibrosis in mice with NASH. Beneficial effects on liver fibrosis were associated with reductions in hepatic steatosis, but occurred without obvious improvement in liver injury. These findings are consistent with evidence that apoptosis triggers HSC activation and liver fibrosis and suggest that caspase inhibitors may be useful as an antifibrotic NASH therapy.

Authors
Witek, RP; Stone, WC; Karaca, FG; Syn, W-K; Pereira, TA; Agboola, KM; Omenetti, A; Jung, Y; Teaberry, V; Choi, SS; Guy, CD; Pollard, J; Charlton, P; Diehl, AM
MLA Citation
Witek, RP, Stone, WC, Karaca, FG, Syn, W-K, Pereira, TA, Agboola, KM, Omenetti, A, Jung, Y, Teaberry, V, Choi, SS, Guy, CD, Pollard, J, Charlton, P, and Diehl, AM. "Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis." Hepatology 50.5 (November 2009): 1421-1430.
PMID
19676126
Source
pubmed
Published In
Hepatology
Volume
50
Issue
5
Publish Date
2009
Start Page
1421
End Page
1430
DOI
10.1002/hep.23167

Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Repair responses define the ultimate outcomes of liver disease. This study evaluated the hypothesis that fibrogenic repair in nonalcoholic fatty liver disease (NAFLD) is mediated by Hedgehog (Hh) pathway activation and consequent induction of epithelial-to-mesenchymal transitions (EMT) in ductular-type progenitors. METHODS: Immature ductular cells were exposed to Sonic hedgehog (Shh) in the presence or absence of the Hh inhibitor cyclopamine to determine whether Hh-pathway activation directly modulates EMT in liver progenitors. Potential biologic correlates of progenitor cell EMT were assessed using mice fed methionine-choline-deficient + ethionine (MCDE) diets with or without cyclopamine. The effects of increased Hh signaling on EMT and fibrogenic repair during diet-induced NAFLD were also compared in wild-type (WT) and Patched haplo-insufficient (Ptc(+/-)) mice. Finally, evidence of Hh-pathway activation and EMT was examined in liver sections from patients with NAFLD. RESULTS: In cultured progenitors, Shh repressed expression of epithelial genes and EMT inhibitors but induced genes that are expressed by myofibroblasts. Cyclopamine reversed these effects. In mouse NAFLD models, Hh-pathway activation, EMT, expansion of myofibroblastic populations, and liver fibrosis occurred. Cyclopamine inhibited Hh-pathway activation and induction of EMT. Ptc(+/-) mice, which have an overactive Hh pathway, exhibited sustained overinduction of Hh target genes and more EMT, myofibroblast accumulation, and fibrosis than WT mice. Numbers of Shh-producing cells and Hh-responsive ductular cells that expressed EMT markers increased in parallel with liver fibrosis in patients with NAFLD. CONCLUSIONS: Hh-mediated EMT in ductular cells contributes to the pathogenesis of cirrhosis in NAFLD.

Authors
Syn, W-K; Jung, Y; Omenetti, A; Abdelmalek, M; Guy, CD; Yang, L; Wang, J; Witek, RP; Fearing, CM; Pereira, TA; Teaberry, V; Choi, SS; Conde-Vancells, J; Karaca, GF; Diehl, AM
MLA Citation
Syn, W-K, Jung, Y, Omenetti, A, Abdelmalek, M, Guy, CD, Yang, L, Wang, J, Witek, RP, Fearing, CM, Pereira, TA, Teaberry, V, Choi, SS, Conde-Vancells, J, Karaca, GF, and Diehl, AM. "Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease." Gastroenterology 137.4 (October 2009): 1478-1488.e8.
PMID
19577569
Source
pubmed
Published In
Gastroenterology
Volume
137
Issue
4
Publish Date
2009
Start Page
1478
End Page
1488.e8
DOI
10.1053/j.gastro.2009.06.051

In vivo quantification of liver stiffness in a rat model of hepatic fibrosis with acoustic radiation force.

Liver fibrosis is currently staged using needle biopsy, a highly invasive procedure with a number of disadvantages. Measurement of liver stiffness changes that accompany progression of the disease may provide a quantitative and noninvasive method to assess the health of the liver. The purpose of this study is to investigate the correlation between liver stiffness measured by radiation force induced shear waves and disease related changes in the liver. An additional aim is to present initial findings on the effects of liver viscosity on radiation force induced shear wave morphology. Liver fibrosis was induced in 10 rats using carbon tetrachloride (CCl(4)), while five rats acted as controls. Liver stiffness was measured in vivo in all rats after a treatment period of 8 weeks using a modified Siemens SONOLINE Antares scanner (Siemens Medical Solutions USA, Ultrasound Division, Issaquah, WA, USA). The spatial coherence of radiation force induced shear waves propagating in the viscoelastic rat liver decreased significantly with propagation distance, compared with shear waves in an elastic phantom and a finite element model of a purely elastic medium. Animals were sacrificed after imaging and liver samples were taken for histopathologic analysis and collagen quantification using picrosirius red staining and hydroxyproline assay. At the end of the treatment period, five rats had healthy livers (stage F0), while six had severe fibrosis (F3) and the rest had light to moderate fibrosis (F1 and F2). The measured liver stiffness for the F0 group was 1.5+/-0.1 kPa (mean+/-95% confidence interval) and for F3 livers was 1.8+/-0.2 kPa. In this study, liver stiffness was found to be linearly correlated with the amount of collagen in the liver measured by picrosirius red staining (r(2)=0.43, p=0.008). In addition, stiffness spatial heterogeneity was also linearly correlated with liver collagen content (r(2)=0.58, p=0.001) by picrosirius red staining. These results are consistent with those obtained by Salameh et al. (2007) and Yin et al. (2007b) using animal models of liver fibrosis and MR elastography. This suggests that stiffness measurement using acoustic radiation force can provide a quantitative assessment of the extent of fibrosis in the liver and can be potentially used for the diagnosis, management and study of liver fibrosis.

Authors
Wang, MH; Palmeri, ML; Guy, CD; Yang, L; Hedlund, LW; Diehl, AM; Nightingale, KR
MLA Citation
Wang, MH, Palmeri, ML, Guy, CD, Yang, L, Hedlund, LW, Diehl, AM, and Nightingale, KR. "In vivo quantification of liver stiffness in a rat model of hepatic fibrosis with acoustic radiation force." Ultrasound Med Biol 35.10 (October 2009): 1709-1721.
PMID
19683381
Source
pubmed
Published In
Ultrasound in Medicine and Biology
Volume
35
Issue
10
Publish Date
2009
Start Page
1709
End Page
1721
DOI
10.1016/j.ultrasmedbio.2009.04.019

TRANSIENT HEDGEHOG PATHWAY ACTIVATION AND ACCUMULATION OF HEDGEHOG-RESPONSIVE MYOFIBROBLASTS PRECEDE EXPANSION OF LIVER EPITHELIAL PROGENITORS AFTER ACUTE CARBON TETRACHLORIDE INJURY

Authors
Witek, RP; Pereira, TA; Syn, W-K; Jung, Y; Agboolo, KM; Choi, SS; Diehl, AM
MLA Citation
Witek, RP, Pereira, TA, Syn, W-K, Jung, Y, Agboolo, KM, Choi, SS, and Diehl, AM. "TRANSIENT HEDGEHOG PATHWAY ACTIVATION AND ACCUMULATION OF HEDGEHOG-RESPONSIVE MYOFIBROBLASTS PRECEDE EXPANSION OF LIVER EPITHELIAL PROGENITORS AFTER ACUTE CARBON TETRACHLORIDE INJURY." October 2009.
Source
wos-lite
Published In
Hepatology
Volume
50
Issue
4
Publish Date
2009
Start Page
822A
End Page
822A

HEDGEHOG SIGNALING, STELLATE CELL/ENDOTHELIAL CELL CROSS-TALK AND PROGRESSION OF VIRAL HEPATITIS

Authors
Pereira, TA; Witek, RP; Syn, W-K; Choi, SS; Jung, Y; Karaca, GF; Omenetti, A; Pereira, FE; Diehl, AM
MLA Citation
Pereira, TA, Witek, RP, Syn, W-K, Choi, SS, Jung, Y, Karaca, GF, Omenetti, A, Pereira, FE, and Diehl, AM. "HEDGEHOG SIGNALING, STELLATE CELL/ENDOTHELIAL CELL CROSS-TALK AND PROGRESSION OF VIRAL HEPATITIS." October 2009.
Source
wos-lite
Published In
Hepatology
Volume
50
Issue
4
Publish Date
2009
Start Page
935A
End Page
935A

NOVEL ROLE FOR HEDGEHOG PATHWAY ACTIVATION IN THE PATHOGENESIS OF PRIMARY SCLEROSING CHOLANGITIS

Authors
Teaberry, VS; Karaca, GF; Witek, RP; Syn, W-K; Omenetti, A; Jung, Y; Choi, SS; Diehl, AM
MLA Citation
Teaberry, VS, Karaca, GF, Witek, RP, Syn, W-K, Omenetti, A, Jung, Y, Choi, SS, and Diehl, AM. "NOVEL ROLE FOR HEDGEHOG PATHWAY ACTIVATION IN THE PATHOGENESIS OF PRIMARY SCLEROSING CHOLANGITIS." October 2009.
Source
wos-lite
Published In
Hepatology
Volume
50
Issue
4
Publish Date
2009
Start Page
995A
End Page
995A

INTERACTION BETWEEN HEDGEHOG PATHWAY SIGNALING AND LEPTIN IN RAT HEPATIC STELLATE CELLS

Authors
Choi, SS; Witek, RP; Syn, W-K; Omenetti, A; Karaca, GF; Jung, Y; Teaberry, VS; Diehl, AM
MLA Citation
Choi, SS, Witek, RP, Syn, W-K, Omenetti, A, Karaca, GF, Jung, Y, Teaberry, VS, and Diehl, AM. "INTERACTION BETWEEN HEDGEHOG PATHWAY SIGNALING AND LEPTIN IN RAT HEPATIC STELLATE CELLS." October 2009.
Source
wos-lite
Published In
Hepatology
Volume
50
Issue
4
Publish Date
2009
Start Page
828A
End Page
828A

HEDGEHOG-RELATED ACCUMULATION OF NKT CELLS PROMOTES FIBROGENESIS IN PROGRESSIVE NON ALCOHOLIC FATTY LIVER DISEASE

Authors
Syn, W-K; Oo, YH; Witek, RP; Pereira, TA; Jung, Y; Karaca, GF; Omenetti, A; Choi, SS; Guy, CD; Fearing, C; Teaberry, VS; Pereira, FE; Adams, DH; Diehl, AM
MLA Citation
Syn, W-K, Oo, YH, Witek, RP, Pereira, TA, Jung, Y, Karaca, GF, Omenetti, A, Choi, SS, Guy, CD, Fearing, C, Teaberry, VS, Pereira, FE, Adams, DH, and Diehl, AM. "HEDGEHOG-RELATED ACCUMULATION OF NKT CELLS PROMOTES FIBROGENESIS IN PROGRESSIVE NON ALCOHOLIC FATTY LIVER DISEASE." October 2009.
Source
wos-lite
Published In
Hepatology
Volume
50
Issue
4
Publish Date
2009
Start Page
351A
End Page
351A

NICOTINE INDUCES STEREOTYPIC FIBROGENIC CHANGES IN HUMAN PRIMARY HEPATIC STELLATE CELLS, VIA PI-3 AND P38 MAP KINASES, TRANSIDUCED THROUGH NICOTINIC ACETYLCHOLINE RECEPTORS, UPREGULATED IN HUMAN FIBROTIC NON-ALCOHOLIC STEATOHEPATITIS

Authors
Soeda, J; Morgan, M; Mckee, C; Sigalo, B; Selden, C; Hodgson, HJF; Roskams, T; Diehl, AM; Oben, JA
MLA Citation
Soeda, J, Morgan, M, Mckee, C, Sigalo, B, Selden, C, Hodgson, HJF, Roskams, T, Diehl, AM, and Oben, JA. "NICOTINE INDUCES STEREOTYPIC FIBROGENIC CHANGES IN HUMAN PRIMARY HEPATIC STELLATE CELLS, VIA PI-3 AND P38 MAP KINASES, TRANSIDUCED THROUGH NICOTINIC ACETYLCHOLINE RECEPTORS, UPREGULATED IN HUMAN FIBROTIC NON-ALCOHOLIC STEATOHEPATITIS." October 2009.
Source
wos-lite
Published In
Hepatology
Volume
50
Issue
4
Publish Date
2009
Start Page
825A
End Page
825A

PHYSICAL ACTIVITY RECOMMENDATIONS, EXERCISE INTENSITY, AND HISTOLOGICAL SEVERITY OF NONALCOHOLIC FATTY LIVER DISEASE

Authors
Kistler, K; Brunt, EM; Clark, JM; Diehl, AM; Schwimmer, JB
MLA Citation
Kistler, K, Brunt, EM, Clark, JM, Diehl, AM, and Schwimmer, JB. "PHYSICAL ACTIVITY RECOMMENDATIONS, EXERCISE INTENSITY, AND HISTOLOGICAL SEVERITY OF NONALCOHOLIC FATTY LIVER DISEASE." October 2009.
Source
wos-lite
Published In
Hepatology
Volume
50
Issue
4
Publish Date
2009
Start Page
388A
End Page
388A

NON-INVASIVE ASSESSMENT OF LIVER FIBROSIS WITH QUANTITATIVE ACOUSTIC RADIATION FORCE METHODS

Authors
Wang, M; Palmeri, M; Rouze, N; Rotemberg, V; Moser, B; Guy, CD; Diehl, AM; Abdelmalek, MF; Nightingale, K
MLA Citation
Wang, M, Palmeri, M, Rouze, N, Rotemberg, V, Moser, B, Guy, CD, Diehl, AM, Abdelmalek, MF, and Nightingale, K. "NON-INVASIVE ASSESSMENT OF LIVER FIBROSIS WITH QUANTITATIVE ACOUSTIC RADIATION FORCE METHODS." October 2009.
Source
wos-lite
Published In
Hepatology
Volume
50
Issue
4
Publish Date
2009
Start Page
743A
End Page
744A

INCREASED DIETARY FRUCTOSE IMPAIRS HEPATIC ATP HOMEOSTASIS IN NAFLD

Authors
Abdelmalek, MF; Lazo, M; Bonekamp, S; Diehl, AM; Clark, JM
MLA Citation
Abdelmalek, MF, Lazo, M, Bonekamp, S, Diehl, AM, and Clark, JM. "INCREASED DIETARY FRUCTOSE IMPAIRS HEPATIC ATP HOMEOSTASIS IN NAFLD." October 2009.
Source
wos-lite
Published In
Hepatology
Volume
50
Issue
4
Publish Date
2009
Start Page
777A
End Page
777A

GENDER AND HORMONAL STATUS ARE ASSOCIATED WITH SEVERITY OF HISTOLOGIC FEATURES AMONG PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE

Authors
Suzuki, A; Guy, CD; Smith, AD; DeMaria, EJ; Pan, Y; Smith, MM; Diehl, AM; Abdelmalek, MF
MLA Citation
Suzuki, A, Guy, CD, Smith, AD, DeMaria, EJ, Pan, Y, Smith, MM, Diehl, AM, and Abdelmalek, MF. "GENDER AND HORMONAL STATUS ARE ASSOCIATED WITH SEVERITY OF HISTOLOGIC FEATURES AMONG PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE." October 2009.
Source
wos-lite
Published In
Hepatology
Volume
50
Issue
4
Publish Date
2009
Start Page
772A
End Page
773A

Genetic differences in oxidative stress and inflammatory responses to diet-induced obesity do not alter liver fibrosis in mice.

OBJECTIVE: To determine how genetic factors might influence the progression of nonalcoholic fatty liver disease (NAFLD). DESIGN/INTERVENTION: Beginning in adolescence, male C57BL6 (BL6) and 129/SVJ mice were fed control (n=15/group) or high-fat (HF) diets (n=30/group) for 6 months. MAIN OUTCOME MEASURES: Assessed were body weight, insulin resistance, hepatic production of free radicals, expression of cytokines and fibrosis-related genes and severity of hepatic steatosis, injury and fibrosis. RESULTS: High-fat diets induced comparable obesity, hepatic steatosis and insulin resistance in the two strains. Compared with BL6 mice, 129/SVJ mice had impaired induction of antioxidant genes, generated three- to four-fold more free radicals and exhibited two-fold greater induction of profibrogenic cytokines (interleukin-4 and transforming growth factor-beta1) and fibrosis-related genes (fibronectin and tissue inhibitor of metalloproteinase-1) (all P<0.05 for 129 vs BL6). Surprisingly, however, induction of collagen I alpha1 mRNA and accumulation of Sirius red-stained fibrils and hepatic hydroxyproline were similar in BL6 and 129/SVJ mice, and although patchy sinusoidal fibrosis emerged in both strains, neither developed bridging fibrosis. CONCLUSIONS: Although BL6 and 129/SVJ mice with diet-induced obesity, insulin resistance and steatosis differed with respect to several factors that are thought to influence human NAFLD progression, they developed comparable liver fibrosis. Moreover, none of the risk factors for NAFLD-related cirrhosis in humans, including obesity, insulin resistance, chronic inflammatory and oxidant stress, steatohepatitis or activation of fibrogenic genes, proved to be sufficient to cause cirrhosis in these mice, even when exposure to one or more of these insults was very prolonged.

Authors
Syn, W-K; Yang, L; Chiang, DJ; Qian, Y; Jung, Y; Karaca, G; Choi, SS; Witek, RP; Omenetti, A; Pereira, TA; Diehl, AM
MLA Citation
Syn, W-K, Yang, L, Chiang, DJ, Qian, Y, Jung, Y, Karaca, G, Choi, SS, Witek, RP, Omenetti, A, Pereira, TA, and Diehl, AM. "Genetic differences in oxidative stress and inflammatory responses to diet-induced obesity do not alter liver fibrosis in mice." Liver Int 29.8 (September 2009): 1262-1272.
PMID
19490416
Source
pubmed
Published In
Liver International
Volume
29
Issue
8
Publish Date
2009
Start Page
1262
End Page
1272
DOI
10.1111/j.1478-3231.2009.02036.x

Repair-related activation of hedgehog signaling promotes cholangiocyte chemokine production.

UNLABELLED: The mechanisms mediating hepatic accumulation of inflammatory cells in cholestatic liver disease remain enigmatic. Our thesis is that Hedgehog (Hh) pathway activation promotes hepatic accumulation of immune cells that interact with cholangiocytes. We believe that myofibroblastic hepatic stellate cells (MF-HSCs) release soluble Hh ligands that stimulate cholangiocytes to express chemokines that recruit mononuclear cell types with cognate receptors for these chemokines, thereby orchestrating a repair-related mechanism for liver inflammation. To address this thesis, we used three experimental systems that allow the definition of Hh-dependent mechanisms that induce phenotypic changes in cholangiocytes. First, cholangiocytes were cultured alone or in the presence of Hh-producing MF-HSCs in a transwell coculture system and/or treated with MF-HSC-conditioned medium with or without Hh-neutralizing antibodies. Changes in the cholangiocyte phenotype were then evaluated by microarray analysis, quantitative reverse-transcriptase polymerase chain reaction (QRT-PCR), and/or enzyme-linked immunosorbent assay for chemokine (C-X-C) motif ligand 16 (Cxcl16). Bile duct ligation was chosen to model biliary fibrosis in mice with an overly active Hh pathway, control littermates, and healthy rats, and the gene profile was evaluated by QRT-PCR in whole liver tissue. Second, a transwell chemotaxis assay was used to examine natural killer T (NKT) cell migration in response to cholangiocytes and particularly cholangiocyte-derived Cxcl16. Finally, we studied liver samples from primary biliary cirrhosis patients and controls by QRT-PCR to compare differences in the Hh pathway and Cxcl16. Co-immunostaining of cytokeratin-7 and Cxcl16 was then performed to localize the phenotypic source of Cxcl16. We found that MF-HSCs release soluble Hh ligands that stimulate cholangiocytes to produce Cxcl16 and recruit NKT cells. Hh pathway activation during cholestatic liver injury also induces cholangiocyte expression of Cxcl16. CONCLUSION: During biliary injury, Hh pathway activation induces cholangiocyte production of chemokines that recruit NKT cells to portal tracts.

Authors
Omenetti, A; Syn, W-K; Jung, Y; Francis, H; Porrello, A; Witek, RP; Choi, SS; Yang, L; Mayo, MJ; Gershwin, ME; Alpini, G; Diehl, AM
MLA Citation
Omenetti, A, Syn, W-K, Jung, Y, Francis, H, Porrello, A, Witek, RP, Choi, SS, Yang, L, Mayo, MJ, Gershwin, ME, Alpini, G, and Diehl, AM. "Repair-related activation of hedgehog signaling promotes cholangiocyte chemokine production." Hepatology 50.2 (August 2009): 518-527.
PMID
19575365
Source
pubmed
Published In
Hepatology
Volume
50
Issue
2
Publish Date
2009
Start Page
518
End Page
527
DOI
10.1002/hep.23019

Activation of glycolysis and apoptosis in glycogen storage disease type Ia.

The deficiency of glucose-6-phosphatase (G6Pase) underlies glycogen storage disease type Ia (GSD-Ia, von Gierke disease; MIM 232200), an autosomal recessive disorder of metabolism associated with life-threatening hypoglycemia, growth retardation, renal failure, hepatic adenomas, and hepatocellular carcinoma. Liver involvement includes the massive accumulation of glycogen and lipids due to accumulated glucose-6-phosphate and glycolytic intermediates. Proteomic analysis revealed elevations in glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and other enzymes involved in glycolysis. GAPDH was markedly increased in murine G6Pase-deficient hepatocytes. The moonlighting role of GAPDH includes increasing apoptosis, which was demonstrated by increased TUNEL assay positivity and caspase 3 activation in the murine GSD-Ia liver. These analyses of hepatic involvement in GSD-Ia mice have implicated the induction of apoptosis in the pathobiology of GSD-Ia.

Authors
Sun, B; Li, S; Yang, L; Damodaran, T; Desai, D; Diehl, AM; Alzate, O; Koeberl, DD
MLA Citation
Sun, B, Li, S, Yang, L, Damodaran, T, Desai, D, Diehl, AM, Alzate, O, and Koeberl, DD. "Activation of glycolysis and apoptosis in glycogen storage disease type Ia." Mol Genet Metab 97.4 (August 2009): 267-271.
PMID
19419892
Source
pubmed
Published In
Molecular Genetics and Metabolism
Volume
97
Issue
4
Publish Date
2009
Start Page
267
End Page
271
DOI
10.1016/j.ymgme.2009.04.003

Co-medications that modulate liver injury and repair influence clinical outcome of acetaminophen-associated liver injury.

BACKGROUND & AIMS: Acetaminophen-induced liver injury is the most common cause of acute liver failure in the United States; it occurs inadvertently in approximately half of all cases. Concomitant use of other medications might impact susceptibility to acetaminophen hepatotoxicity. We investigated its association with administration of drugs that have been shown to modulate liver injury and/or repair in preclinical studies. METHODS: We analyzed data from 6386 cases of acetaminophen-associated liver injury that were defined in the FDA database of reported adverse events. Data reported in the severe adverse event categories of "died" or "life-threatening" (defined as "fatal" cases, n = 2512) were compared with those of "non-fatal" cases (n = 3874). Potential associations between fatality and concomitant use of 9 drug classes were assessed using multiple logistic regression analyses after adjusting for other variables. RESULTS: Among female subjects, concomitant use of statins, fibrates or nonsteroidal anti-inflammatory drugs was associated with decreased likelihood of fatality, whereas ethanol use was associated with increased likelihood. Among male subjects, concomitant use of statins was associated with decreased likelihood of fatality, whereas concomitant use of sympathetic stimulants or ethanol was associated with increased likelihood. Concomitant use of angiotensin converting enzyme inhibitors or angiotensin receptor II antagonists was associated with decreased likelihood of fatality among younger subjects. CONCLUSIONS: Concomitant use of medications that have been shown in preclinical studies to modulate liver injury and/or repair influenced acetaminophen hepatotoxicity. Drugs that reduce injury or increase repair are protective, whereas those that exacerbate injury or reduce repair are detrimental.

Authors
Suzuki, A; Yuen, N; Walsh, J; Papay, J; Hunt, CM; Diehl, AM
MLA Citation
Suzuki, A, Yuen, N, Walsh, J, Papay, J, Hunt, CM, and Diehl, AM. "Co-medications that modulate liver injury and repair influence clinical outcome of acetaminophen-associated liver injury." Clin Gastroenterol Hepatol 7.8 (August 2009): 882-888.
PMID
19362607
Source
pubmed
Published In
Clinical Gastroenterology and Hepatology
Volume
7
Issue
8
Publish Date
2009
Start Page
882
End Page
888
DOI
10.1016/j.cgh.2009.03.034

Role for hedgehog pathway in regulating growth and function of invariant NKT cells.

Lymphocyte accumulation is characteristic of chronic hepatitis, but the mechanisms regulating lymphocyte numbers and their roles in liver disease progression are poorly understood. The Hedgehog (Hh) pathway regulates thymic development and lymphopoeisis during embryogenesis, and is activated in fibrosing liver disease in adults. Our objective was to determine if Hh ligands regulate the viability and phenotype of NKT cells, which comprise a substantial sub-population of resident lymphocytes in healthy adult livers and often accumulate during liver fibrosis. The results demonstrate that a mouse invariant NKT cell line (DN32 iNKT cells), mouse primary liver iNKT cells, and human peripheral blood iNKT cells are all responsive to sonic hedgehog (Shh). In cultured iNKT cells, Shh enhances proliferation, inhibits apoptosis, induces activation, and stimulates expression of the pro-fibrogenic cytokine, IL-13. Livers of transgenic mice with an overly active Hh pathway harbor increased numbers of iNKT cells. iNKT cells also express Shh. These results demonstrate that iNKT cells produce and respond to Hh ligands, and that Hh pathway activation regulates the size and cytokine production of liver iNKT cell populations. Therefore, Hh pathway activation may contribute to the local expansion of pro-fibrogenic iNKT cell populations during certain types of fibrosing liver damage.

Authors
Syn, W-K; Witek, RP; Curbishley, SM; Jung, Y; Choi, SS; Enrich, B; Omenetti, A; Agboola, KM; Fearing, CM; Tilg, H; Adams, DH; Diehl, AM
MLA Citation
Syn, W-K, Witek, RP, Curbishley, SM, Jung, Y, Choi, SS, Enrich, B, Omenetti, A, Agboola, KM, Fearing, CM, Tilg, H, Adams, DH, and Diehl, AM. "Role for hedgehog pathway in regulating growth and function of invariant NKT cells." Eur J Immunol 39.7 (July 2009): 1879-1892.
PMID
19544307
Source
pubmed
Published In
European Journal of Immunology
Volume
39
Issue
7
Publish Date
2009
Start Page
1879
End Page
1892
DOI
10.1002/eji.200838890

REGULATION OF PROGENITOR RESPONSE TO ALCOHOL-INDUCED LIVER INJURY

Authors
Jung, Y; Omenetti, A; Syn, W-K; Witek, R; Choi, S; Diehl, AM
MLA Citation
Jung, Y, Omenetti, A, Syn, W-K, Witek, R, Choi, S, and Diehl, AM. "REGULATION OF PROGENITOR RESPONSE TO ALCOHOL-INDUCED LIVER INJURY." ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH 33.6 (June 2009): 270A-270A.
Source
wos-lite
Published In
Alcoholism: Clinical and Experimental Research
Volume
33
Issue
6
Publish Date
2009
Start Page
270A
End Page
270A

Similarities and differences in the pathogenesis of alcoholic and nonalcoholic steatohepatitis.

Subpopulations of individuals with alcohol-induced fatty livers and nonalcoholic steatosis develop steatohepatitis. Steatohepatitis is defined histologically: increased numbers of injured and dying hepatocytes distinguish this condition from simple steatosis. The increased hepatocyte death is generally accompanied by hepatic accumulation of inflammatory cells and sometimes increases in myofibroblastic cells, leading to hepatic fibrosis and eventually, cirrhosis. The purpose of this review is to summarize similarities and differences in the pathogenesis of steatohepatitis in alcoholic fatty liver disease and nonalcoholic fatty liver disease.

Authors
Syn, W-K; Teaberry, V; Choi, SS; Diehl, AM
MLA Citation
Syn, W-K, Teaberry, V, Choi, SS, and Diehl, AM. "Similarities and differences in the pathogenesis of alcoholic and nonalcoholic steatohepatitis." Semin Liver Dis 29.2 (May 2009): 200-210. (Review)
PMID
19387919
Source
pubmed
Published In
Seminars in Liver Disease
Volume
29
Issue
2
Publish Date
2009
Start Page
200
End Page
210
DOI
10.1055/s-0029-1214375

Myofibroblasts Promote the Growth of Biliary Tree During Cholestatic Liver Injury By Suppressing Tryptophan Hydroxylase 2 (TPH2) Expression and Serotonin Secretion in Neighboring Cholangiocytese

Authors
Omenetti, A; Yang, L; Gainetdinov, RR; Choi, SS; Witek, RP; Jung, Y; Syn, W-K; Chen, W; Caron, MG; Diehl, AM
MLA Citation
Omenetti, A, Yang, L, Gainetdinov, RR, Choi, SS, Witek, RP, Jung, Y, Syn, W-K, Chen, W, Caron, MG, and Diehl, AM. "Myofibroblasts Promote the Growth of Biliary Tree During Cholestatic Liver Injury By Suppressing Tryptophan Hydroxylase 2 (TPH2) Expression and Serotonin Secretion in Neighboring Cholangiocytese." May 2009.
Source
wos-lite
Published In
Gastroenterology
Volume
136
Issue
5
Publish Date
2009
Start Page
A800
End Page
A800

Sustained Activation of RAC1 Enhances Hedgehog-Mediated Epithelial-Mesenchymal Transition in Mice with Chronic Liver Injury

Authors
Choi, SS; Witek, RP; Omenetti, A; Yang, L; Syn, W-K; Jung, Y; Sicklick, JK; Diehl, AM
MLA Citation
Choi, SS, Witek, RP, Omenetti, A, Yang, L, Syn, W-K, Jung, Y, Sicklick, JK, and Diehl, AM. "Sustained Activation of RAC1 Enhances Hedgehog-Mediated Epithelial-Mesenchymal Transition in Mice with Chronic Liver Injury." May 2009.
Source
wos-lite
Published In
Gastroenterology
Volume
136
Issue
5
Publish Date
2009
Start Page
A792
End Page
A792

Specific Inhibition of Ikk beta in Hepatocytes Induces Proliferation of Liver Progenitors in Injured Livers

Authors
Jung, Y; Witek, RP; Syn, W-K; Choi, SS; Omenetti, A; Diehl, AM
MLA Citation
Jung, Y, Witek, RP, Syn, W-K, Choi, SS, Omenetti, A, and Diehl, AM. "Specific Inhibition of Ikk beta in Hepatocytes Induces Proliferation of Liver Progenitors in Injured Livers." May 2009.
Source
wos-lite
Published In
Gastroenterology
Volume
136
Issue
5
Publish Date
2009
Start Page
A789
End Page
A789

Sexual Development and Its Influence On Regional Anthropometric Measures and Histologic Features Among Pediatric Patients with NAFLD

Authors
Suzuki, A; Abdelmalek, MF; Guy, CD; Schwimmer, J; Lavine, JE; Scheimann, AO; Diehl, AM
MLA Citation
Suzuki, A, Abdelmalek, MF, Guy, CD, Schwimmer, J, Lavine, JE, Scheimann, AO, and Diehl, AM. "Sexual Development and Its Influence On Regional Anthropometric Measures and Histologic Features Among Pediatric Patients with NAFLD." May 2009.
Source
wos-lite
Published In
Gastroenterology
Volume
136
Issue
5
Publish Date
2009
Start Page
A845
End Page
A845

Sonic hedgehog ligand partners with caveolin-1 for intracellular transport.

Prenatal alcohol exposure is the most common environmental factor leading to congenital birth defects in the United States. Although significant progress has been made in this field, the detailed molecular pathology of fetal alcohol syndrome (FAS) remains to be determined. Previously, we have shown that alcohol exposure perturbs hedgehog signal transduction in zebrafish embryos by inhibiting the post-translational cholesterol modification of Sonic hedgehog (Shh), leading to decreased levels of mature Shh ligand that is associated with the plasma membrane, and causing transient loss of Hh signaling, resulting in permanent FAS-related morphological abnormalities. In the present study, we further elucidate the mechanisms that regulate the intracellular transportation and secretion of Shh using the hepatic stellate cell line HSC8B. We have found that Shh is associated with caveolin-1 in the Golgi apparatus to form protein complexes and that these complexes are packaged as large punctuate structures (transport vesicles) that are transported to the plasma membrane in lipid raft microdomains. Alcohol exposure does not significantly interrupt translation of shh mRNA in endoplasmic reticulum (ER) or the trafficking of Shh from the ER to the Golgi apparatus. However, alcohol does prevent the entry of Shh into transport vesicles from the Golgi to the plasma membrane and specifically decreases the amount of caveolin-1/Shh complex found in lipid rafts, causing cytoplasmic accumulation of Shh and leading to a deficiency of Shh ligand secretion into the extracellular matrix.

Authors
Mao, H; Diehl, AM; Li, Y-X
MLA Citation
Mao, H, Diehl, AM, and Li, Y-X. "Sonic hedgehog ligand partners with caveolin-1 for intracellular transport." Lab Invest 89.3 (March 2009): 290-300.
PMID
19139721
Source
pubmed
Published In
Laboratory Investigation
Volume
89
Issue
3
Publish Date
2009
Start Page
290
End Page
300
DOI
10.1038/labinvest.2008.163

Novel Mutant Smoothened in Hepatomas Can Activate Hedgehog Signaling

Authors
Sicklick, JK; Wang, J; Watkins, DN; Huang, J; Chen, W; Diehl, AM
MLA Citation
Sicklick, JK, Wang, J, Watkins, DN, Huang, J, Chen, W, and Diehl, AM. "Novel Mutant Smoothened in Hepatomas Can Activate Hedgehog Signaling." ANNALS OF SURGICAL ONCOLOGY 16 (February 2009): 15-15.
Source
wos-lite
Published In
Annals of Surgical Oncology
Volume
16
Publish Date
2009
Start Page
15
End Page
15

Analysis of Hepatic Progenitor Populations in Methyl Deficient Liver Injury

Authors
Sicklick, JK; Huang, J; McCall, SJ; Torbenson, MS; Diehl, AM
MLA Citation
Sicklick, JK, Huang, J, McCall, SJ, Torbenson, MS, and Diehl, AM. "Analysis of Hepatic Progenitor Populations in Methyl Deficient Liver Injury." ANNALS OF SURGICAL ONCOLOGY 16 (February 2009): 33-33.
Source
wos-lite
Published In
Annals of Surgical Oncology
Volume
16
Publish Date
2009
Start Page
33
End Page
33

Liver cell-derived microparticles activate hedgehog signaling and alter gene expression in hepatic endothelial cells.

BACKGROUND & AIMS: Angiogenesis contributes to vascular remodeling during cirrhosis. In cirrhotic livers, cholangiocytes, and myofibroblastic hepatic stellate cells (MF-HSC) produce Hedgehog (Hh) ligands. During embryogenesis Hh ligands are released from ligand-producing cells in microparticles and activate Hh signaling in endothelial cells. We studied whether adult liver cell-derived microparticles contain Hh ligands that alter hepatic sinusoidal endothelial cells (SEC). METHODS: MF-HSC and cholangiocytes were exposed to platelet-derived growth factor to induce Hh ligands; microparticles were isolated from medium, analyzed by transmission electron microscopy and immunoblots, and applied to Hh-reporter-containing cells. Microparticles were obtained from serum and bile of rats after bile duct ligation (BDL) or sham surgery and applied to normal primary liver SEC with or without cyclopamine, an Hh signaling inhibitor. Effects on SEC gene expression were evaluated by quantitative reverse-transcription polymerase chain reaction and immunoblotting. Hh target gene expression and SEC activation markers were compared in primary SEC and in liver sections from healthy and BDL rats. RESULTS: Platelet-derived growth factor-treated MF-HSC and cholangiocytes released exosome-enriched microparticles containing biologically-active Hh ligands. BDL increased release of Hh-containing exosome-enriched microparticles into plasma and bile. Transmission electron microscopy and immunoblots revealed similarities among microparticles from all sources; all microparticles induced similar Hh-dependent changes in SEC gene expression. SEC from healthy livers did not express Hh target genes or activation markers, but both were up-regulated in SEC after BDL. CONCLUSIONS: Hh-containing exosome-enriched microparticles released from liver cells alter hepatic SEC gene expression, suggesting a novel mechanism for cirrhotic vasculopathy.

Authors
Witek, RP; Yang, L; Liu, R; Jung, Y; Omenetti, A; Syn, W-K; Choi, SS; Cheong, Y; Fearing, CM; Agboola, KM; Chen, W; Diehl, AM
MLA Citation
Witek, RP, Yang, L, Liu, R, Jung, Y, Omenetti, A, Syn, W-K, Choi, SS, Cheong, Y, Fearing, CM, Agboola, KM, Chen, W, and Diehl, AM. "Liver cell-derived microparticles activate hedgehog signaling and alter gene expression in hepatic endothelial cells." Gastroenterology 136.1 (January 2009): 320-330.e2.
PMID
19013163
Source
pubmed
Published In
Gastroenterology
Volume
136
Issue
1
Publish Date
2009
Start Page
320
End Page
330.e2
DOI
10.1053/j.gastro.2008.09.066

Portal chronic inflammation in nonalcoholic fatty liver disease (NAFLD): A histologic marker of advanced NAFLD - Clinicopathologic correlations from the nonalcoholic steatohepatitis clinical research network

Adult nonalcoholic fatty liver disease (NAFLD) is characterized by absent or mild portal chronic inflammation (CI); in children, portal CI may be predominant. This study correlated clinical features with portal CI. Centrally-graded biopsies and temporally-related clinical parameters from 728 adults and 205 children. From the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) were evaluated. Mild, more than mild and no portal CI were found in 60%, 23% and 16% of adult biopsies and 76%, 14% and 10% of pediatric biopsies. Autoantibodies, and elevated alanine aminotransferase were not associated with portal CI. Clinical features associated with "more than mild" in adults were older age (P<0.0001), female gender (P= 0.001), higher body mass index (P < 0.0001), elevated insulin levels (P = 0.001), higher homeostasis model assessment of insulin resistance score (HOMA-IR) (P < 0.0001), and medications used for NAFLD (P=0.0004), diabetes (P<0.0001), and hypertension (P<0.0001). "More than mild" in the pediatric biopsies correlated with younger age (P=0.01), but not with body mass index, insulin or HOMA-IR. In both groups, lobular and portal inflammation scores had no association, but there was an association with definite steatohepatitis (P < 0.0001). Features associated in the adult biopsies with "more than mild" were steatosis amount (P=0.01) and location (P<0.0001), ballooning (P<0.0001), and advanced fibrosis (P<0.0001). In the pediatric biopsies, "more than mild" was associated with steatosis location (P = 0.0008) and fibrosis score (P < 0.0001), specifically, the portal/periportal fibrosis or greater fibrosis) (P < 0.01). Conclusion: Increased portal CI is associated with many clinical and pathologic features of progressive NAFLD in both adults and children, but not with ALT, autoantibodies, or lobular inflammation. More than mild portal CI in liver biopsies of untreated NAFLD may be considered a marker of advanced disease. Copyright © 2008 by the American Association for the Study of Liver Diseases.

Authors
Brunt, EM; Kleiner, DE; Wilson, LA; Unalp, A; Behling, CE; Lavine, JE; Neuschwander-Tetri, BA; Abrams, S; Arceo, D; Espinosa, D; Fairly, L; Bringman, D; Hawkins, C; Liu, Y-C; Rogers, N; Stager, M; McCullough, A; Dasarathy, S; Edwards, K; Sargent, R; Coffey, M; Murray, K; Young, M; Mohan, P; Nair, K; Abdelmalek, M; Diehl, AM; Gottfried, M; Guy, C; Killenberg, P; Kwan, S; Pan, Y-P; Piercy, D; Smith, M; Bhimalli, P; Chalasani, N; Cummings, OW; Lee, L; Ragozzino, L; Vuppalanchi, R; Calabrese, B et al.
MLA Citation
Brunt, EM, Kleiner, DE, Wilson, LA, Unalp, A, Behling, CE, Lavine, JE, Neuschwander-Tetri, BA, Abrams, S, Arceo, D, Espinosa, D, Fairly, L, Bringman, D, Hawkins, C, Liu, Y-C, Rogers, N, Stager, M, McCullough, A, Dasarathy, S, Edwards, K, Sargent, R, Coffey, M, Murray, K, Young, M, Mohan, P, Nair, K, Abdelmalek, M, Diehl, AM, Gottfried, M, Guy, C, Killenberg, P, Kwan, S, Pan, Y-P, Piercy, D, Smith, M, Bhimalli, P, Chalasani, N, Cummings, OW, Lee, L, Ragozzino, L, Vuppalanchi, R, and Calabrese, B et al. "Portal chronic inflammation in nonalcoholic fatty liver disease (NAFLD): A histologic marker of advanced NAFLD - Clinicopathologic correlations from the nonalcoholic steatohepatitis clinical research network." Hepatology 49.3 (2009): 809-820.
PMID
19142989
Source
scival
Published In
Hepatology
Volume
49
Issue
3
Publish Date
2009
Start Page
809
End Page
820
DOI
10.1002/hep.22724

Quality of life in adults with nonalcoholic fatty liver disease: Baseline data from the nonalcoholic steatohepatitis clinical research network

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States. The association between NAFLD and quality of life (QOL) remains unclear. These data are important to estimate the burden of illness in NAFLD. The aim was to report QOL scores of adults with NAFLD and examine the association between NAFLD severity and QOL. QOL data were collected from adults with NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network using the Short Form 36 (SF-36) survey, and scores were compared with normative U.S. population scores. Liver biopsy histology was reviewed by a central pathology committee. A total of 713 subjects with NAFLD (male = 269, female = 444) were included. Mean age of subjects was 48.3 years; 61% had definite nonalcoholic steatohepatitis (NASH), and 28% had bridging fibrosis or cirrhosis. Diabetes was present in 27% of subjects. Subjects with NAFLD had worse physical (mean, 45.2) and mental health scores (mean, 47.6) compared with the U.S. population with (mean, 50) and without (physical, 55.8; mental, 52.5) chronic illness. Subjects with NASH reported lower physical health compared with subjects with fatty liver disease without NASH (44.5 versus 47.1, P = 0.02). Subjects with cirrhosis had significantly (P<0.001) poorer physical health scores (38.4) than subjects with no (47.6), mild (46.2), moderate (44.6), or bridging fibrosis (44.6). Cirrhosis was associated with poorer physical health after adjusting for potential confounders. Mental health scores did not differ between participants with and without NASH or by degree of fibrosis. Conclusion: Adults with NAFLDhave a significant decrement inQOL.Treatment ofNAFLDshould incorporate strategies to improve QOL, especially physical health. Copyright © 2009 by the American Association for the Study of Liver Diseases.

Authors
David, K; Kowdley, KV; Unalp, A; Kanwal, F; Brunt, EM; Schwimmer, JB; Abrams, S; Arceo, D; Espinosa, D; Fairly, L; McCullough, A; Bringman, D; Dasarathy, S; Hawkins, C; Liu, Y-C; Rogers, N; Stager, M; Edwards, K; Sargent, R; Coffey, M; Murray, K; Young, M; Mohan, P; Nair, K; Diehl, AM; Gortfried, M; Guy, C; Killenberg, P; Kwan, S; Pan, Y-P; Piercy, D; Smith, M; Bhimalli, P; Chalasani, N; Cummings, OW; Lee, L; Ragozzino, L; Vuppalanchi, R; Scheimann, A; Torbenson, M; Klipsch, A; Molleston, J et al.
MLA Citation
David, K, Kowdley, KV, Unalp, A, Kanwal, F, Brunt, EM, Schwimmer, JB, Abrams, S, Arceo, D, Espinosa, D, Fairly, L, McCullough, A, Bringman, D, Dasarathy, S, Hawkins, C, Liu, Y-C, Rogers, N, Stager, M, Edwards, K, Sargent, R, Coffey, M, Murray, K, Young, M, Mohan, P, Nair, K, Diehl, AM, Gortfried, M, Guy, C, Killenberg, P, Kwan, S, Pan, Y-P, Piercy, D, Smith, M, Bhimalli, P, Chalasani, N, Cummings, OW, Lee, L, Ragozzino, L, Vuppalanchi, R, Scheimann, A, Torbenson, M, Klipsch, A, and Molleston, J et al. "Quality of life in adults with nonalcoholic fatty liver disease: Baseline data from the nonalcoholic steatohepatitis clinical research network." Hepatology 49.6 (2009): 1904-1912.
PMID
19434741
Source
scival
Published In
Hepatology
Volume
49
Issue
6
Publish Date
2009
Start Page
1904
End Page
1912
DOI
10.1002/hep.22868

Erratum: A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities (Proceedings of the National Academy of Sciences of the United States of America (2008) 105:49 (19432-19437) Doi: 10.1073/pnas.0806674105)

Authors
Garman, KS; Acharya, CR; Edelman, E; Grade, M; Gaedcke, J; Sud, S; Barry, W; Diehl, AM; Provenzale, D; Ginsburg, GS; Ghadimi, BM; Ried, T; Nevins, JR; Mukherjee, S; Hsu, D; Potti, A
MLA Citation
Garman, KS, Acharya, CR, Edelman, E, Grade, M, Gaedcke, J, Sud, S, Barry, W, Diehl, AM, Provenzale, D, Ginsburg, GS, Ghadimi, BM, Ried, T, Nevins, JR, Mukherjee, S, Hsu, D, and Potti, A. "Erratum: A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities (Proceedings of the National Academy of Sciences of the United States of America (2008) 105:49 (19432-19437) Doi: 10.1073/pnas.0806674105)." Proceedings of the National Academy of Sciences of the United States of America 106.16 (2009): 6878--.
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
106
Issue
16
Publish Date
2009
Start Page
6878-
DOI
10.1073/pnas.0902004106

Recruitment of host progenitor cells in rat liver transplants

Despite major histocompatibility complex incompatibility, liver transplants from Lewis rats to dark agouti (DA) rats survive indefinitely without immunosuppression, and the studies we report sought the mechanism(s) responsible for this. At 1 year, most of the liver reacted positively to host anti-DA antibody. When small (50%) grafts were transplanted, recruitment was more rapid because most of the organ assumed the host phenotype at 3 months. After transplantation, the Y chromosome was detected in the hepatocytes of XX to XY grafts by both in situ hybridization and polymerase chain reaction. Further, livers from transgenic Lewis rats carrying strong green fluorescent protein (GFP) markers lost the marker with time after transplantation to DA, GFP-negative hosts. Few liver cells contained the Y chromosome in syngeneic XX to XY liver grafts or when the hosts of Lewis XX to DA XY allografts were treated with cyclosporine A at 10 mg/kg/day. This dosage also impeded enlargement of the liver at 10 days. Using GFP-positive XX Lewis donors transplanted to GFP-negative XY DA hosts, we found little Y DNA in GFP-positive cells at 10 days. Host-derived OV-6-positive and c-kit-positive, albumin-positive cells were present at 3-10 days, but cells with the CD34 marker were less common and some clearly still had the donor phenotype at 10 days. Cells positive for chemokine cysteine-X-cysteine receptor-4 increased with time and were abundant 1month after transplantation. We conclude: (1) extrahepatic cells can differentiate into liver tissues; (2) regenerative stimuli accelerate stem cell recruitment; (3) both regeneration and recruitment are impeded by cyclosporine A immunosuppression, and (4) donor GFPpositive cells contained little host Y chromosome after transplantation, suggesting that cell fusion was uncommon and, therefore, unlikely to be the mechanism leading to the changes in genotype and phenotype we observed. Copyright © 2008 by the American Association for the Study of Liver Diseases.

Authors
Sun, Z; Zhang, X; Locke, JE; Zheng, Q; Tachibana, S; Diehl, AM; Williams, GM
MLA Citation
Sun, Z, Zhang, X, Locke, JE, Zheng, Q, Tachibana, S, Diehl, AM, and Williams, GM. "Recruitment of host progenitor cells in rat liver transplants." Hepatology 49.2 (2009): 587-597.
PMID
18972402
Source
scival
Published In
Hepatology
Volume
49
Issue
2
Publish Date
2009
Start Page
587
End Page
597
DOI
10.1002/hep.22653

MYOFIBROBLASTS PROVIDE HEDGEHOG PARACRINE SIGNALS THAT DRIVE CHOLANGIOCYTES TO RECRUIT NKT CELLS TO PORTAL TRACTS

Authors
Omenetti, A; Syn, W-K; Jung, Y; Witek, RP; Choi, SS; Diehl, AM
MLA Citation
Omenetti, A, Syn, W-K, Jung, Y, Witek, RP, Choi, SS, and Diehl, AM. "MYOFIBROBLASTS PROVIDE HEDGEHOG PARACRINE SIGNALS THAT DRIVE CHOLANGIOCYTES TO RECRUIT NKT CELLS TO PORTAL TRACTS." JOURNAL OF HEPATOLOGY 50 (2009): S31-S32.
Source
wos-lite
Published In
Journal of Hepatology
Volume
50
Publish Date
2009
Start Page
S31
End Page
S32

A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities.

Gene expression profiles provide an opportunity to dissect the heterogeneity of solid tumors, including colon cancer, to improve prognosis and predict response to therapies. Bayesian binary regression methods were used to generate a signature of disease recurrence in patients with resected early stage colon cancer validated in an independent cohort. A 50-gene signature was developed that effectively distinguished early stage colon cancer patients with a low or high risk of disease recurrence. RT-PCR analysis of the 50-gene signature validated 9 of the top 10 differentially expressed genes. When applied to two independent validation cohorts of 55 and 73 patients, the 50-gene model accurately predicted recurrence. Standard Kaplan-Meier survival analysis confirmed the prognostic accuracy (P < 0.01, log rank), as did multivariate Cox proportional hazard models. We tested potential targeted therapeutic options for patients at high risk for disease recurrence and found a clinically important relationship between sensitivity to celecoxib, LY-294002 (PI3kinase inhibitor), retinol, and sulindac in colon cancer cell lines expressing the poor prognostic phenotype (P < 0.01, t test), which performed better than standard chemotherapy (5-FU and oxaliplatin). We present a genomic strategy in early stage colon cancer to identify patients at highest risk of recurrence. An ability to move beyond current staging by refining the estimation of prognosis in early stage colon cancer also has implications for individualized therapy.

Authors
Garman, KS; Acharya, CR; Edelman, E; Grade, M; Gaedcke, J; Sud, S; Barry, W; Diehl, AM; Provenzale, D; Ginsburg, GS; Ghadimi, BM; Ried, T; Nevins, JR; Mukherjee, S; Hsu, D; Potti, A
MLA Citation
Garman, KS, Acharya, CR, Edelman, E, Grade, M, Gaedcke, J, Sud, S, Barry, W, Diehl, AM, Provenzale, D, Ginsburg, GS, Ghadimi, BM, Ried, T, Nevins, JR, Mukherjee, S, Hsu, D, and Potti, A. "A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities." Proc Natl Acad Sci U S A 105.49 (December 9, 2008): 19432-19437.
PMID
19050079
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
105
Issue
49
Publish Date
2008
Start Page
19432
End Page
19437
DOI
10.1073/pnas.0806674105

Mechanisms of disease progression in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic pathology, ranging from simple steatosis (also called nonalcoholic fatty liver or NAFL) in its most benign form, to cirrhosis in its most advanced form. Nonalcoholic steatohepatitis (NASH) is an intermediate level of hepatic pathology. Hepatocyte accumulation of triglyceride is a hallmark of NAFL and NASH, but this sometimes subsides once cirrhosis has developed. Triglyceride storage per se is not hepatotoxic. Rather, it is a marker of increased exposure of hepatocytes to potentially toxic fatty acids. NAFL progresses to NASH when adaptive mechanisms that protect hepatocytes from fatty acid-mediated lipotoxicity become overwhelmed and rates of hepatocyte death begin to outstrip mechanisms that normally regenerate dead hepatocytes. This triggers repair responses that involve activation of hepatic stellate cells to myofibroblasts. The myofibroblasts generate excessive matrix and produce factors that stimulate expansion of liver progenitor populations. The progenitor cells produce chemokines to attract various kinds of inflammatory cells to the liver. They also differentiate to replace the dead hepatocytes. The intensity of these repair responses generally parallel the degree of hepatocyte death, resulting in variable distortion of the hepatic architecture with fibrosis, infiltrating immune cells, and regenerating epithelial nodules. As in other types of chronic liver injury, cirrhosis ensues in patients with NAFLD when repair is extreme and sustained, but ultimately unsuccessful, at reconstituting healthy hepatic epithelia.

Authors
Jou, J; Choi, SS; Diehl, AM
MLA Citation
Jou, J, Choi, SS, and Diehl, AM. "Mechanisms of disease progression in nonalcoholic fatty liver disease." Semin Liver Dis 28.4 (November 2008): 370-379. (Review)
PMID
18956293
Source
pubmed
Published In
Seminars in Liver Disease
Volume
28
Issue
4
Publish Date
2008
Start Page
370
End Page
379
DOI
10.1055/s-0028-1091981

Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans.

Epithelial-mesenchymal transitions (EMTs) play an important role in tissue construction during embryogenesis, and evidence suggests that this process may also help to remodel some adult tissues after injury. Activation of the hedgehog (Hh) signaling pathway regulates EMT during development. This pathway is also induced by chronic biliary injury, a condition in which EMT has been suggested to have a role. We evaluated the hypothesis that Hh signaling promotes EMT in adult bile ductular cells (cholangiocytes). In liver sections from patients with chronic biliary injury and in primary cholangiocytes isolated from rats that had undergone bile duct ligation (BDL), an experimental model of biliary fibrosis, EMT was localized to cholangiocytes with Hh pathway activity. Relief of ductal obstruction in BDL rats reduced Hh pathway activity, EMT, and biliary fibrosis. In mouse cholangiocytes, coculture with myofibroblastic hepatic stellate cells, a source of soluble Hh ligands, promoted EMT and cell migration. Addition of Hh-neutralizing antibodies to cocultures blocked these effects. Finally, we found that EMT responses to BDL were enhanced in patched-deficient mice, which display excessive activation of the Hh pathway. Together, these data suggest that activation of Hh signaling promotes EMT and contributes to the evolution of biliary fibrosis during chronic cholestasis.

Authors
Omenetti, A; Porrello, A; Jung, Y; Yang, L; Popov, Y; Choi, SS; Witek, RP; Alpini, G; Venter, J; Vandongen, HM; Syn, W-K; Baroni, GS; Benedetti, A; Schuppan, D; Diehl, AM
MLA Citation
Omenetti, A, Porrello, A, Jung, Y, Yang, L, Popov, Y, Choi, SS, Witek, RP, Alpini, G, Venter, J, Vandongen, HM, Syn, W-K, Baroni, GS, Benedetti, A, Schuppan, D, and Diehl, AM. "Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans." J Clin Invest 118.10 (October 2008): 3331-3342.
PMID
18802480
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
118
Issue
10
Publish Date
2008
Start Page
3331
End Page
3342
DOI
10.1172/JCI35875

SUSTAINED ACTIVATION OF RAC1 ENHANCES HEDGEHOG-MEDIATED EPITHELIAL-MESENCHYMAL TRANSITION IN CULTURED RAT HEPATIC STELLATE CELLS

Authors
Choi, SS; Omenetti, A; Witek, RP; Ren, X-R; Yang, L; Syn, W-K; Sicklick, JK; Jung, Y; Chen, W; Diehl, AM
MLA Citation
Choi, SS, Omenetti, A, Witek, RP, Ren, X-R, Yang, L, Syn, W-K, Sicklick, JK, Jung, Y, Chen, W, and Diehl, AM. "SUSTAINED ACTIVATION OF RAC1 ENHANCES HEDGEHOG-MEDIATED EPITHELIAL-MESENCHYMAL TRANSITION IN CULTURED RAT HEPATIC STELLATE CELLS." October 2008.
Source
wos-lite
Published In
Hepatology
Volume
48
Issue
4
Publish Date
2008
Start Page
380A
End Page
381A

EXOSOMES RELEASED BY HEPATIC STELLATE CELLS AND IMMATURE BILIARY EPITHELIAL CELLS CONTAIN BIOLOGICALLY-ACTIVE HEDGEHOG LIGANDS

Authors
Witek, RP; Liu, R; Syn, W-K; Jung, Y; Omenetti, A; Yang, L; Choi, SS; Chen, W; Diehl, AM
MLA Citation
Witek, RP, Liu, R, Syn, W-K, Jung, Y, Omenetti, A, Yang, L, Choi, SS, Chen, W, and Diehl, AM. "EXOSOMES RELEASED BY HEPATIC STELLATE CELLS AND IMMATURE BILIARY EPITHELIAL CELLS CONTAIN BIOLOGICALLY-ACTIVE HEDGEHOG LIGANDS." October 2008.
Source
wos-lite
Published In
Hepatology
Volume
48
Issue
4
Publish Date
2008
Start Page
407A
End Page
407A

HEDGEHOG ACTIVATES AND MODULATES HEPATIC INVARIANT NKT (INKT) RESPONSES

Authors
Syn, W-K; Witek, RP; Jung, Y; Choi, SS; Omenetti, A; Diehl, AM
MLA Citation
Syn, W-K, Witek, RP, Jung, Y, Choi, SS, Omenetti, A, and Diehl, AM. "HEDGEHOG ACTIVATES AND MODULATES HEPATIC INVARIANT NKT (INKT) RESPONSES." October 2008.
Source
wos-lite
Published In
Hepatology
Volume
48
Issue
4
Publish Date
2008
Start Page
1001A
End Page
1001A

PARACRINE HEDGEHOG SIGNALING BETWEEN CHOLANGIOCYTES AND MYOFIBROBLASTS PROMOTES NKT CELL MIGRATION TOWARDS BILIARY EPITHELIAL CELLS: A NOVEL MECHANISM FOR NKT CELL ACCUMULATION IN PRIMARY BILIARY CIRRHOSIS

Authors
Omenetti, A; Syn, W-K; Jung, Y; Witek, RP; Choi, SS; Gershwin, ME; Diehl, AM
MLA Citation
Omenetti, A, Syn, W-K, Jung, Y, Witek, RP, Choi, SS, Gershwin, ME, and Diehl, AM. "PARACRINE HEDGEHOG SIGNALING BETWEEN CHOLANGIOCYTES AND MYOFIBROBLASTS PROMOTES NKT CELL MIGRATION TOWARDS BILIARY EPITHELIAL CELLS: A NOVEL MECHANISM FOR NKT CELL ACCUMULATION IN PRIMARY BILIARY CIRRHOSIS." October 2008.
Source
wos-lite
Published In
Hepatology
Volume
48
Issue
4
Publish Date
2008
Start Page
595A
End Page
596A

GENE EXPRESSION PROFILES COUPLED WITH SIGNATURES OF ONCOGENIC PATHWAY DYSREGULATION PROVIDE A RATIONAL APPROACH TO DISSECTING THE MOLECULAR HETEROGENEITY OF HEPATOCELLULAR CARCINOMA

Authors
Moylan, CA; Choi, SS; Acharya, CR; Salter, K; Muir, AJ; Potti, A; Diehl, AM
MLA Citation
Moylan, CA, Choi, SS, Acharya, CR, Salter, K, Muir, AJ, Potti, A, and Diehl, AM. "GENE EXPRESSION PROFILES COUPLED WITH SIGNATURES OF ONCOGENIC PATHWAY DYSREGULATION PROVIDE A RATIONAL APPROACH TO DISSECTING THE MOLECULAR HETEROGENEITY OF HEPATOCELLULAR CARCINOMA." October 2008.
Source
wos-lite
Published In
Hepatology
Volume
48
Issue
4
Publish Date
2008
Start Page
1120A
End Page
1120A

HEDGEHOG PATHWAY ACTIVATION PROMOTES HEPATIC FIBROSIS IN MICE WITH DIET-INDUCED NON-ALCOHOLIC STEATOHEPATITIS

Authors
Syn, W-K; Yang, L; Jung, Y; Witek, RP; Choi, SS; Omenetti, A; Diehl, AM
MLA Citation
Syn, W-K, Yang, L, Jung, Y, Witek, RP, Choi, SS, Omenetti, A, and Diehl, AM. "HEDGEHOG PATHWAY ACTIVATION PROMOTES HEPATIC FIBROSIS IN MICE WITH DIET-INDUCED NON-ALCOHOLIC STEATOHEPATITIS." October 2008.
Source
wos-lite
Published In
Hepatology
Volume
48
Issue
4
Publish Date
2008
Start Page
828A
End Page
829A

PROPRANOLOL PROMOTES OVAL CELL ACCUMULATION BY ENHANCING HEPATOCYTE DEATH IN NON ALCOHOLIC STEATOHEPATITIS

Authors
Oben, JA; Mckee, C; Li, Z; Roskams, T; Diehl, AM
MLA Citation
Oben, JA, Mckee, C, Li, Z, Roskams, T, and Diehl, AM. "PROPRANOLOL PROMOTES OVAL CELL ACCUMULATION BY ENHANCING HEPATOCYTE DEATH IN NON ALCOHOLIC STEATOHEPATITIS." October 2008.
Source
wos-lite
Published In
Hepatology
Volume
48
Issue
4
Publish Date
2008
Start Page
831A
End Page
831A

POSSIBLE MODULATION OF ACETAMINOPHEN-ASSOCIATED LIVER INJURY BY DIVERSE CO-MEDICATIONS IN THE AERS DATABASE - A QUANTITATIVE SIGNAL DETECTION ANALYSIS

Authors
Suzuki, A; Yuen, NA; Walsh, JS; Adkison, KK; Papay, JI; Ilic, K; Diehl, AM; Hunt, CM
MLA Citation
Suzuki, A, Yuen, NA, Walsh, JS, Adkison, KK, Papay, JI, Ilic, K, Diehl, AM, and Hunt, CM. "POSSIBLE MODULATION OF ACETAMINOPHEN-ASSOCIATED LIVER INJURY BY DIVERSE CO-MEDICATIONS IN THE AERS DATABASE - A QUANTITATIVE SIGNAL DETECTION ANALYSIS." October 2008.
Source
wos-lite
Published In
Hepatology
Volume
48
Issue
4
Publish Date
2008
Start Page
471A
End Page
472A

THE EFFECT OF ONE YEAR OF INTENSIVE LIFESTYLE INTERVENTION ON HEPATIC STEATOSIS

Authors
Lazo, M; Solga, SF; Horska, A; Bonekamp, S; Diehl, AM; Brancati, FL; Clark, J
MLA Citation
Lazo, M, Solga, SF, Horska, A, Bonekamp, S, Diehl, AM, Brancati, FL, and Clark, J. "THE EFFECT OF ONE YEAR OF INTENSIVE LIFESTYLE INTERVENTION ON HEPATIC STEATOSIS." October 2008.
Source
wos-lite
Published In
Hepatology
Volume
48
Issue
4
Publish Date
2008
Start Page
812A
End Page
812A

GENDER-SPECIFIC ASSOCIATIONS BETWEEN REGIONAL ANTHROPOMETRIC MEASURES AND HEPATIC FIBROSIS IN PATIENTS WITH NAFLD

Authors
Suzuki, A; Abdelmalek, MF; Guy, CD; Diehl, AM
MLA Citation
Suzuki, A, Abdelmalek, MF, Guy, CD, and Diehl, AM. "GENDER-SPECIFIC ASSOCIATIONS BETWEEN REGIONAL ANTHROPOMETRIC MEASURES AND HEPATIC FIBROSIS IN PATIENTS WITH NAFLD." October 2008.
Source
wos-lite
Published In
Hepatology
Volume
48
Issue
4
Publish Date
2008
Start Page
804A
End Page
804A

PROGRESSIVE HEDGEHOG PATHWAY ACTIVATION ACCOMPANIES THE DUCTULAR REACTION DURING NAFLD PROGRESSION IN MICE AND HUMANS

Authors
Jung, Y; Guy, CD; Yang, L; Abdelmalek, MF; Diehl, AM
MLA Citation
Jung, Y, Guy, CD, Yang, L, Abdelmalek, MF, and Diehl, AM. "PROGRESSIVE HEDGEHOG PATHWAY ACTIVATION ACCOMPANIES THE DUCTULAR REACTION DURING NAFLD PROGRESSION IN MICE AND HUMANS." October 2008.
Source
wos-lite
Published In
Hepatology
Volume
48
Issue
4
Publish Date
2008
Start Page
829A
End Page
829A

The hedgehog pathway regulates remodelling responses to biliary obstruction in rats.

BACKGROUND: Chronic biliary obstruction provokes fibrosis and accumulation of immature ductular cells. This fibroductular reaction resolves following biliary decompression, suggesting that it may also be involved in the repair of biliary damage. The hedgehog (Hh) pathway becomes activated in liver after bile duct ligation (BDL), and might modulate hepatic remodelling because Hh ligands are potent morphogens. OBJECTIVE: To study the induction of the Hh pathway during progression and resolution of biliary fibrosis, and to clarify whether Hh signalling regulates accumulation of bile duct progenitor cells. DESIGN AND MAIN OUTCOME MEASURES: Livers from rats with BDL were examined by quantitative real-time polymerase chain reaction analysis and immunohistochemistry to identify factors that might stimulate Hh signalling. BDL rats were subjected to Roux-en-Y hepaticojejunostomy (R-Y) to relieve biliary obstruction in order to determine whether these factors and Hh signalling declined as ductular populations and concomitant fibrosis regressed. Cultures of immature ductular cells were treated with putative Hh inducers and Hh ligands to confirm their functional relevance. RESULTS: BDL increased expression of platelet-derived growth factor-BB (PDGF-BB) and sonic hedgehog (Shh), downregulated hedgehog-interacting protein (Hip), activated Hh signalling, and expanded populations of Hh-responsive ductular cells that expressed pancyotkeratin, a liver progenitor cell marker. After R-Y, Hip remained suppressed, expression of PDGF-BB and Shh gradually declined, and populations of hedgehog-responsive ductular cells regressed. In cultured ductular cells, PDGF-BB treatment induced Shh expression, and incubation with Shh inhibited apoptotic activity. CONCLUSIONS: These results identify a mechanism for activation of the Hh pathway during cholestasis and suggest that Hh signalling regulates ductular cell accumulation after biliary injury.

Authors
Omenetti, A; Popov, Y; Jung, Y; Choi, SS; Witek, RP; Yang, L; Brown, KD; Schuppan, D; Diehl, AM
MLA Citation
Omenetti, A, Popov, Y, Jung, Y, Choi, SS, Witek, RP, Yang, L, Brown, KD, Schuppan, D, and Diehl, AM. "The hedgehog pathway regulates remodelling responses to biliary obstruction in rats." Gut 57.9 (September 2008): 1275-1282.
PMID
18375471
Source
pubmed
Published In
Gut
Volume
57
Issue
9
Publish Date
2008
Start Page
1275
End Page
1282
DOI
10.1136/gut.2008.148619

Fate-mapping evidence that hepatic stellate cells are epithelial progenitors in adult mouse livers.

Liver injury activates quiescent hepatic stellate cells (Q-HSC) to proliferative myofibroblasts. Accumulation of myofibroblastic hepatic stellate cells (MF-HSC) sometimes causes cirrhosis and liver failure. However, MF-HSC also promote liver regeneration by producing growth factors for oval cells, bipotent progenitors of hepatocytes and cholangiocytes. Genes that are expressed by primary hepatic stellate cell (HSC) isolates overlap those expressed by oval cells, and hepatocytic and ductular cells emerge when HSC are cultured under certain conditions. We evaluated the hypothesis that HSC are a type of oval cell and, thus, capable of generating hepatocytes to regenerate injured livers. Because Q-HSC express glial fibrillary acidic protein (GFAP), we crossed mice in which GFAP promoter elements regulated Cre-recombinase with ROSA-loxP-stop-loxP-green fluorescent protein (GFP) mice to generate GFAP-Cre/GFP double-transgenic mice. These mice were fed methionine choline-deficient, ethionine-supplemented diets to activate and expand HSC and oval cell populations. GFP(+) progeny of GFAP-expressing precursors were characterized by immunohistochemistry. Basal expression of mesenchymal markers was negligible in GFAP(+)Q-HSC. When activated by liver injury or culture, HSC downregulated expression of GFAP but remained GFP(+); they became highly proliferative and began to coexpress markers of mesenchyme and oval cells. These transitional cells disappeared as GFP-expressing hepatocytes emerged, began to express albumin, and eventually repopulated large areas of the hepatic parenchyma. Ductular cells also expressed GFAP and GFP, but their proliferative activity did not increase in this model. These findings suggest that HSC are a type of oval cell that transitions through a mesenchymal phase before differentiating into hepatocytes during liver regeneration. Disclosure of potential conflicts of interest is found at the end of this article.

Authors
Yang, L; Jung, Y; Omenetti, A; Witek, RP; Choi, S; Vandongen, HM; Huang, J; Alpini, GD; Diehl, AM
MLA Citation
Yang, L, Jung, Y, Omenetti, A, Witek, RP, Choi, S, Vandongen, HM, Huang, J, Alpini, GD, and Diehl, AM. "Fate-mapping evidence that hepatic stellate cells are epithelial progenitors in adult mouse livers." Stem Cells 26.8 (August 2008): 2104-2113.
PMID
18511600
Source
pubmed
Published In
Stem Cells
Volume
26
Issue
8
Publish Date
2008
Start Page
2104
End Page
2113
DOI
10.1634/stemcells.2008-0115

Hepatic triglyceride synthesis and nonalcoholic fatty liver disease.

PURPOSE OF REVIEW: Nonalcoholic fatty liver disease is a spectrum of diseases ranging from simple steatosis to cirrhosis. The hallmark of nonalcoholic fatty liver disease is hepatocyte accumulation of triglycerides. We will review the role of triglyceride synthesis in nonalcoholic fatty liver disease progression and summarize recent findings about triglyceride synthesis inhibition and prevention of progressive disease. RECENT FINDINGS: Attempts to inhibit triglyceride synthesis in animal models have resulted in improvement in hepatic steatosis. Studies in animal models of nonalcoholic fatty liver disease demonstrate that inhibition of acyl-coenzyme A:diacylglycerol acyltransferase, the enzyme that catalyzes the final step in triglyceride synthesis, results in improvement in hepatic steatosis and insulin sensitivity. We recently confirmed that hepatic specific inhibition of acyl-coenzyme A:diacylglycerol acyltransferase with antisense oligonucleotides improves hepatic steatosis in obese, diabetic mice but, unexpectedly, exacerbated injury and fibrosis in that model of progressive nonalcoholic fatty liver disease. When hepatocyte triglyceride synthesis was inhibited, free fatty acids accumulated in the liver, leading to induction of fatty acid oxidizing systems that increased hepatic oxidative stress and liver damage. These findings suggest that the ability to synthesize triglycerides may, in fact, be protective in obesity. SUMMARY: Nonalcoholic fatty liver disease is strongly associated with obesity and peripheral insulin resistance. Peripheral insulin resistance increases lipolysis in adipose depots, promoting increased free fatty acid delivery to the liver. In states of energy excess, such as obesity, the latter normally triggers hepatic triglyceride synthesis. When hepatic triglyceride synthesis is unable to accommodate increased hepatocyte free fatty acid accumulation, however, lipotoxicity results. Thus, rather than being hepatotoxic, liver triglyceride accumulation is actually hepato-protective in obese, insulin-resistant individuals.

Authors
Choi, SS; Diehl, AM
MLA Citation
Choi, SS, and Diehl, AM. "Hepatic triglyceride synthesis and nonalcoholic fatty liver disease." Curr Opin Lipidol 19.3 (June 2008): 295-300. (Review)
PMID
18460922
Source
pubmed
Published In
Current Opinion in Lipidology
Volume
19
Issue
3
Publish Date
2008
Start Page
295
End Page
300
DOI
10.1097/MOL.0b013e3282ff5e55

Fructose consumption as a risk factor for non-alcoholic fatty liver disease.

BACKGROUND/AIMS: While the rise in non-alcoholic fatty liver disease (NAFLD) parallels the increase in obesity and diabetes, a significant increase in dietary fructose consumption in industrialized countries has also occurred. The increased consumption of high fructose corn syrup, primarily in the form of soft drinks, is linked with complications of the insulin resistance syndrome. Furthermore, the hepatic metabolism of fructose favors de novo lipogenesis and ATP depletion. We hypothesize that increased fructose consumption contributes to the development of NAFLD. METHODS: A dietary history and paired serum and liver tissue were obtained from patients with evidence of biopsy-proven NAFLD (n=49) without cirrhosis and controls (n=24) matched for gender, age (+/-5 years), and body mass index (+/-3 points). RESULTS: Consumption of fructose in patients with NAFLD was nearly 2- to 3-fold higher than controls [365 kcal vs 170 kcal (p<0.05)]. In patients with NAFLD (n=6), hepatic mRNA expression of fructokinase (KHK), an important enzyme for fructose metabolism, and fatty acid synthase, an important enzyme for lipogenesis were increased (p=0.04 and p=0.02, respectively). In an AML hepatocyte cell line, fructose resulted in dose-dependent increase in KHK protein and activity. CONCLUSIONS: The pathogenic mechanism underlying the development of NAFLD may be associated with excessive dietary fructose consumption.

Authors
Ouyang, X; Cirillo, P; Sautin, Y; McCall, S; Bruchette, JL; Diehl, AM; Johnson, RJ; Abdelmalek, MF
MLA Citation
Ouyang, X, Cirillo, P, Sautin, Y, McCall, S, Bruchette, JL, Diehl, AM, Johnson, RJ, and Abdelmalek, MF. "Fructose consumption as a risk factor for non-alcoholic fatty liver disease." J Hepatol 48.6 (June 2008): 993-999.
PMID
18395287
Source
pubmed
Published In
Journal of Hepatology
Volume
48
Issue
6
Publish Date
2008
Start Page
993
End Page
999
DOI
10.1016/j.jhep.2008.02.011

Hepatic fat and adenosine triphosphate measurement in overweight and obese adults using 1H and 31P magnetic resonance spectroscopy.

BACKGROUND/AIMS: Magnetic resonance spectroscopy (MRS) measures hepatic fat and adenosine triphosphate (ATP), but magnetic resonance studies are challenging in obese subjects. We aimed to evaluate the inter- and intrarater reliability and stability of hepatic fat and ATP measurements in a cohort of overweight and obese adults. METHODS: We measured hepatic fat and ATP using proton MRS ((1)H MRS) and phosphorus MRS ((31)P MRS) at baseline in adults enrolled in the Action for Health in Diabetes (Look AHEAD) clinical trial at one site. Using logistic regression, we determined factors associated with successful MRS data acquisition. We calculated the intra- and inter-rater reliability for hepatic fat and ATP based on 20 scans analysed twice by two readers. We also calculated the stability of these measures three times on five healthy volunteers. RESULTS: Of 244 participants recruited into our ancillary study, 185 agreed to MRS. We obtained usable hepatic fat data from 151 (82%) and ATP data from 105 (58%). Obesity was the strongest predictor of failed data acquisition; every unit increase in the body mass index reduced the likelihood of successful fat data by 11% and ATP data by 14%. The inter- and intrarater reliability were excellent for fat (intraclass correlation coefficient=0.99), but substantially more variable for ATP. Fat measures appeared relatively stable, but this was less true for ATP. CONCLUSIONS: Obesity can hinder (1)H and (31)P MRS data acquisition and subsequent analysis. This impact was greater for hepatic ATP than hepatic fat.

Authors
Solga, SF; Horska, A; Hemker, S; Crawford, S; Diggs, C; Diehl, AM; Brancati, FL; Clark, JM
MLA Citation
Solga, SF, Horska, A, Hemker, S, Crawford, S, Diggs, C, Diehl, AM, Brancati, FL, and Clark, JM. "Hepatic fat and adenosine triphosphate measurement in overweight and obese adults using 1H and 31P magnetic resonance spectroscopy." Liver Int 28.5 (May 2008): 675-681.
PMID
18331237
Source
pubmed
Published In
Liver International
Volume
28
Issue
5
Publish Date
2008
Start Page
675
End Page
681
DOI
10.1111/j.1478-3231.2008.01705.x

Accumulation of hedgehog-responsive progenitors parallels alcoholic liver disease severity in mice and humans.

BACKGROUND & AIMS: Improving outcomes in alcoholic liver disease (ALD) necessitates better understanding of how habitual ethanol (EtOH) consumption alters normal regenerative mechanisms within the liver. Hedgehog (Hh) pathway activation promotes expansion of progenitor populations in other tissues. We evaluated the hypothesis that chronic EtOH exposure activates Hh signaling in liver. METHODS: Hh signaling, liver progenitors, transforming growth factor (TGF)-beta induction, and liver damage were compared in mice fed chow, high-fat diets (HF), or HF + EtOH for 4 weeks. Susceptibility to TGF-beta-mediated apoptosis was compared in Hh-responsive liver cells (eg, immature cholangiocytes and oval cells) and mature hepatocytes (which are unresponsive to Hh). Hepatic accumulation of Hh-responsive cells were compared in controls and ALD patients and correlated with a discriminant function (DF) that predicts subacute mortality. RESULTS: Hh signaling and numbers of Hh-responsive cells were increased in HF mice and greatest in HF+EtOH mice. In both, progenitor and stromal cell populations harbored Hh-responsive cells. More ductular-type progenitors and fibrosis markers were noted in HF+EtOH mice than in HF mice. The former also expressed more TGF-beta-1. TGF-beta-1 treatment selectively promoted the viability of Hh-responsive immature liver cells and caused mature hepatocytes that survived to produce Hh ligands. Hh-responsive cells were increased in ALD patients. Lobular accumulation of Hh-responsive immature ductular cells was greater in those with a DF >32 than those with a DF <32. CONCLUSIONS: Hh signaling is increased in ALD and may influence ALD outcomes by promoting hepatic accumulation of immature ductular cells.

Authors
Jung, Y; Brown, KD; Witek, RP; Omenetti, A; Yang, L; Vandongen, M; Milton, RJ; Hines, IN; Rippe, RA; Spahr, L; Rubbia-Brandt, L; Diehl, AM
MLA Citation
Jung, Y, Brown, KD, Witek, RP, Omenetti, A, Yang, L, Vandongen, M, Milton, RJ, Hines, IN, Rippe, RA, Spahr, L, Rubbia-Brandt, L, and Diehl, AM. "Accumulation of hedgehog-responsive progenitors parallels alcoholic liver disease severity in mice and humans." Gastroenterology 134.5 (May 2008): 1532-1543.
PMID
18471524
Source
pubmed
Published In
Gastroenterology
Volume
134
Issue
5
Publish Date
2008
Start Page
1532
End Page
1543
DOI
10.1053/j.gastro.2008.02.022

Regulation of the Liver Cell Mass

Authors
Malek, NP; Rudolph, KL; Diehl, AM
MLA Citation
Malek, NP, Rudolph, KL, and Diehl, AM. "Regulation of the Liver Cell Mass." (April 15, 2008): 274-289. (Chapter)
Source
scopus
Publish Date
2008
Start Page
274
End Page
289
DOI
10.1002/9780470691861.ch2e

Hedgehog signaling pathway in primary human hepatic stellate cells

Authors
Brown, KD; Oben, JA; Sigala, B; Yang, L; Omenetti, A; Sicklick, JK; Vandongen, H; Diehl, AM
MLA Citation
Brown, KD, Oben, JA, Sigala, B, Yang, L, Omenetti, A, Sicklick, JK, Vandongen, H, and Diehl, AM. "Hedgehog signaling pathway in primary human hepatic stellate cells." April 2008.
Source
wos-lite
Published In
Gastroenterology
Volume
134
Issue
4
Publish Date
2008
Start Page
A798
End Page
A798

Increased short-term risk for liver-related mortality parallels accumulation of hedgehog-responsive progenitors in patients with alcoholic steatohepatitis

Authors
Jung, Y; Brown, KD; Witek, RP; Omenetti, A; Yang, L; Vandongen, H; Milton, RJ; Hines, I; Rippe, RA; Spahr, L; Rubbia-Brandt, L; Diehl, AM
MLA Citation
Jung, Y, Brown, KD, Witek, RP, Omenetti, A, Yang, L, Vandongen, H, Milton, RJ, Hines, I, Rippe, RA, Spahr, L, Rubbia-Brandt, L, and Diehl, AM. "Increased short-term risk for liver-related mortality parallels accumulation of hedgehog-responsive progenitors in patients with alcoholic steatohepatitis." April 2008.
Source
wos-lite
Published In
Gastroenterology
Volume
134
Issue
4
Publish Date
2008
Start Page
A785
End Page
A785

Myofibroblast-derived soluble factors upregulate chemokine gene expression in neighboring cholangiocytes

Authors
Omenetti, A; Porrello, A; Syn, W-K; Choi, SS; Jung, Y; Yang, L; Brown, KD; Witek, RP; Vandongen, H; Diehl, AM
MLA Citation
Omenetti, A, Porrello, A, Syn, W-K, Choi, SS, Jung, Y, Yang, L, Brown, KD, Witek, RP, Vandongen, H, and Diehl, AM. "Myofibroblast-derived soluble factors upregulate chemokine gene expression in neighboring cholangiocytes." April 2008.
Source
wos-lite
Published In
Gastroenterology
Volume
134
Issue
4
Publish Date
2008
Start Page
A776
End Page
A776

Liver-derived microparticles carry biologically-active Hedgehog morphogens, in blood and bile

Authors
Witek, RP; Liu, R; Yang, L; Jung, Y; Brown, K; Omenetti, A; Vazquez-Chantada, M; Syn, W-K; Choi, SS; Huang, J; Chen, W; Diehl, AM
MLA Citation
Witek, RP, Liu, R, Yang, L, Jung, Y, Brown, K, Omenetti, A, Vazquez-Chantada, M, Syn, W-K, Choi, SS, Huang, J, Chen, W, and Diehl, AM. "Liver-derived microparticles carry biologically-active Hedgehog morphogens, in blood and bile." April 2008.
Source
wos-lite
Published In
Gastroenterology
Volume
134
Issue
4
Publish Date
2008
Start Page
A570
End Page
A570

Glial fibrillary acidic protein(+) progenitors regenerate adult livers

Authors
Yang, L; Jung, Y; Huang, J; Omenetti, A; Witek, RP; Choi, SS; Alpini, G; Diehl, AM
MLA Citation
Yang, L, Jung, Y, Huang, J, Omenetti, A, Witek, RP, Choi, SS, Alpini, G, and Diehl, AM. "Glial fibrillary acidic protein(+) progenitors regenerate adult livers." April 2008.
Source
wos-lite
Published In
Gastroenterology
Volume
134
Issue
4
Publish Date
2008
Start Page
A768
End Page
A769

Culture activation of murine hepatic stellate cells involves hedgehog pathway activation and epithelial-to-mesenchymal transitions

Authors
Choi, SS; Omenetti, A; Yang, L; Witek, RP; Brown, KD; Vazquez-Chantada, M; Huang, J; Jung, Y; Syn, W-K; Sicklick, JK; Diehl, AM
MLA Citation
Choi, SS, Omenetti, A, Yang, L, Witek, RP, Brown, KD, Vazquez-Chantada, M, Huang, J, Jung, Y, Syn, W-K, Sicklick, JK, and Diehl, AM. "Culture activation of murine hepatic stellate cells involves hedgehog pathway activation and epithelial-to-mesenchymal transitions." April 2008.
Source
wos-lite
Published In
Gastroenterology
Volume
134
Issue
4
Publish Date
2008
Start Page
A797
End Page
A797

The adventures of sonic hedgehog in development and repair. II. Sonic hedgehog and liver development, inflammation, and cancer.

Hedgehog (Hh) signaling modulates tissue remodeling by controlling the fate of Hh-responsive cells. Healthy adult livers exhibit little Hh activity. However, cells involved in adult liver repair, including myofibroblasts and progenitors, are capable of producing and responding to Hh ligands. During adult liver injury, Hh ligand production increases and populations of Hh-responsive cells expand. This process is accompanied by fibrosis. Ligand production and Hh-responsive cells diminish as fibrosis resolves and normal hepatic architecture is restored, but Hh signaling persists in hepatocellular carcinomas. These findings suggest that the Hh pathway mediates remodeling responses that are triggered by adult liver damage.

Authors
Omenetti, A; Diehl, AM
MLA Citation
Omenetti, A, and Diehl, AM. "The adventures of sonic hedgehog in development and repair. II. Sonic hedgehog and liver development, inflammation, and cancer." Am J Physiol Gastrointest Liver Physiol 294.3 (March 2008): G595-G598. (Review)
PMID
18218671
Source
pubmed
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
294
Issue
3
Publish Date
2008
Start Page
G595
End Page
G598
DOI
10.1152/ajpgi.00543.2007

Diacylglycerol acyltranferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis.

UNLABELLED: Retinyl ester (RE) stores decrease during hepatic stellate cell (HSC) activation and liver fibrosis. Although retinol esterification is mostly catalyzed by lecithin:retinol acyltransferase (LRAT), diacylglycerol acyltransferase (DGAT)1 also does this. In previous reports, LRAT(-/-) mice had reduced hepatic RE but neither excessive HSC activation nor liver fibrosis, and DGAT1(-/-) mice had increased liver levels of RE and retinol. We sought to clarify the role of DGAT1 in liver fibrosis. Expression of DGAT1/2 was compared by real time PCR in freshly isolated, primary mouse HSCs and hepatocytes. To induce nonalcoholic steatohepatitis (NASH) and liver fibrosis, adult male db/db mice were fed methionine choline-deficient (MCD) diets. Half were treated with DGAT1 antisense oligonucleotide (ASO); the rest were injected with saline. Results were compared with chow-fed controls. Inhibition of DGAT1 in liver had no effect on hepatic triglyceride content or liver necroinflammation but reduced HSC activation and liver fibrosis in mice with NASH. To evaluate the role of DGAT1 in HSC activation, HSC were isolated from healthy rats treated with DGAT1 ASO or saline. DGAT1 was expressed at relatively high levels in HSCs. HSC isolated from DGAT1 ASO-treated rats had reduced DGAT1 expression and increased messenger RNA (mRNA) levels of LRAT and cellular retinol binding protein-1. During culture, they retained more vitamin A, had repressed collagen a2 (I) transcriptional activity, and expressed less collagen a1 (I) and a2 (I) mRNA. CONCLUSION: DGAT1 may be a therapeutic target in NASH because inhibiting DGAT1 favorably altered. HSC retinoid homeostasis and inhibited hepatic fibrosis in mice with NASH.

Authors
Yamaguchi, K; Yang, L; McCall, S; Huang, J; Yu, XX; Pandey, SK; Bhanot, S; Monia, BP; Li, Y-X; Diehl, AM
MLA Citation
Yamaguchi, K, Yang, L, McCall, S, Huang, J, Yu, XX, Pandey, SK, Bhanot, S, Monia, BP, Li, Y-X, and Diehl, AM. "Diacylglycerol acyltranferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis." Hepatology 47.2 (February 2008): 625-635.
PMID
18000880
Source
pubmed
Published In
Hepatology
Volume
47
Issue
2
Publish Date
2008
Start Page
625
End Page
635
DOI
10.1002/hep.21988

Specific polymorphisms in hepatitis C virus genotype 3 core protein associated with intracellular lipid accumulation.

BACKGROUND: Steatosis is a common histological finding and a poor prognostic indicator in patients with hepatitis C virus (HCV) infection. In HCV genotype 3-infected patients, the etiology of steatosis appears to be closely correlated with unknown viral factors that increase intracellular lipid levels. We hypothesize that specific sequence polymorphisms in HCV genotype 3 core protein may be associated with hepatic intracellular lipid accumulation. METHODS: Using selected serum samples from 8 HCV genotype 3-infected patients with or without steatosis, we sequenced the HCV core gene to identify candidate polymorphisms associated with increased intracellular lipid levels. RESULTS: Two polymorphisms at positions 182 and 186 of the core protein correlated with the presence (P= .03) and absence (P= .005) of intrahepatic steatosis. Transfected liver cell lines expressing core protein with steatosis-associated polymorphisms had increased intracellular lipid levels compared with non-steatosis-associated core isolates, as measured by oil red O staining (P= .02). Site-specific mutagenesis performed at positions 182 and 186 in steatosis-associated core genes yielded proteins that had decreased intracellular lipid levels in transfected cells (P= .03). CONCLUSIONS: We have identified polymorphisms in HCV core protein genotype 3 that produce increased intracellular lipid levels and thus may play a significant role in lipid metabolism or trafficking, contributing to steatosis.

Authors
Jhaveri, R; McHutchison, J; Patel, K; Qiang, G; Diehl, AM
MLA Citation
Jhaveri, R, McHutchison, J, Patel, K, Qiang, G, and Diehl, AM. "Specific polymorphisms in hepatitis C virus genotype 3 core protein associated with intracellular lipid accumulation." J Infect Dis 197.2 (January 15, 2008): 283-291.
PMID
18177246
Source
pubmed
Published In
Journal of Infectious Diseases
Volume
197
Issue
2
Publish Date
2008
Start Page
283
End Page
291
DOI
10.1086/524846

Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells.

BACKGROUND/AIMS: Factors released during liver injury, such as platelet derived growth factor-BB (PDGF), promote accumulation of myofibroblastic hepatic stellate cells (MFB) that drive the pathogenesis of cirrhosis. The hedgehog (Hh) pathway regulates remodeling of other injured tissues. This study evaluates the hypothesis that autocrine production of Sonic hedgehog (Shh) promotes MFB growth. METHODS: Primary rat hepatic stellate cells (HSC) were treated without or with PDGF, a pharmacologic inhibitor of PDGF-regulated kinases, adenovirus expressing activated or dominant negative AKT, or Hh signaling inhibitors. Shh production, expression of Hh inhibitors and target genes, and HSC growth were assessed. RESULTS: HSC expressed Shh, Hh pathway components, and the Hh inhibitor, Hip. During culture Hip expression fell, Shh production increased, and Hh target gene expression was induced. Neutralizing Shh antibodies promoted apoptosis. Adding PDGF increased Shh expression and MFB growth. Both processes followed activation of AKT and were abrogated by AKT inhibitors. Adenoviral delivery of activated AKT up-regulated Shh expression, demonstrating a direct role for AKT in regulating Shh expression. Shh-neutralizing antibodies and other Hh pathway inhibitors blocked the mitogenic effects of PDGF. CONCLUSIONS: These results identify Shh as an autocrine growth factor for MFB and suggest a role for Hh signaling in the pathogenesis of cirrhosis.

Authors
Yang, L; Wang, Y; Mao, H; Fleig, S; Omenetti, A; Brown, KD; Sicklick, JK; Li, Y-X; Diehl, AM
MLA Citation
Yang, L, Wang, Y, Mao, H, Fleig, S, Omenetti, A, Brown, KD, Sicklick, JK, Li, Y-X, and Diehl, AM. "Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells." J Hepatol 48.1 (January 2008): 98-106.
PMID
18022723
Source
pubmed
Published In
Journal of Hepatology
Volume
48
Issue
1
Publish Date
2008
Start Page
98
End Page
106
DOI
10.1016/j.jhep.2007.07.032

The effect of a probiotic on hepatic steatosis

Authors
Solga, SF; Buckley, G; Clark, JM; Horska, A; Diehl, AM
MLA Citation
Solga, SF, Buckley, G, Clark, JM, Horska, A, and Diehl, AM. "The effect of a probiotic on hepatic steatosis." Journal of Clinical Gastroenterology 42.10 (2008): 1117-1119.
PMID
18936646
Source
scival
Published In
Journal of Clinical Gastroenterology
Volume
42
Issue
10
Publish Date
2008
Start Page
1117
End Page
1119
DOI
10.1097/MCG.0b013e31816d920c

Quantitative comparison and evaluation of software packages for assessment of abdominal adipose tissue distribution by magnetic resonance imaging

Objective: To examine five available software packages for the assessment of abdominal adipose tissue with magnetic resonance imaging, compare their features and assess the reliability of measurement results. Design: Feature evaluation and test-retest reliability of softwares (NIHImage, SliceOmatic, Analyze, HippoFat and EasyVision) used in manual, semi-automated or automated segmentation of abdominal adipose tissue. Subjects: A random sample of 15 obese adults with type 2 diabetes. Measurements: Axial T1-weighted spin echo images centered at vertebral bodies of L2-L3 were acquired at 1.5 T. Five software packages were evaluated (NIHImage, SliceOmatic, Analyze, HippoFat and EasyVision), comparing manual, semi-automated and automated segmentation approaches. Images were segmented into cross-sectional area (CSA), and the areas of visceral (VAT) and subcutaneous adipose tissue (SAT). Ease of learning and use and the design of the graphical user interface (GUI) were rated. Intra-observer accuracy and agreement between the software packages were calculated using intra-class correlation. Intra-class correlation coefficient was used to obtain test-retest reliability. Results: Three of the five evaluated programs offered a semi-automated technique to segment the images based on histogram values or a user-defined threshold. One software package allowed manual delineation only. One fully automated program demonstrated the drawbacks of uncritical automated processing. The semi-automated approaches reduced variability and measurement error, and improved reproducibility. There was no significant difference in the intra-observer agreement in SAT and CSA. The VAT measurements showed significantly lower test-retest reliability. There were some differences between the software packages in qualitative aspects, such as user friendliness. Conclusion: Four out of five packages provided essentially the same results with respect to the inter- and intra-rater reproducibility. Our results using SliceOmatic, Analyze or NIHImage were comparable and could be used interchangeably. Newly developed fully automated approaches should be compared to one of the examined software packages. © 2008 Nature Publishing Group All rights reserved.

Authors
Bonekamp, S; Ghosh, P; Crawford, S; Solga, SF; Horska, A; Brancati, FL; Diehl, AM; Smith, S; Clark, JM
MLA Citation
Bonekamp, S, Ghosh, P, Crawford, S, Solga, SF, Horska, A, Brancati, FL, Diehl, AM, Smith, S, and Clark, JM. "Quantitative comparison and evaluation of software packages for assessment of abdominal adipose tissue distribution by magnetic resonance imaging." International Journal of Obesity 32.1 (2008): 100-111.
PMID
17700582
Source
scival
Published In
International Journal of Obesity
Volume
32
Issue
1
Publish Date
2008
Start Page
100
End Page
111
DOI
10.1038/sj.ijo.0803696

Acetylcholine induces fibrogenic effects in human primary hepatic stellate cell

Authors
Morgan, M; Sigala, B; Selden, C; Diehl, AM; Oben, JA
MLA Citation
Morgan, M, Sigala, B, Selden, C, Diehl, AM, and Oben, JA. "Acetylcholine induces fibrogenic effects in human primary hepatic stellate cell." 2008.
Source
wos-lite
Published In
Journal of Hepatology
Volume
48
Publish Date
2008
Start Page
S183
End Page
S183
DOI
10.1016/S0168-8278(08)60484-5

Role of immune response in nonalcoholic fatty liver disease: Evidence in human and animal studies

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of hepatic pathology ranging from nonalcoholic fatty liver (NAFL; steatosis) at the most clinically benign end of the spectrum to cirrhosis at the opposite extreme, where most liver-related morbidity and mortality occur. Nonalcoholic steatohepatitis (NASH) is a lesion of intermediate severity. NASH is characterized by overt hepatocyte injury and death. It is often accompanied by hepatic infiltration with inflammatory cells (1). Some individuals with NASH gradually accumulate hepatic fibrosis, and eventually develop cirrhosis (2). Over time, hepatocellular carcinomas emerge in a small proportion of individuals with NAFLD-related cirrhosis (3). The pathogenesis of NAFLD is the subject of much research because NAFLD is one of the most common causes of chronic liver disease, particularly in countries such as the United States that are in the midst of an obesity epidemic (4,(5)). © 2007 Humana Press Inc.

Authors
Yang, L; Diehl, AM
MLA Citation
Yang, L, and Diehl, AM. "Role of immune response in nonalcoholic fatty liver disease: Evidence in human and animal studies." (December 1, 2007): 337-345. (Chapter)
Source
scopus
Publish Date
2007
Start Page
337
End Page
345
DOI
10.1007/978-1-59745-518-3_27

Hepatic accumulation of Hedgehog-reactive progenitors increases with severity of fatty liver damage in mice.

Progenitors regenerate fatty livers but the mechanisms involved are uncertain. The Hedgehog pathway regulates mesendodermal progenitors and modulates mesenchymal-epithelial interactions during tissue remodeling. To determine if Hedgehog signaling increases in liver progenitors during fatty liver injury, we compared expression of Hedgehog ligands and target genes across a spectrum of injury. Leptin-deficient ob/ob mice with fatty livers and their healthy lean littermates were studied before and after exposure to the hepatotoxin, ethionine. At baseline, ob/ob mice had greater liver damage than controls. Ethionine induced liver injury in both ob/ob and lean mice, with greater injury occurring in ob/ob mice. After ethionine, the ob/ob mice developed liver atrophy and fibrosis. Liver injury increased hepatic accumulation of progenitors, including ductular cells that produced and responded to Hedgehog ligands. A dose-response relationship was demonstrated between liver injury and expansion of Hedgehog-responsive progenitors. In severely damaged, atrophic livers, nuclei in mature-appearing hepatocytes accumulated the Hedgehog-regulated mesenchymal transcription factor, Gli2 and lost expression of the liver epithelial transcription factor, hepatocyte nuclear factor 6 (HNF-6). Hepatic levels of collagen mRNA and pericellular collagen fibrils increased concomitantly. Hence, fatty liver injury increases Hedgehog activity in liver progenitors, and this might promote epithelial-mesenchymal transitions that result in liver fibrosis.

Authors
Fleig, SV; Choi, SS; Yang, L; Jung, Y; Omenetti, A; VanDongen, HM; Huang, J; Sicklick, JK; Diehl, AM
MLA Citation
Fleig, SV, Choi, SS, Yang, L, Jung, Y, Omenetti, A, VanDongen, HM, Huang, J, Sicklick, JK, and Diehl, AM. "Hepatic accumulation of Hedgehog-reactive progenitors increases with severity of fatty liver damage in mice." Lab Invest 87.12 (December 2007): 1227-1239.
PMID
17952094
Source
pubmed
Published In
Laboratory Investigation
Volume
87
Issue
12
Publish Date
2007
Start Page
1227
End Page
1239
DOI
10.1038/labinvest.3700689

Nonalcoholic fatty liver disease as a complication of insulin resistance.

Nonalcoholic fatty liver disease (NAFLD) refers to a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and rarely, progression to cirrhosis. The pathogenesis of NAFLD is thought to be related to insulin resistance and oxidant stress. Truncal obesity, dyslipidema, hypertension, and hyperglycemia are strongly associated with NAFLD; therefore, management of NAFLD entails identification and treatment of metabolic risk factors, improving insulin sensitivity, and increasing antioxidant defenses in the liver. This article briefly summarizes advances in our understanding of the relationship between NAFLD and the insulin resistance (metabolic) syndrome, its prevalence, natural history, and treatment.

Authors
Abdelmalek, MF; Diehl, AM
MLA Citation
Abdelmalek, MF, and Diehl, AM. "Nonalcoholic fatty liver disease as a complication of insulin resistance." Med Clin North Am 91.6 (November 2007): 1125-ix. (Review)
PMID
17964913
Source
pubmed
Published In
Medical Clinics of North America
Volume
91
Issue
6
Publish Date
2007
Start Page
1125
End Page
ix
DOI
10.1016/j.mcna.2007.06.001

Influence of impaired glucose tolerance, glucose control status, light to moderate alcohol consumption, and reduced carbohydrate diets on serum ALT change during rapid weight loss in the residential weight loss program

Authors
Suzuki, A; Sha, R; Wachholtz, A; Binks, M; Diehl, AM
MLA Citation
Suzuki, A, Sha, R, Wachholtz, A, Binks, M, and Diehl, AM. "Influence of impaired glucose tolerance, glucose control status, light to moderate alcohol consumption, and reduced carbohydrate diets on serum ALT change during rapid weight loss in the residential weight loss program." October 2007.
Source
wos-lite
Published In
Hepatology
Volume
46
Issue
4
Publish Date
2007
Start Page
740A
End Page
740A

Association of AST and ALT with liver histology in adults with NAFLD

Authors
Clark, JM; Van Natta, M; Kleiner, D; Chalasani, NP; McCullogh, AJ; Neuschwander-Tetri, BA; Uenalp, A; Hoofnagle, JH; Diehl, AM
MLA Citation
Clark, JM, Van Natta, M, Kleiner, D, Chalasani, NP, McCullogh, AJ, Neuschwander-Tetri, BA, Uenalp, A, Hoofnagle, JH, and Diehl, AM. "Association of AST and ALT with liver histology in adults with NAFLD." October 2007.
Source
wos-lite
Published In
Hepatology
Volume
46
Issue
4
Publish Date
2007
Start Page
738A
End Page
738A

Hedgehog signaling and epithelial mesenchymal transitions during biliary fibrosis

Authors
Omenetti, A; Porrello, A; Popov, Y; Yang, L; Jung, Y; Vandongen, HM; Schuppan, D; Diehl, AM
MLA Citation
Omenetti, A, Porrello, A, Popov, Y, Yang, L, Jung, Y, Vandongen, HM, Schuppan, D, and Diehl, AM. "Hedgehog signaling and epithelial mesenchymal transitions during biliary fibrosis." October 2007.
Source
wos-lite
Published In
Hepatology
Volume
46
Issue
4
Publish Date
2007
Start Page
336A
End Page
336A

Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells

Authors
Yang, L; Wang, Y; Mao, H; Fleig, S; Omenetti, A; Brown, K; Sicklick, JK; Li, Y-X; Diehl, AM
MLA Citation
Yang, L, Wang, Y, Mao, H, Fleig, S, Omenetti, A, Brown, K, Sicklick, JK, Li, Y-X, and Diehl, AM. "Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells." October 2007.
Source
wos-lite
Published In
Hepatology
Volume
46
Issue
4
Publish Date
2007
Start Page
866A
End Page
867A

Fructose induced hyperuricemia as a causal mechanism for nonalcoholic fatty liver disease

Authors
Abdelmalek, MF; Suzuki, A; Guy, C; Johnson, RJ; Diehl, AM; Grp, NASHCR
MLA Citation
Abdelmalek, MF, Suzuki, A, Guy, C, Johnson, RJ, Diehl, AM, and Grp, NASHCR. "Fructose induced hyperuricemia as a causal mechanism for nonalcoholic fatty liver disease." October 2007.
Source
wos-lite
Published In
Hepatology
Volume
46
Issue
4
Publish Date
2007
Start Page
293A
End Page
293A

Targeting hedgehog signaling in medulloblastoma

Authors
Wang, J; Liu, R; Bond, M; Chen, M; Singh, S; Ali-Osman, F; Lefkowitz, RJ; Diehl, AM; Lyerly, HK; Barak, L; Chen, W
MLA Citation
Wang, J, Liu, R, Bond, M, Chen, M, Singh, S, Ali-Osman, F, Lefkowitz, RJ, Diehl, AM, Lyerly, HK, Barak, L, and Chen, W. "Targeting hedgehog signaling in medulloblastoma." October 2007.
Source
wos-lite
Published In
Neuro-Oncology
Volume
9
Issue
4
Publish Date
2007
Start Page
560
End Page
561

Endoplasmic reticulum stress, hepatocyte CD1d and NKT cell abnormalities in murine fatty livers.

The liver regulates lipid homeostasis and is enriched with natural killer T (NKT) cells that respond to lipid antigens. Optimal maturation and activation of NKT cells requires their interaction with lipid antigens that are presented by cluster of differentiation-1 (CD-1) molecules on antigen-presenting cells. Hepatocytes express CD1d and present lipid antigens to NKT cells. Depletion and dysregulation of hepatic NKT cells occurs in mice with fatty livers. Herein, we assess whether reduced CD1d content on steatotic hepatocytes contributes to fatty liver-associated NKT cell abnormalities. We show that despite expressing normal levels of CD1d mRNA, fatty hepatocytes from ob/ob mice have significantly less CD1d on their plasma membranes than normal hepatocytes. This has functional significance because ob/ob hepatocytes are less able to activate CD1d-restricted T-cell responses in vitro, and CD1d-reactive NKT cells are reduced in ob/ob livers. Events in the endoplasmic reticulum (ER) normally regulate CD1d trafficking to plasma membranes. Hepatic steatosis has been associated with ER stress. To determine if ER stress reduces CD-1 accumulation on hepatocytes, we evaluated hepatic ER stress in ob/ob mice and treated cultured hepatocytes and lean mice with tunicamycin to induce ER stress. Lipid accumulation and ER stress occurred in the livers of both ob/ob and tunicamycin-treated mice. Tunicamycin caused dose-dependent decreases in hepatocyte CD1d, inhibited hepatocyte activation of CD1d-restricted T-cell responses, depleted liver populations of CD1d-reactive NKT cells and promoted Th-1 polarization of hepatic cytokine production. In conclusion, ER stress-related decreases in hepatocyte CD1d contribute to NKT cell dysregulation in fatty livers.

Authors
Yang, L; Jhaveri, R; Huang, J; Qi, Y; Diehl, AM
MLA Citation
Yang, L, Jhaveri, R, Huang, J, Qi, Y, and Diehl, AM. "Endoplasmic reticulum stress, hepatocyte CD1d and NKT cell abnormalities in murine fatty livers." Lab Invest 87.9 (September 2007): 927-937.
PMID
17607300
Source
pubmed
Published In
Laboratory Investigation
Volume
87
Issue
9
Publish Date
2007
Start Page
927
End Page
937
DOI
10.1038/labinvest.3700603

De novo nonalcoholic fatty liver disease after liver transplantation.

Authors
Abdelmalek, MF; Diehl, AM
MLA Citation
Abdelmalek, MF, and Diehl, AM. "De novo nonalcoholic fatty liver disease after liver transplantation." Liver Transpl 13.6 (June 2007): 788-790.
PMID
17538998
Source
pubmed
Published In
Liver Transplantation
Volume
13
Issue
6
Publish Date
2007
Start Page
788
End Page
790
DOI
10.1002/lt.21103

Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis.

UNLABELLED: In the early stages of nonalcoholic fatty liver disease (NAFLD), triglycerides accumulate in hepatocytes. Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step in hepatocyte triglyceride biosynthesis. DGAT2 antisense oligonucleotide (ASO) treatment improved hepatic steatosis dramatically in a previous study of obese mice. According to the 2-hit hypothesis for progression of NAFLD, hepatic steatosis is a risk factor for nonalcoholic steatohepatitis (NASH) and fibrosis. To evaluate this hypothesis, we inhibited DGAT2 in a mouse model of NASH induced by a diet deficient in methionine and choline (MCD). Six-week-old genetically obese and diabetic male db/db mice were fed either the control or the MCD diet for 4 or 8 weeks. The MCD diet group was treated with either 25 mg/kg DGAT2 ASO or saline intraperitoneally twice weekly. Hepatic steatosis, injury, fibrosis, markers of lipid peroxidation/oxidant stress, and systemic insulin sensitivity were evaluated. Hepatic steatosis, necroinflammation, and fibrosis were increased in saline-treated MCD diet-fed mice compared to controls. Treating MCD diet-fed mice with DGAT2 ASO for 4 and 8 weeks decreased hepatic steatosis, but increased hepatic free fatty acids, cytochrome P4502E1, markers of lipid peroxidation/oxidant stress, lobular necroinflammation, and fibrosis. Progression of liver damage occurred despite reduced hepatic expression of tumor necrosis factor alpha, increased serum adiponectin, and striking improvement in systemic insulin sensitivity. CONCLUSION: Results from this mouse model would suggest accumulation of triglycerides may be a protective mechanism to prevent progressive liver damage in NAFLD.

Authors
Yamaguchi, K; Yang, L; McCall, S; Huang, J; Yu, XX; Pandey, SK; Bhanot, S; Monia, BP; Li, Y-X; Diehl, AM
MLA Citation
Yamaguchi, K, Yang, L, McCall, S, Huang, J, Yu, XX, Pandey, SK, Bhanot, S, Monia, BP, Li, Y-X, and Diehl, AM. "Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis." Hepatology 45.6 (June 2007): 1366-1374.
PMID
17476695
Source
pubmed
Published In
Hepatology
Volume
45
Issue
6
Publish Date
2007
Start Page
1366
End Page
1374
DOI
10.1002/hep.21655

Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligation.

In bile duct-ligated (BDL) rodents, as in humans with chronic cholangiopathies, biliary obstruction triggers proliferation of bile ductular cells that are surrounded by fibrosis produced by adjacent myofibroblastic cells in the hepatic mesenchyme. The proximity of the myofibroblasts and cholangiocytes suggests that mesenchymal-epithelial crosstalk promotes the fibroproliferative response to cholestatic liver injury. Studying BDL mice, we found that bile duct obstruction induces activity of the Hedgehog (Hh) pathway, a system that regulates the viability and differentiation of various progenitors during embryogenesis. After BDL, many bile ductular cells and fibroblastic-appearing cells in the portal stroma express Hh ligands, receptor and/or target genes. Transwell cocultures of an immature cholangiocyte line that expresses the Hh receptor, Patched (Ptc), with liver myofibroblastic cells demonstrated that both cell types produced Hh ligands that enhanced each other's viability and proliferation. Further support for the concept that Hh signaling modulates the response to BDL was generated by studying PtcLacZ mice, which have an impaired ability to constrain Hh signaling due to a heterozygous deficiency of Ptc. After BDL, PtcLacZ mice upregulated fibrosis gene expression earlier than wild-type controls and manifested an unusually intense ductular reaction, more expanded fibrotic portal areas, and a greater number of lobular necrotic foci. Our findings reveal that adult livers resurrect developmental signaling systems, such as the Hh pathway, to guide remodeling of the biliary epithelia and stroma after cholestatic injury.

Authors
Omenetti, A; Yang, L; Li, Y-X; McCall, SJ; Jung, Y; Sicklick, JK; Huang, J; Choi, S; Suzuki, A; Diehl, AM
MLA Citation
Omenetti, A, Yang, L, Li, Y-X, McCall, SJ, Jung, Y, Sicklick, JK, Huang, J, Choi, S, Suzuki, A, and Diehl, AM. "Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligation." Lab Invest 87.5 (May 2007): 499-514.
PMID
17334411
Source
pubmed
Published In
Laboratory Investigation
Volume
87
Issue
5
Publish Date
2007
Start Page
499
End Page
514
DOI
10.1038/labinvest.3700537

Bile ductules and stromal cells express hedgehog ligands and/or hedgehog target genes in primary biliary cirrhosis.

UNLABELLED: Indian Hedgehog (Ihh) regulates tissue morphogenesis. Hedgehog (Hh) activity has been demonstrated in human cholangiocarcinoma and hepatocellular carcinoma lines, and in myofibroblasts and progenitors from adult rodent livers. We evaluated Hh pathway involvement in the response to biliary injury in primary biliary cirrhosis (PBC). Liver sections from 3 PBC patients and 3 controls without liver disease were studied. Immunohistochemistry was used to determine if cells that accumulate in PBC livers express Ihh or Hh-target genes including the Hh-receptor, Patched (Ptc), and the Hh-transcriptional activator glioblastoma (Gli) 2. Positive cells were further identified by costaining for cytokeratin (CK) 19, a biliary marker, or OV6, a hepatic progenitor marker. In all subjects, Gli2 and Ptc expression localized in portal areas. The numbers of Gli2- or Ptc-expressing cells/portal triad were each 10-fold greater in patients with PBC than in controls (P<0.05). In PBC livers, some CK19+ cells coexpressed Gli2 or Ptc. Many stromal fibroblastic cells were also Gli2+. Strong Ihh expression was detected in most bile ductular cells. Scattered stromal cells also expressed Ihh. The number of Ihh+ cells/portal triad was 6-fold greater in PBC livers than controls (P<0.05). OV6+ progenitors increased significantly in PBC livers, and some of these cells coexpressed Ihh, Ptc, and/or Gli2. CONCLUSION: This is the first direct evidence that noncancerous, adult human livers harbor several types of cells that produce and/or respond to Hh ligands. Such Hh-responsive cells accumulate during the fibroproliferative response to chronic cholestatic liver injury, suggesting a role for Hh signaling in this process.

Authors
Jung, Y; McCall, SJ; Li, Y-X; Diehl, AM
MLA Citation
Jung, Y, McCall, SJ, Li, Y-X, and Diehl, AM. "Bile ductules and stromal cells express hedgehog ligands and/or hedgehog target genes in primary biliary cirrhosis." Hepatology 45.5 (May 2007): 1091-1096.
PMID
17464985
Source
pubmed
Published In
Hepatology
Volume
45
Issue
5
Publish Date
2007
Start Page
1091
End Page
1096
DOI
10.1002/hep.21660

Fetal alcohol exposure impairs Hedgehog cholesterol modification and signaling.

Consumption of alcohol by pregnant women can cause fetal alcohol spectrum defects (FASD), a congenital disease, which is characterized by an array of developmental defects that include neurological, craniofacial, cardiac, and limb malformations, as well as generalized growth retardation. FASD remains a significant clinical challenge and an important social problem. Although there has been great progress in delineating the mechanisms contributing to alcohol-induced birth defects, gaps in our knowledge still remain; for instance, why does alcohol preferentially induce a spectrum of defects in specific organs and why is the spectrum of defects reproducible and predictable. In this study, we show that exposure of zebrafish embryos to low levels of alcohol during gastrulation blocks covalent modification of Sonic hedgehog by cholesterol. This leads to impaired Hh signal transduction and results in a dose-dependent spectrum of permanent developmental defects that closely resemble FASD. Furthermore, supplementing alcohol-exposed embryos with cholesterol rescues the loss of Shh signal transduction, and prevents embryos from developing FASD-like morphologic defects. Overall, we have shown that a simple post-translational modification defect in a key morphogen may contribute to an environmentally induced complex congenital syndrome. This insight into FASD pathogenesis may suggest novel strategies for preventing these common congenital defects.

Authors
Li, Y-X; Yang, H-T; Zdanowicz, M; Sicklick, JK; Qi, Y; Camp, TJ; Diehl, AM
MLA Citation
Li, Y-X, Yang, H-T, Zdanowicz, M, Sicklick, JK, Qi, Y, Camp, TJ, and Diehl, AM. "Fetal alcohol exposure impairs Hedgehog cholesterol modification and signaling." Lab Invest 87.3 (March 2007): 231-240.
PMID
17237799
Source
pubmed
Published In
Laboratory Investigation
Volume
87
Issue
3
Publish Date
2007
Start Page
231
End Page
240
DOI
10.1038/labinvest.3700516

Dependence of in vivo, radiation force derived hepatic shear modulus estimates on imaging approach: Intercostal vs. subcostal

The speed at which shear waves propagate can be used to quantify the shear modulus of tissue. Focused, impulsive, acoustic radiation force excitations can be used to generate transient displacement fields in soft tissue that create shear waves that propagate away from the region of excitation (ROE). These shear wave displacements can be ultrasonically tracked through time. The speed at which these shear waves propagate away from the ROE can be estimated using a time of flight-based method that estimates linear trends in times to peak (TTP) displacement at locations laterally offset from the ROE. This method has been previously described as the Lateral TTP algorithm. The purpose of this study is to evaluate the differences that may exist when reconstructing liver shear moduli from subcostal and intercostal approaches using acoustic radiation force excitations with the Lateral TTP algorithm, and to evaluate the repeatability of such measurements. Liver shear moduli have been reconstructed between 0.9 and 3.0 kPa in vivo, with an average precision of ± 0.4 kPa in a 20 volunteer study with body mass indices ranging from normal to obese. Repeated intercostal liver shear modulus reconstructions were performed on 9 different days in 2 volunteers over a 105 day period, yielding an average shear modulus of 1.9 ± 0.5 kPa (1.3-2.5 kPa) in the first volunteer, and 1.8 ± 0.4 kPa (1.1-3.0 kPa) in the second volunteer. Shear moduli have been successfully reconstructed in patients undergoing liver biopsy with BMI > 40. Dynamic linear motion filters are capable of removing physiologic and hand-held transducer motion artifacts without needing ECG data acquisition triggering. The in vivo data to date demonstrate that this method is capable of generating accurate and repeatable liver stiffness measurements and is promising as a clinical tool for quantifying liver stiffness. ©2007 IEEE.

Authors
Palmeri, ML; Wang, MH; Frinkley, KD; Nightingale, KR; Abdelmalek, MF; Diehl, AM
MLA Citation
Palmeri, ML, Wang, MH, Frinkley, KD, Nightingale, KR, Abdelmalek, MF, and Diehl, AM. "Dependence of in vivo, radiation force derived hepatic shear modulus estimates on imaging approach: Intercostal vs. subcostal." Proceedings - IEEE Ultrasonics Symposium (2007): 566-569.
Source
scival
Published In
Proceedings of the IEEE Ultrasonics Symposium
Publish Date
2007
Start Page
566
End Page
569
DOI
10.1109/ULTSYM.2007.147

In-vivo staging of liver fibrosis in a rat model using acoustic radiation force

Liver fibrosis is currently staged using needle biopsy, a highly invasive procedure with a number of disadvantages. Measurement of liver stiffness changes which accompany progression of the disease may provide a quantitative and noninvasive method to assess the health of the liver. The purpose of this study is to investigate the correlation between radiation force derived shear wave speed and disease related changes in the liver. Liver fibrosis was induced in 10 rats using carbon tetrachloride (CCl4), while 5 rats acted as controls. Liver stiffness was measured in vivo in all rats after a treatment period of 8 weeks using a modified Siemens SONOLINE Antares™ scanner. The animals were sacrificed after imaging and liver samples were taken for fibrosis staging using the Batts and Ludwig scale and collagen quantification using Sirius red staining. At the end of the treatment period, 4 rats had healthy livers (stage F0), while 8 had severe fibrosis (F3), and the rest had light to moderate fibrosis (Fl and F2). The mean measured liver stiffness for the F0 group was 1.2±0.1kPa, and for F3 livers was 1.6±0.2kPa. The difference in population means of FO and F3 liver stiffness was significant (p < 0.01), suggesting that radiation force can be used to differentiate F0 and F3 livers. However, the nonquantitative nature of fibrosis staging using the Batts and Ludwig method coupled with the relatively small changes in liver stiffness between F0 and F3 livers may make detecting stiffness differences between livers with light to moderate stage fibrosis (F1 and F2) difficult. Nevertheless, other quantitative measures of the liver health exist, which may better reflect changes observed in liver stiffness than fibrosis stage. In this study, liver stiffness was found to be strongly correlated with the amount of collagen in the liver measured by Sirius red staining (r = 0.7, p < 0.01). The relationship between radiation force measured liver stiffness and other quantitative parameters characterizing the liver health are currently being explored. ©2007 IEEE.

Authors
Wang, MH; Hedlund, LW; Palmeri, ML; Guy, CD; Yang, L; Diehl, AM; Nightingale, KR
MLA Citation
Wang, MH, Hedlund, LW, Palmeri, ML, Guy, CD, Yang, L, Diehl, AM, and Nightingale, KR. "In-vivo staging of liver fibrosis in a rat model using acoustic radiation force." Proceedings - IEEE Ultrasonics Symposium (2007): 562-565.
Source
scival
Published In
Proceedings of the IEEE Ultrasonics Symposium
Publish Date
2007
Start Page
562
End Page
565
DOI
10.1109/ULTSYM.2007.146

NASH: bench to bedside - lessons from animal models

Authors
Diehl, AM; Abdelmalek, MF
MLA Citation
Diehl, AM, and Abdelmalek, MF. "NASH: bench to bedside - lessons from animal models." 2007.
Source
wos-lite
Published In
Chronic Hepatitis: Metabolic, Cholestatic, Viral and Autoimmune
Volume
157
Publish Date
2007
Start Page
3
End Page
15
DOI
10.1007/978-1-4020-6523-1_1

PPARgamma agonists prevent TGFbeta1/Smad3-signaling in human hepatic stellate cells.

PPARgamma agonists inhibit liver fibrosis, but the mechanisms involved are uncertain. We hypothesized that PPARgamma agonists inhibit transforming growth factor (TGF)beta1-activation of TGFbeta receptor (TGFbetaR)-1 signaling in quiescent stellate cells, thereby abrogating Smad3-dependent induction of extracellular matrix (ECM) genes, such as PAI-1 and collagen-1alphaI. To test this, human HSC were cultured to induce a quiescent phenotype, characterized by lipid accumulation and PPARgamma expression and transcriptional activity. These adipocytic HSC were then treated with TGFbeta1+/-a TGFbetaR-1 kinase inhibitor (SB431542) or a PPARgamma agonist (GW7845). TGFbeta1 caused dose- and time-dependent increases in Smad3 phosphorylation, followed by induction of collagen and PAI-1 expression. Like the TGFbetaR-1 kinase inhibitor, the PPARgamma agonist caused dose-dependent inhibition of all of these responses without effecting HSC proliferation or viability. Thus, the anti-fibrotic actions of PPARgamma agonists reflect their ability to inhibit TGFbeta1-TGFbetaR1 signaling that initiates ECM gene expression in quiescent HSC.

Authors
Zhao, C; Chen, W; Yang, L; Chen, L; Stimpson, SA; Diehl, AM
MLA Citation
Zhao, C, Chen, W, Yang, L, Chen, L, Stimpson, SA, and Diehl, AM. "PPARgamma agonists prevent TGFbeta1/Smad3-signaling in human hepatic stellate cells." Biochem Biophys Res Commun 350.2 (November 17, 2006): 385-391.
PMID
17010940
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
350
Issue
2
Publish Date
2006
Start Page
385
End Page
391
DOI
10.1016/j.bbrc.2006.09.069

Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice.

Rac, a small, GTP-binding protein in the Rho family, regulates several cellular functions, including the activation of NADPH oxidase, a major intracellular producer of reactive oxygen species (ROS). Hepatic stellate cells (HSCs) isolated from mice that are genetically deficient in NADPH oxidase produce less ROS, and their activation during chronic liver injury is abrogated, resulting in decreased liver fibrosis. Therefore, we hypothesized that HSC ROS production and activation would be enhanced, and fibrosis worsened, by increasing Rac expression in HSCs. To achieve this, we used transgenic mice that express constitutively active human Rac1 under the control of the alpha-smooth muscle actin (alpha-sma) promoter, because alpha-sma expression is induced spontaneously during HSC activation. Transgene expression was upregulated progressively during culture of primary Rac-transgenic HSCs, and this increased HSC ROS production as well as expression of activation markers and collagen. Similarly, Rac mice treated with carbon tetrachloride (CCl(4)) accumulated greater numbers of activated HSCs and had more liver damage, hepatocyte apoptosis, and liver fibrosis-as well as higher mortality-than CCl(4)-treated wild-type mice. In conclusion, sustained activation of Rac in HSCs perpetuates their activation and exacerbates toxin-induced liver injury and fibrosis, prompting speculation that Rac may be a therapeutic target in patients with cirrhosis.

Authors
Choi, SS; Sicklick, JK; Ma, Q; Yang, L; Huang, J; Qi, Y; Chen, W; Li, Y-X; Goldschmidt-Clermont, PJ; Diehl, AM
MLA Citation
Choi, SS, Sicklick, JK, Ma, Q, Yang, L, Huang, J, Qi, Y, Chen, W, Li, Y-X, Goldschmidt-Clermont, PJ, and Diehl, AM. "Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice." Hepatology 44.5 (November 2006): 1267-1277.
PMID
17058265
Source
pubmed
Published In
Hepatology
Volume
44
Issue
5
Publish Date
2006
Start Page
1267
End Page
1277
DOI
10.1002/hep.21375

Evidence for epithelial-mesenchymal transitions in adult liver cells.

Both myofibroblastic hepatic stellate cells (HSC) and hepatic epithelial progenitors accumulate in damaged livers. In some injured organs, the ability to distinguish between fibroblastic and epithelial cells is sometimes difficult because cells undergo epithelial-mesenchymal transitions (EMT). During EMT, cells coexpress epithelial and mesenchymal cell markers. To determine whether EMT occurs in adult liver cells, we analyzed the expression profile of primary HSC, two HSC lines, and hepatic epithelial progenitors. As expected, all HSC expressed HSC markers. Surprisingly, these markers were also expressed by epithelial progenitors. In addition, one HSC line expressed typical epithelial progenitor mRNAs, and these epithelial markers were inducible in the second HSC line. In normal and damaged livers, small ductular-type cells stained positive for an HSC marker. In conclusion, HSC and hepatic epithelial progenitors both coexpress epithelial and mesenchymal markers, providing evidence that EMT occurs in adult liver cells.

Authors
Sicklick, JK; Choi, SS; Bustamante, M; McCall, SJ; Pérez, EH; Huang, J; Li, Y-X; Rojkind, M; Diehl, AM
MLA Citation
Sicklick, JK, Choi, SS, Bustamante, M, McCall, SJ, Pérez, EH, Huang, J, Li, Y-X, Rojkind, M, and Diehl, AM. "Evidence for epithelial-mesenchymal transitions in adult liver cells." Am J Physiol Gastrointest Liver Physiol 291.4 (October 2006): G575-G583.
PMID
16710052
Source
pubmed
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
291
Issue
4
Publish Date
2006
Start Page
G575
End Page
G583
DOI
10.1152/ajpgi.00102.2006

Peroxisome proliferator-activated receptor gamma inhibits transforming growth factor beta-induced plasminogen activator inhibitor-1 expression in human stellate cells by interfering with Smad3 phosphorylation

Authors
Zhao, C; Chen, W; Yang, L; Chen, L; Stimpson, SA; Diehl, AM
MLA Citation
Zhao, C, Chen, W, Yang, L, Chen, L, Stimpson, SA, and Diehl, AM. "Peroxisome proliferator-activated receptor gamma inhibits transforming growth factor beta-induced plasminogen activator inhibitor-1 expression in human stellate cells by interfering with Smad3 phosphorylation." October 2006.
Source
wos-lite
Published In
Hepatology
Volume
44
Issue
4
Publish Date
2006
Start Page
690A
End Page
690A

Cross-talk between hepatic stellate cells and cholangiocytes regulates biliary growth through serotonin

Authors
Omenetti, A; Li, Y-X; Chen, W; Gainetdinov, RR; Yang, L; Diehl, AM
MLA Citation
Omenetti, A, Li, Y-X, Chen, W, Gainetdinov, RR, Yang, L, and Diehl, AM. "Cross-talk between hepatic stellate cells and cholangiocytes regulates biliary growth through serotonin." October 2006.
Source
wos-lite
Published In
Hepatology
Volume
44
Issue
4
Publish Date
2006
Start Page
392A
End Page
393A

Mesenchymal-epithelial signalling by the Hedgehog pathway promotes proliferation of bile ductular cells

Authors
Omenetti, A; Li, Y-X; Yang, L; Sicklick, JK; Choi, S; Suzuki, A; Diehl, AM
MLA Citation
Omenetti, A, Li, Y-X, Yang, L, Sicklick, JK, Choi, S, Suzuki, A, and Diehl, AM. "Mesenchymal-epithelial signalling by the Hedgehog pathway promotes proliferation of bile ductular cells." October 2006.
Source
wos-lite
Published In
Hepatology
Volume
44
Issue
4
Publish Date
2006
Start Page
389A
End Page
389A

A novel model for harvesting adult liver progenitor cells

Authors
Yamaguchi, K; Yuen, BB; Camp, T; Zdanowicz, M; Sicklick, J; Hinton, D; Diehl, AM; Li, Y-X
MLA Citation
Yamaguchi, K, Yuen, BB, Camp, T, Zdanowicz, M, Sicklick, J, Hinton, D, Diehl, AM, and Li, Y-X. "A novel model for harvesting adult liver progenitor cells." October 2006.
Source
wos-lite
Published In
Hepatology
Volume
44
Issue
4
Publish Date
2006
Start Page
473A
End Page
473A

Influence of lifestyle factors and comorbidities on liver function in patients undergoing weight loss treatment

Authors
Suzuki, A; Binks, M; Sha, R; Eisenson, H; Diehl, AM
MLA Citation
Suzuki, A, Binks, M, Sha, R, Eisenson, H, and Diehl, AM. "Influence of lifestyle factors and comorbidities on liver function in patients undergoing weight loss treatment." October 2006.
Source
wos-lite
Published In
Hepatology
Volume
44
Issue
4
Publish Date
2006
Start Page
646A
End Page
646A

DGAT2 aso treatment improves hepatic steatosis, but not fibrosis in DB/DB mice fed methionine choline deficient diets

Authors
Yamaguchi, K; Yang, L; McCall, S; Huang, J; Yu, XX; Pandey, SK; Hanot, S; Monia, BP; Li, Y-X; Diehl, AM
MLA Citation
Yamaguchi, K, Yang, L, McCall, S, Huang, J, Yu, XX, Pandey, SK, Hanot, S, Monia, BP, Li, Y-X, and Diehl, AM. "DGAT2 aso treatment improves hepatic steatosis, but not fibrosis in DB/DB mice fed methionine choline deficient diets." October 2006.
Source
wos-lite
Published In
Hepatology
Volume
44
Issue
4
Publish Date
2006
Start Page
665A
End Page
665A

The role of hepatitis C genotype 3 core protein domain 3 in intrahepatic steatosis

Authors
Jhaveri, R; McHutchison, JG; Patel, K; Diehl, AM
MLA Citation
Jhaveri, R, McHutchison, JG, Patel, K, and Diehl, AM. "The role of hepatitis C genotype 3 core protein domain 3 in intrahepatic steatosis." October 2006.
Source
wos-lite
Published In
Hepatology
Volume
44
Issue
4
Publish Date
2006
Start Page
300A
End Page
300A

DGAT1 ASO treatment reduces hepatic fibrosis without improving hepatic steatosis in DB/DB mice fed methionine choline deficient diets

Authors
Yamaguchi, K; Yang, L; McCall, S; Huang, J; Yu, XX; Pandey, SK; Bhanot, S; Monia, BP; Li, Y-X; Diehl, AM
MLA Citation
Yamaguchi, K, Yang, L, McCall, S, Huang, J, Yu, XX, Pandey, SK, Bhanot, S, Monia, BP, Li, Y-X, and Diehl, AM. "DGAT1 ASO treatment reduces hepatic fibrosis without improving hepatic steatosis in DB/DB mice fed methionine choline deficient diets." October 2006.
Source
wos-lite
Published In
Hepatology
Volume
44
Issue
4
Publish Date
2006
Start Page
663A
End Page
663A

Interleukin-15 increases hepatic regenerative activity.

BACKGROUND/AIMS: Interleukin-15 (IL-15) is expressed in many organs. It generally inhibits apoptosis and increases cellular proliferation and differentiation. However, IL-15's roles in liver are unknown. We aimed to determine if IL-15 influences hepatic integrity and regenerative activity. METHODS: Expression of IL-15 and its receptors was evaluated in several liver injury models, primary hepatocytes, and two liver cell lines. Effects of IL-15 on viability, proliferation, and apoptosis were assessed in cultured liver cells, and also in the livers of healthy mice. RESULTS: IL-15 and its receptors are expressed constitutively in healthy livers, and ligand expression is induced in injured livers. Cultured primary hepatocytes and liver cell lines express IL-15 and its receptors. Administration of IL-15 has minimal effects on cultured liver cells, but significantly up-regulates oval cell accumulation, cyclin mRNA expression, and mature hepatocyte replication in healthy mice. These effects are associated with focal hepatic inflammation and increased expression of TNF-alpha and IFN-gamma, but not with increased cell death or aminotransferase release. CONCLUSIONS: IL-15 expression increases during liver injury and IL-15 treatment induces a wound healing-type response in healthy adult mice. These findings suggest that IL-15 may contribute to regenerative activity in damaged liver.

Authors
Suzuki, A; McCall, S; Choi, SS; Sicklick, JK; Huang, J; Qi, Y; Zdanowicz, M; Camp, T; Li, Y-X; Diehl, AM
MLA Citation
Suzuki, A, McCall, S, Choi, SS, Sicklick, JK, Huang, J, Qi, Y, Zdanowicz, M, Camp, T, Li, Y-X, and Diehl, AM. "Interleukin-15 increases hepatic regenerative activity." J Hepatol 45.3 (September 2006): 410-418.
PMID
16781000
Source
pubmed
Published In
Journal of Hepatology
Volume
45
Issue
3
Publish Date
2006
Start Page
410
End Page
418
DOI
10.1016/j.jhep.2006.04.008

Hedgehog signaling maintains resident hepatic progenitors throughout life.

Hedgehog signaling through its receptor, Patched, activates transcription of genes, including Patched, that regulate the fate of various progenitors. Although Hedgehog signaling is required for endodermal commitment and hepatogenesis, the possibility that it regulates liver turnover in adults had not been considered because mature liver epithelial cells lack Hedgehog signaling. Herein, we show that this pathway is essential throughout life for maintaining hepatic progenitors. Patched-expressing cells have been identified among endodermally lineage-restricted, murine embryonic stem cells as well as in livers of fetal and adult Ptc-lacZ mice. An adult-derived, murine hepatic progenitor cell line expresses Patched, and Hedgehog-responsive cells exist in stem cell compartments of fetal and adult human livers. In both species, manipulation of Hedgehog activity influences hepatic progenitor cell survival. Therefore, Hedgehog signaling is conserved in hepatic progenitors from fetal development through adulthood and may be a new therapeutic target in patients with liver damage.

Authors
Sicklick, JK; Li, Y-X; Melhem, A; Schmelzer, E; Zdanowicz, M; Huang, J; Caballero, M; Fair, JH; Ludlow, JW; McClelland, RE; Reid, LM; Diehl, AM
MLA Citation
Sicklick, JK, Li, Y-X, Melhem, A, Schmelzer, E, Zdanowicz, M, Huang, J, Caballero, M, Fair, JH, Ludlow, JW, McClelland, RE, Reid, LM, and Diehl, AM. "Hedgehog signaling maintains resident hepatic progenitors throughout life." Am J Physiol Gastrointest Liver Physiol 290.5 (May 2006): G859-G870.
PMID
16322088
Source
pubmed
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
290
Issue
5
Publish Date
2006
Start Page
G859
End Page
G870
DOI
10.1152/ajpgi.00456.2005

Nonalcoholic steatohepatitis and nonalcoholic Fatty liver disease in young women with polycystic ovary syndrome.

CONTEXT: Nonalcoholic fatty liver disease and polycystic ovary syndrome (PCOS) are both associated with insulin resistance. Thus, women with PCOS may have an increased prevalence of nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis (NASH). OBJECTIVE: The objective of the study was to determine the prevalence and characteristics of NASH and abnormal aminotransferase activity in women with PCOS. DESIGN: The study is a retrospective chart review. SETTING: The setting is an academic endocrinology clinic. PATIENTS: Patients were 200 women with PCOS, defined as irregular menses and hyperandrogenism. MAIN OUTCOME MEASURES: Biopsy-documented NASH and aminotransferase levels were the main outcome measures. RESULTS: Fifteen percent (29 of 200) had aspartate aminotransferase and/or alanine aminotransferase more than 60 U/liter. Women with aminotransferase elevations had lower high-density lipoprotein (HDL) (41 vs. 50 mg/dl, P = 0.006), higher triglycerides (174 vs. 129 mg/dl, P = 0.024), and higher fasting insulin (21 vs. 12 microIU/ml, P = 0.036) compared with women with normal aminotransferases. Six women (mean age 29 yr) with persistent aminotransferase elevations underwent liver biopsy. All six had NASH with fibrosis. Compared with the 194 of 200 PCOS women who did not undergo biopsy, women with biopsy-documented NASH had lower HDL (median 34 vs. 50 mg/dl, P < 0.001), and higher triglycerides (245 vs. 132 mg/dl, P = 0.025), fasting insulin (26 vs. 13 microIU/ml, P = 0.038), aspartate aminotransferase (144 vs. 22 U/liter, P < 0.001), and alanine aminotransferase (143 vs. 28 U/liter, P < 0.001). CONCLUSION: Abnormal aminotransferase activity is common in women with PCOS. Low HDL, high triglycerides, and high fasting insulin were associated with abnormal aminotransferase activity. Some women already had evidence of NASH with fibrosis. Further studies are needed to evaluate whether to screen PCOS women for liver disease at an earlier age than is currently recommended for the general population.

Authors
Setji, TL; Holland, ND; Sanders, LL; Pereira, KC; Diehl, AM; Brown, AJ
MLA Citation
Setji, TL, Holland, ND, Sanders, LL, Pereira, KC, Diehl, AM, and Brown, AJ. "Nonalcoholic steatohepatitis and nonalcoholic Fatty liver disease in young women with polycystic ovary syndrome." J Clin Endocrinol Metab 91.5 (May 2006): 1741-1747.
PMID
16492691
Source
pubmed
Published In
Journal of Clinical Endocrinology and Metabolism
Volume
91
Issue
5
Publish Date
2006
Start Page
1741
End Page
1747
DOI
10.1210/jc.2005-2774

What impact does a specialized center for transplantation and heptobiliary disease have on post-graduate resident training of gastroenterologists and surgeons?

Authors
Tuttle-Newhall, JE; Diehl, AM
MLA Citation
Tuttle-Newhall, JE, and Diehl, AM. "What impact does a specialized center for transplantation and heptobiliary disease have on post-graduate resident training of gastroenterologists and surgeons?." J Hepatol 44.4 (April 2006): 659-662.
PMID
16503084
Source
pubmed
Published In
Journal of Hepatology
Volume
44
Issue
4
Publish Date
2006
Start Page
659
End Page
662
DOI
10.1016/j.jhep.2006.01.021

Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis.

Hedgehog (Hh) pathway activation promotes tumors in several endodermally derived tissues, but its role in the pathogenesis of hepatocellular carcinoma (HCC) is unknown. Although normal hepatocytes lack Hh signaling, activation of the Hh pathway in endodermal progenitors is required for liver development. Thus, we hypothesized that hepatocarcinogenesis may involve regulation of Hh signaling. This pathway is activated when Hh ligand binds to its receptor, Patched (PTC). In an unoccupied state, PTC normally functions as a tumor suppressor that inhibits Smoothened (SMO), a proto-oncoprotein, from activating downstream components and transcription of target genes. Here we show that in HCCs, overexpression of the Smo proto-oncogene, as well as an increase in the stoichiometric ratio of Smo to Ptc mRNA levels, correlated with tumor size, a prognostic indicator in HCC biology. In one tumor we identified a novel Smo mutation in an evolutionarily conserved residue. We also demonstrated that HCC cell lines (HepG2 and Hep3B) expressed Hh pathway components and activated Hh transcriptional targets. In Hep3B cells, cyclopamine, an inhibitor of wild-type SMO, had no effect, but KAAD-cyclopamine, a blocker of oncogenic SMO, inhibited Hh signaling activity by 50%, decreased expression of the hepatocarcinogenic oncogene, c-myc, by 8-fold, and inhibited the growth rate of Hep3B cells by 94%. These data support our hypothesis that Hh signaling is dysregulated in human hepatocarcinogenesis. We demonstrate that overexpression and/or tumorigenic activation of the Smo proto-oncogene mediates c-myc overexpression which plays a critical role in hepatocarcinogenesis and suggests that Smo is a prognostic factor in HCC tumorigenesis.

Authors
Sicklick, JK; Li, Y-X; Jayaraman, A; Kannangai, R; Qi, Y; Vivekanandan, P; Ludlow, JW; Owzar, K; Chen, W; Torbenson, MS; Diehl, AM
MLA Citation
Sicklick, JK, Li, Y-X, Jayaraman, A, Kannangai, R, Qi, Y, Vivekanandan, P, Ludlow, JW, Owzar, K, Chen, W, Torbenson, MS, and Diehl, AM. "Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis." Carcinogenesis 27.4 (April 2006): 748-757.
PMID
16339184
Source
pubmed
Published In
Carcinogenesis
Volume
27
Issue
4
Publish Date
2006
Start Page
748
End Page
757
DOI
10.1093/carcin/bgi292

Breath biomarkers and non-alcoholic fatty liver disease: preliminary observations.

Breath biomarkers have the potential to offer information that is similar to conventional clinical tests or they are entirely unique. Preliminary data support the use of breath biomarkers in the study of liver disease, in particular non-alcoholic fatty liver disease (NAFLD). It was evaluated whether breath ethanol, ethane, sulfur compounds and acetone would be associated with hepatic histopathology amongst morbidly obese patients presenting for bariatric surgery. Breath samples were collected during a preoperative visit and compared with liver biopsies obtained during the surgery. A Student's two-tailed t-test was used to compare differences between the two groups. Linear regression was used to analyse associations between the concentrations of breath molecules and independent predictor variables. It was found that breath ethanol, ethane and acetone can be useful biomarkers in patients with NAFLD. In particular, breath ethanol can be associated with hepatic steatosis, and breath acetone can be associated with non-alcoholic steatohepatitis.

Authors
Solga, SF; Alkhuraishe, A; Cope, K; Tabesh, A; Clark, JM; Torbenson, M; Schwartz, P; Magnuson, T; Diehl, AM; Risby, TH
MLA Citation
Solga, SF, Alkhuraishe, A, Cope, K, Tabesh, A, Clark, JM, Torbenson, M, Schwartz, P, Magnuson, T, Diehl, AM, and Risby, TH. "Breath biomarkers and non-alcoholic fatty liver disease: preliminary observations." Biomarkers 11.2 (March 2006): 174-183.
PMID
16766393
Source
pubmed
Published In
Biomarkers (Informa)
Volume
11
Issue
2
Publish Date
2006
Start Page
174
End Page
183
DOI
10.1080/13547500500421070

Abnormal exhaled ethane concentrations in scleroderma.

Scleroderma (systemic sclerosis) is a chronic multisystem autoimmune disease in which oxidative stress is suspected to play a role in the pathophysiology. Therefore, it was postulated that patients with scleroderma would have abnormally high breath ethane concentrations, which is a volatile product of free-radical-mediated lipid peroxidation, compared with a group of controls. There was a significant difference (p<0.05) between the mean exhaled ethane concentration of 5.27 pmol ml(-1) CO(2) (SEM=0.76) in the scleroderma patients (n=36) versus the mean exhaled concentration of 2.72 pmol ml(-1) CO(2) (SEM=0.71) in a group of healthy controls (n=21). Within the scleroderma group, those subjects taking a calcium channel blocker had lower ethane concentrations compared with patients who were not taking these drugs (p=0.05). There was a significant inverse association between lung diffusion capacity for carbon monoxide (per cent of predicted) and ethane concentration (b=-2.8, p=0.026, CI=-5.2 to -0.35). These data support the presence of increased oxidative stress among patients with scleroderma that is detected by measuring breath ethane concentrations.

Authors
Cope, KA; Solga, SF; Hummers, LK; Wigley, FM; Diehl, AM; Risby, TH
MLA Citation
Cope, KA, Solga, SF, Hummers, LK, Wigley, FM, Diehl, AM, and Risby, TH. "Abnormal exhaled ethane concentrations in scleroderma." Biomarkers 11.1 (January 2006): 70-84.
PMID
16484138
Source
pubmed
Published In
Biomarkers (Informa)
Volume
11
Issue
1
Publish Date
2006
Start Page
70
End Page
84
DOI
10.1080/13547500500515046

Mechanisms underlying nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD), a spectrum of liver damage, encompasses steatosis, steatohepatitis, an intermediate stage of liver disease and cirrhosis. Although NAFLD is the leading cause of chronic liver disease, no effective therapies currently exist. Complex interactions between injury and repair mechanisms likely determine disease progression in NAFLD. The development of successful treatments for NAFLD can be facilitated by understanding disease mechanisms. © 2006 Elsevier Ltd. All rights reserved.

Authors
Abdelmalek, MF; Diehl, AM
MLA Citation
Abdelmalek, MF, and Diehl, AM. "Mechanisms underlying nonalcoholic steatohepatitis." Drug Discovery Today: Disease Mechanisms 3.4 (2006): 479-488.
Source
scival
Published In
Drug Discovery Today: Disease Mechanisms
Volume
3
Issue
4
Publish Date
2006
Start Page
479
End Page
488
DOI
10.1016/j.ddmec.2006.11.001

Role of insulin resistance and extrahepatic signalling in fatty liver disease

Authors
Diehl, AM
MLA Citation
Diehl, AM. "Role of insulin resistance and extrahepatic signalling in fatty liver disease." 2006.
Source
wos-lite
Published In
Disease Progression and Disease Prevention in Hepatology and Gastroenterology
Volume
150
Publish Date
2006
Start Page
167
End Page
172

Role of inflammation in nonalcoholic steatohepatitis.

PURPOSE OF REVIEW: Products of hepatic macrophages and lymphocytes are acknowledged regulators of liver injury and repair. Recent studies have identified inflammatory modulators from sources within and outside the liver that are critical to the pathogenesis and progression of chronic liver diseases, including nonalcoholic fatty liver disease. This review will focus on these developments to clarify how inflammatory mediators from adipose tissue and the liver interact to mediate the pathogenesis of nonalcoholic fatty liver disease. RECENT FINDINGS: Hepatic steatosis and steatohepatitis are extremely prevalent in obese individuals with the metabolic syndrome. The metabolic syndrome results from abnormal production of various adipose-derived and liver-derived factors that modulate energy substrate flux to coordinate tissue anabolism and catabolism. Individuals with the metabolic syndrome produce a relative excess of proinflammatory factors. Some factors inhibit hepatic fat disposal and promote lipid accumulation within hepatocytes. The latter induces sustained hepatic generation of proinflammatory cytokines, particularly when the hepatic innate immune system becomes Th-1 polarized. Although chronic inflammation induces production of various profibrogenic factors, progression to latter stages of nonalcoholic fatty liver disease is relatively unusual in individuals with the metabolic syndrome. This may reflect requirements for additional factors that become abundant only in individuals who have additional defects in hepatic innate immunity. SUMMARY: Obesity and the metabolic syndrome represent chronic inflammatory states and are associated with nonalcoholic fatty liver disease. Liver injury that ensues is dictated by metabolic and immunomodulatory factors that are produced by adipose tissue and within the liver.

Authors
Choi, S; Diehl, AM
MLA Citation
Choi, S, and Diehl, AM. "Role of inflammation in nonalcoholic steatohepatitis." Curr Opin Gastroenterol 21.6 (November 2005): 702-707. (Review)
PMID
16220049
Source
pubmed
Published In
Current Opinion in Gastroenterology
Volume
21
Issue
6
Publish Date
2005
Start Page
702
End Page
707

Role for hedgehog signaling in hepatic stellate cell activation and viability.

Hepatic stellate cells (HSC) have a complex phenotype that includes both neural and myofibroblastic features. The Hedgehog (Hh) pathway has been shown to direct the fate of neural and myofibroblastic cells during embryogenesis and during tissue remodeling in adults. Therefore, we hypothesized that Hh signaling may regulate the fate of HSC in adults. In this study, we find that freshly isolated stellate cells from adult Patched-lacZ transgenic mice exhibit beta-galactosidase activity, indicating Hh pathway activity. Transcripts of Hh ligands, the Hh pathway receptor, and Hh-regulated transcription factors are expressed by stellate cells from mice, rats, and humans. Transfection experiments in a cell line using a Hh-inducible luciferase reporter demonstrate constitutive Hh pathway activity. Moreover, neutralizing antibodies to Hh increase apoptosis, while viability is restored by treatment with Hh ligand. In vitro treatment of primary stellate cells with cyclopamine (Cyc), a pharmacologic inhibitor of the Hh pathway, inhibits activation and slightly decreases cell survival, while a single injection of Cyc into healthy adult mice reduces activation of HSC by more than 50% without producing obvious liver damage. Our findings reveal a novel mechanism, namely the Hh pathway, that regulates the activation and viability of HSC.

Authors
Sicklick, JK; Li, Y-X; Choi, SS; Qi, Y; Chen, W; Bustamante, M; Huang, J; Zdanowicz, M; Camp, T; Torbenson, MS; Rojkind, M; Diehl, AM
MLA Citation
Sicklick, JK, Li, Y-X, Choi, SS, Qi, Y, Chen, W, Bustamante, M, Huang, J, Zdanowicz, M, Camp, T, Torbenson, MS, Rojkind, M, and Diehl, AM. "Role for hedgehog signaling in hepatic stellate cell activation and viability." Lab Invest 85.11 (November 2005): 1368-1380.
PMID
16170335
Source
pubmed
Published In
Laboratory Investigation
Volume
85
Issue
11
Publish Date
2005
Start Page
1368
End Page
1380
DOI
10.1038/labinvest.3700349

Lessons from animal models of NASH.

Studies of animals with obesity-related liver disease have taught us much about the mechanisms that mediate this pathology. Our work with genetically obese, insulin-resistant ob/ob mice demonstrates that hepatocytes become steatotic and die at increased rates. Thus, ob/ob mice develop non-alcoholic steatohepatitis (NASH) spontaneously. NASH is intimately related to the insulin resistance (i.e., metabolic) syndrome, a constellation of disorders that result from abnormal production of hormones and cytokines that regulate inflammatory responses. Like humans with the metabolic syndrome, ob/ob mice exhibit increased tumor necrosis factor (TNF) but relatively low levels of adiponectin. Because TNF and adiponectin typically antagonize each other, the combination of increased TNF and decreased adiponectin promotes a state of high TNF activity. Consequently, hepatocytes generate excessive reactive oxygen species (ROS), have altered viability, accumulate lipid and are resistant to insulin. Treatments that inhibit TNF activity or that increase adiponectin improve NASH in ob/ob mice, other mice and humans with NASH. Hence, there is no doubt that cytokine and hormonal imbalances play a key role in the pathogenesis of NASH. However, the fundamental cellular events involved are still poorly understood. Even within very small areas of livers with NASH, most hepatocytes are merely steatotic, while others are ballooned (pre-necrotic), and still others have succumbed to apoptosis. This observation suggests cell-to-cell variability in the response to chronic inflammatory stress. In NASH, most steatotic hepatocytes survive by inducing adaptive, cytoprotective factors. However, such cells respond to super-imposed toxic and mitogenic stimuli differently than (3)naïve(2) (un-adapted) hepatocytes. Fatty hepatocytes tend to be more vulnerable to ATP depletion and less proliferative, perpetuating chronic liver injury while encouraging the expansion of liver progenitor populations that may become neoplastic. Finally, like other causes of chronic injury, NASH increases the risk for cirrhosis. Studies of ob/ob mice demonstrate that progression to cirrhosis is potentiated by leptin. Leptin probably acts at multiple levels to promote hepatic fibrosis, including direct activation of stellate cells via leptin receptors, regulation of pro- and anti-fibrogenic cytokine production by innate immune cells, and modulation of other neuronal factors that regulate stellate cell activation. The latter two mechanisms seem to dominate because stellate cell activation, fibrogenic cytokine production, collagen gene expression and fibrosis can all be induced by manipulating cytokines and neuronal factors in ob/ob mice (that are genetically deficient in leptin). Thus, studies in mice have uncovered several basic mechanisms that explain the dysfunction that occurs in different types of liver cells during the metabolic syndrome. This has important therapeutic implications for human NASH.

Authors
Diehl, AM
MLA Citation
Diehl, AM. "Lessons from animal models of NASH." Hepatol Res 33.2 (October 2005): 138-144.
PMID
16198624
Source
pubmed
Published In
Hepatology Research
Volume
33
Issue
2
Publish Date
2005
Start Page
138
End Page
144
DOI
10.1016/j.hepres.2005.09.022

Hedgehog signaling in hepatic stellate cells from adult mice and rats

Authors
Sicklick, JK; Rojkind, M; Qi, Y; Chen, W; Bustamante, M; Choi, SS; Huang, JW; Camp, T; Torbenson, MS; Li, YX; Diehl, AM
MLA Citation
Sicklick, JK, Rojkind, M, Qi, Y, Chen, W, Bustamante, M, Choi, SS, Huang, JW, Camp, T, Torbenson, MS, Li, YX, and Diehl, AM. "Hedgehog signaling in hepatic stellate cells from adult mice and rats." October 2005.
Source
wos-lite
Published In
Hepatology
Volume
42
Issue
4
Publish Date
2005
Start Page
733A
End Page
733A

Rac over-expression in activated hepatic stellate cells increases susceptibility to liver injury

Authors
Choi, SS; Huang, JW; Sicklick, JK; Ma, Q; Camp, JT; Goldschmidt-Clermont, PJ; Diehl, AM
MLA Citation
Choi, SS, Huang, JW, Sicklick, JK, Ma, Q, Camp, JT, Goldschmidt-Clermont, PJ, and Diehl, AM. "Rac over-expression in activated hepatic stellate cells increases susceptibility to liver injury." October 2005.
Source
wos-lite
Published In
Hepatology
Volume
42
Issue
4
Publish Date
2005
Start Page
267A
End Page
267A

Conserved hedgehog pathway regulation of murine and human hepatic progenitors throughout life

Authors
Sicklick, JK; Li, YX; Melhem, A; Schmelzer, E; Zdanowicz, M; Huang, JW; Caballero, M; Fair, JH; Ludlow, JW; Reid, LM; Diehl, AM
MLA Citation
Sicklick, JK, Li, YX, Melhem, A, Schmelzer, E, Zdanowicz, M, Huang, JW, Caballero, M, Fair, JH, Ludlow, JW, Reid, LM, and Diehl, AM. "Conserved hedgehog pathway regulation of murine and human hepatic progenitors throughout life." October 2005.
Source
wos-lite
Published In
Hepatology
Volume
42
Issue
4
Publish Date
2005
Start Page
740A
End Page
740A

Insulin resistance and steatosis in hepatitis C virus infection.

The relationship between hepatitis C virus (HCV), steatosis, and insulin resistance is genotype specific, and steatosis and insulin resistance are closely linked to the progression of liver disease in HCV infected patients.

Authors
Zekry, A; McHutchison, JG; Diehl, AM
MLA Citation
Zekry, A, McHutchison, JG, and Diehl, AM. "Insulin resistance and steatosis in hepatitis C virus infection." Gut 54.7 (July 2005): 903-906. (Review)
PMID
15951532
Source
pubmed
Published In
Gut
Volume
54
Issue
7
Publish Date
2005
Start Page
903
End Page
906
DOI
10.1136/gut.2004.059873

Hedgehog signaling correlates with hepatocellular carcinoma progression.

Authors
Sicklick, JK; Jayaraman, A; Kannangai, R; Torbenson, MS; Choti, MA; Diehl, AM
MLA Citation
Sicklick, JK, Jayaraman, A, Kannangai, R, Torbenson, MS, Choti, MA, and Diehl, AM. "Hedgehog signaling correlates with hepatocellular carcinoma progression." June 1, 2005.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
863S
End Page
863S

Should nonalcoholic fatty liver disease be treated differently in elderly patients?

Authors
Suzuki, A; Diehl, AM
MLA Citation
Suzuki, A, and Diehl, AM. "Should nonalcoholic fatty liver disease be treated differently in elderly patients?." Nat Clin Pract Gastroenterol Hepatol 2.5 (May 2005): 208-209.
PMID
16265200
Source
pubmed
Published In
Nature Clinical Practice Gastroenterology & Hepatology
Volume
2
Issue
5
Publish Date
2005
Start Page
208
End Page
209
DOI
10.1038/ncpgasthep0172

Repopulation of liver allografts by recipient-derived progenitor cells via mixed cell fusion and transdifferentiation: A new insight of tolerance and regeneration.

Authors
Sun, ZL; Zheng, QZ; Nagakawa, Y; Williams, GM; Montgomery, RA; Diehl, AM; Klein, AS
MLA Citation
Sun, ZL, Zheng, QZ, Nagakawa, Y, Williams, GM, Montgomery, RA, Diehl, AM, and Klein, AS. "Repopulation of liver allografts by recipient-derived progenitor cells via mixed cell fusion and transdifferentiation: A new insight of tolerance and regeneration." May 2005.
Source
wos-lite
Published In
American Journal of Transplantation
Volume
5
Publish Date
2005
Start Page
513
End Page
513

A zebrafish model of Fetal Alcohol Syndrome parallels Hedgehog signaling defects

Authors
Zdanowicz, M; Sicklick, JK; Diehl, AM; Li, YX
MLA Citation
Zdanowicz, M, Sicklick, JK, Diehl, AM, and Li, YX. "A zebrafish model of Fetal Alcohol Syndrome parallels Hedgehog signaling defects." May 2005.
Source
wos-lite
Published In
Alcoholism: Clinical and Experimental Research
Volume
29
Issue
5
Publish Date
2005
Start Page
86A
End Page
86A

Hepatic Stellate cell heterogeneity may reflect cells at different stages of differentiation

Authors
Hernandez-Perez, E; Bustamante, M; Desierto, G; Sicklick, J; Diehl, AM; Rojkind, M
MLA Citation
Hernandez-Perez, E, Bustamante, M, Desierto, G, Sicklick, J, Diehl, AM, and Rojkind, M. "Hepatic Stellate cell heterogeneity may reflect cells at different stages of differentiation." March 4, 2005.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
19
Issue
4
Publish Date
2005
Start Page
A479
End Page
A479

Hepatic complications of obesity.

Obesity increases the risk and severity of liver disease. The most common form of liver disease that occurs in obesity is NAFLD. A better understanding of the basic disease mechanisms and natural histories ofNAFLD is needed to guide management and treatment of obese patients and others with this disorder. Large, prospective, randomized, controlled treatment trials also are needed. Ideally, such studies will focus on well-defined patient subsets and monitor the impact of therapy on clinically relevant endpoints, such as liver-related morbidity and mortality.

Authors
Diehl, AM
MLA Citation
Diehl, AM. "Hepatic complications of obesity." Gastroenterol Clin North Am 34.1 (March 2005): 45-61. (Review)
PMID
15823438
Source
pubmed
Published In
Gastroenterology Clinics of North America
Volume
34
Issue
1
Publish Date
2005
Start Page
45
End Page
61
DOI
10.1016/j.gtc.2004.12.012

Cytokines and the pathogenesis of non-alcoholic steatohepatitis.

Authors
Diehl, AM; Li, ZP; Lin, HZ; Yang, SQ
MLA Citation
Diehl, AM, Li, ZP, Lin, HZ, and Yang, SQ. "Cytokines and the pathogenesis of non-alcoholic steatohepatitis." Gut 54.2 (February 2005): 303-306. (Review)
PMID
15647199
Source
pubmed
Published In
Gut
Volume
54
Issue
2
Publish Date
2005
Start Page
303
End Page
306
DOI
10.1136/gut.2003.024935

Recent events in alcoholic liver disease V. effects of ethanol on liver regeneration.

Liver regeneration is necessary to recover from alcoholic liver injury. Herein, we review evidence that ethanol interferes with liver regeneration. Briefly, alcoholic fatty livers demonstrate increased rates of hepatocyte death. The latter provides a regenerative stimulus. However, unlike mature hepatocytes in healthy adult livers, most surviving mature hepatocytes in alcoholic fatty livers cannot replicate. Therefore, less mature cells (progenitors) must differentiate to replace dead hepatocytes. Little is known about the general mechanisms that modulate the differentiation of liver progenitors in adults. Delineation of these mechanisms and clarification of how ethanol influences them might suggest new therapies for alcoholic liver disease.

Authors
Diehl, AM
MLA Citation
Diehl, AM. "Recent events in alcoholic liver disease V. effects of ethanol on liver regeneration." Am J Physiol Gastrointest Liver Physiol 288.1 (January 2005): G1-G6. (Review)
PMID
15591584
Source
pubmed
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
288
Issue
1
Publish Date
2005
Start Page
G1
End Page
G6
DOI
10.1152/ajpgi.00376.2004

Hepatic angiomyolipomas share a similar gene expression profile with hepatic stellate cells

Authors
Torbenson, A; Kannangai, R; Rojkind, M; Sicklick, J; Diehl, AM
MLA Citation
Torbenson, A, Kannangai, R, Rojkind, M, Sicklick, J, and Diehl, AM. "Hepatic angiomyolipomas share a similar gene expression profile with hepatic stellate cells." January 2005.
Source
wos-lite
Published In
Laboratory Investigation
Volume
85
Publish Date
2005
Start Page
288A
End Page
288A

Hepatic Angiomyolipomas share a similar gene expression profile with hepatic stellate cells

Authors
Torbenson, M; Kannangai, R; Rojkind, M; Sicklick, J; Diehl, AM
MLA Citation
Torbenson, M, Kannangai, R, Rojkind, M, Sicklick, J, and Diehl, AM. "Hepatic Angiomyolipomas share a similar gene expression profile with hepatic stellate cells." January 2005.
Source
wos-lite
Published In
Modern Pathology
Volume
18
Publish Date
2005
Start Page
288A
End Page
288A

Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease

Dietary factors promote obesity and obesity-related disorders, such as fatty liver disease. Natural killer T (NKT) cells are components of the innate immune system that regulate proinflammatory (Th-1) and anti-inflammatory (Th-2) immune responses. Previously, we noted that NKT cells are selectively reduced in the fatty livers of obese, leptin-deficient ob/ob mice and demonstrated that this promotes proinflammatory polarization of hepatic cytokine production, exacerbating lipopolysaccharide (LPS) liver injury in these animals. In the current study, we show that hepatic NKT cells are also depleted by diets that induce obesity and fatty livers in wild-type mice, promoting Th-1 polarization of hepatic cytokine production and sensitization to LPS liver injury despite persistent leptin. Adult male C57BL6 mice fed diets containing high amounts of either fat or sucrose, or combined high-fat, high-sucrose, develop increased hepatic NKT cell apoptosis and reduced liver NKT cells. The hepatic lymphocytes are more Th-1 polarized with increased intracellular interferon gamma and tumor necrosis factor alpha. Mice fed high-fat diets also exhibit more liver injury, reflected by 2-fold greater serum alanine aminotransferase (ALT) than control animals after receiving LPS. In conclusion, when otherwise normal mice are fed with high-fat or sucrose diet, they become obese, develop fatty livers, and acquire hepatic innate immune system abnormalities, including increased NKT cell apoptosis. The latter reduces liver NKT cell populations and promotes excessive hepatic production of Th-1 cytokines that promote hepatic inflammation. These diet-induced alterations in the hepatic innate immune system may contribute to obesity-related liver disease. Copyright © 2005 by the American Association for the Study of Liver Diseases.

Authors
Li, Z; Soloski, MJ; Diehl, AM
MLA Citation
Li, Z, Soloski, MJ, and Diehl, AM. "Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease." Hepatology 42.4 (2005): 880-885.
PMID
16175608
Source
scival
Published In
Hepatology
Volume
42
Issue
4
Publish Date
2005
Start Page
880
End Page
885
DOI
10.1002/hep.20826

Hepatic 31P magnetic resonance spectroscopy: A hepatologist's user guide

Hepatic phosphorus magnetic resonance spectroscopy (31P MRS) offers the exciting potential of studying metabolic processes in the human liver in vivo. Many investigators have utilized 31P MRS to research a broad range of metabolic questions, and there is outstanding potential for this imaging modality in the future. However, at times it is difficult to appreciate this potential because most published series have been small, and comparisons between studies are difficult. Indeed, the published literature contains significant variation in data acquisition and data analysis techniques and, perhaps most importantly, the interpretation of the data itself. As MR technology continues to evolve and more studies are being performed, perhaps a greater consensus of study techniques and endpoints will emerge. This review summarizes the present literature on human hepatic 31P MRS. © Blackwell Munksgaard 2005.

Authors
Solga, SF; Horska, A; Clark, JM; Diehl, AM
MLA Citation
Solga, SF, Horska, A, Clark, JM, and Diehl, AM. "Hepatic 31P magnetic resonance spectroscopy: A hepatologist's user guide." Liver International 25.3 (2005): 490-500.
PMID
15910484
Source
scival
Published In
Liver International
Volume
25
Issue
3
Publish Date
2005
Start Page
490
End Page
500
DOI
10.1111/j.1478-3231.2005.01131.x

Hepatic angiomyolipoma and hepatic stellate cells share a similar gene expression profile

Background and Aims: Angiomyolipomas (AMLs) of the liver are rare neoplasms composed of large epithelioid cells with intermixed fat and blood vessels. Hepatic AMLs have no clear normal-cell counterpart in the liver. However, AMLs and stellate cells both are positive for neural crest-derived markers including HMB-45 antigen. Methods: To further explore the similarities between hepatic AMLs and stellate cells, gene expression of a hepatic AML was studied by cDNA microarray. Real-time polymerase chain reaction was used to confirm gene expression. Hepatic stellate cells can be quiescent, activated, or have a myofibroblastic phenotype depending on their state of activation. Expression of known markers of activated stellate cells was compared between the AML, activated primary mouse stellate cells, and stellate cell lines with activated and myofibroblastic phenotypes. Next, 5 novel genes from the AML were selected because they were not previously known to be markers of stellate cells and mRNA expression measured in the activated mouse stellate cells and in myofibroblastic stellate cell lines. Finally, expression levels of 10 novel genes were determined in 5 cirrhotic and 5 noncirrhotic human livers. Results: Overexpression of known markers of activated stellate cells including transforming growth factor β (TGF-β), smooth muscle actin, and collagen was found in the hepatic AML. Three of 5 novel markers that were identified in the AML, RRAD (Ras-related associated with diabetes), CTSK (cathepsin K), and NIBAN were also found to be overexpressed in activated stellate cells compared with quiescent or myofibroblastic stellate cells. In addition, 9 of 10 novel genes overexpressed in AML were also overexpressed in cirrhotic human livers versus noncirrhotic livers. Conclusions: Hepatic AMLs share a similar gene expression profile and may differentiate toward activated stellate cells. © 2005 Elsevier Inc. All rights reserved.

Authors
Kannangai, R; Diehl, AM; Sicklick, J; Rojkind, M; Thomas, D; Torbenson, M
MLA Citation
Kannangai, R, Diehl, AM, Sicklick, J, Rojkind, M, Thomas, D, and Torbenson, M. "Hepatic angiomyolipoma and hepatic stellate cells share a similar gene expression profile." Human Pathology 36.4 (2005): 341-347.
PMID
15891994
Source
scival
Published In
Human Pathology
Volume
36
Issue
4
Publish Date
2005
Start Page
341
End Page
347
DOI
10.1016/j.humpath.2005.01.002

Race and comorbid factors predict nonalcoholic fatty liver disease histopathology in severely obese patients

Purpose: Nonalcoholic fatty liver disease (NAFLD) is a common and potentially serious form of chronic liver disease. Although NAFLD is known to be associated with obesity and some comorbid conditions, less is known about the severity of NAFLD among different racial groups. Methods: We prospectively studied 237 consecutive morbidly obese patients presenting for bariatric surgery. All patients underwent intraoperative liver biopsy and chart review. After excluding subjects who reported alcohol use (n = 37) or who had missing biopsy data (n = 11), 189 patients were available for analysis. Clinical and laboratory associations with each of the histological components of NAFLD were assessed using multiple logistic regression analysis. Results: The mean age was 43.1 years, 84% were female, and 13% were African American. It was found that 88% had steatosis, including 35% with moderate to severe steatosis (> 33% of hepatocytes involved). Of these patients, 67% had inflammation, 46% had fibrosis, and 45% met Brunt's criteria for NASH. Compared with Caucasians and after adjustment, African Americans had significantly lower odds of severe hepatic pathology, with adjusted odds ratios of 0.1 (P = .02) for the presence of moderate or severe steatosis, 0.2 for inflammation (P = .006), 0.3 for fibrosis (P = .05), and 0.2 for NASH (P = .02). In addition, participants with one or more features of the metabolic syndrome (ie, diabetes, hypertension, or dyslipidemia) or elevated aminotransferase levels had significantly higher odds of severe hepatic histopathology. Conclusion: Among obese patients presenting for bariatric surgery, NAFLD is more common in Caucasians, patients with features of the metabolic syndrome, and those with elevated aminotransferase levels. © 2005 American Society for Bariatric Surgery.

Authors
Solga, SF; Clark, JM; Alkhuraishi, AR; Torbenson, M; Tabesh, A; Schweitzer, M; Diehl, AM; Magnuson, TH
MLA Citation
Solga, SF, Clark, JM, Alkhuraishi, AR, Torbenson, M, Tabesh, A, Schweitzer, M, Diehl, AM, and Magnuson, TH. "Race and comorbid factors predict nonalcoholic fatty liver disease histopathology in severely obese patients." Surgery for Obesity and Related Diseases 1.1 (2005): 6-11.
PMID
16925194
Source
scival
Published In
Surgery for Obesity and Related Diseases
Volume
1
Issue
1
Publish Date
2005
Start Page
6
End Page
11
DOI
10.1016/j.soard.2004.12.006

Roux-en-Y gastric bypass improves liver histology in patients with non-alcoholic fatty liver disease

Objectives: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in the United States and is prevalent in morbidly obese patients. While weight loss and treatment of risk factors are recommended, the reported effects of bariatric surgery on NAFLD are mixed. Research Methods and Procedures: We examined liver histology at the time of Roux-en-Y gastric bypass surgery and at elective incisional hernia repair after weight loss for 16 patients at one center. Slides were read by one pathologist, blinded to clinical data, using the Brunt criteria. Clinical and laboratory data were extracted from chart review. Alcohol use was ascertained by two interviews. Results: At baseline, the mean age was 44 years, 50% were women, 88% were white, and the mean BMI was 51 kg/m 2. None had significant alcohol use. On initial biopsy, all patients showed steatosis, 94% had inflammation, 88% had ballooning degeneration, 88% had perisinusoidal fibrosis, and 81% had portal fibrosis. The mean time between the two biopsies was 305 ± 131 (SD) days. The mean weight loss was 118 ± 29 1b. Steatosis improved in 15 of 16 patients, with resolution in 13. Twelve of 15 patients with inflammation at baseline showed improvement, and 12 of 14 showed less ballooning. Six of 14 patients with perisinusoidal fibrosis and 6 of 13 with portal fibrosis showed improvement. No patient had worsening of steatosis, inflammation, ballooning, or fibrosis. Discussion: Our study shows improvement in all of the histological features of NAFLD after Roux-en-Y gastric bypass surgery-induced weight loss, despite significant histopathology at baseline and substantial weight loss. Copyright © 2005 NAASO.

Authors
Clark, JM; Alkhuraishi, ARA; Solga, SF; Alli, P; Diehl, AM; Magnuson, TH
MLA Citation
Clark, JM, Alkhuraishi, ARA, Solga, SF, Alli, P, Diehl, AM, and Magnuson, TH. "Roux-en-Y gastric bypass improves liver histology in patients with non-alcoholic fatty liver disease." Obesity Research 13.7 (2005): 1180-1186.
PMID
16076987
Source
scival
Published In
Obesity research
Volume
13
Issue
7
Publish Date
2005
Start Page
1180
End Page
1186

Arterial homeostasis, inflammation, and erythropoietic growth factors.

A neurohumoral link between kidneys and the heart has been established, particularly in the context of hypertension and cardiomyopathy. Beyond this neuro-endocrine pathway, another connecting system theoretically recruits growth factors that are selectively produced by the kidneys and have the ability to promote a distant reaction at the level of bone marrow. This reaction differentiates and circulates vascular progenitor cells capable of repairing the injured cardiovascular system. Reducing injuries (prevention) stabilizes disease processes by reducing tissue damage and destruction but the gradual degradation of the body's natural repair mechanisms eventually allows progressive reactivation of disease processes. In this light, a focus on tissue repair rather than injury prevention may hold the key to controlling chronic heart diseases. This article examines the medical therapies, including recombinant human erythropoietin, that have been shown to improve the function and survival of endothelial progenitor cells and promote the healing of damaged tissue.

Authors
Goldschmidt-Clermont, PJ; Diehl, AM
MLA Citation
Goldschmidt-Clermont, PJ, and Diehl, AM. "Arterial homeostasis, inflammation, and erythropoietic growth factors." Rev Cardiovasc Med 6 Suppl 3 (2005): S22-S26. (Review)
PMID
16340935
Source
pubmed
Published In
Reviews in cardiovascular medicine
Volume
6 Suppl 3
Publish Date
2005
Start Page
S22
End Page
S26

Dietary factors influence hepatic innate immune system and inflammation.

Authors
Li, ZP; Diehl, AM
MLA Citation
Li, ZP, and Diehl, AM. "Dietary factors influence hepatic innate immune system and inflammation." October 2004.
Source
wos-lite
Published In
Hepatology
Volume
40
Issue
4
Publish Date
2004
Start Page
285A
End Page
285A

Activation of embryonic developmental programs in non-alcoholic fatty liver disease

Authors
Sicklick, J; Huang, JW; Lin, HZ; Karhadkar, S; Beachy, P; Diehl, AM
MLA Citation
Sicklick, J, Huang, JW, Lin, HZ, Karhadkar, S, Beachy, P, and Diehl, AM. "Activation of embryonic developmental programs in non-alcoholic fatty liver disease." October 2004.
Source
wos-lite
Published In
Hepatology
Volume
40
Issue
4
Publish Date
2004
Start Page
196A
End Page
196A

Natural killer T cells regulate liver regeneration.

Authors
Li, ZP; Anders, RA; Fu, YX; Diehl, AM
MLA Citation
Li, ZP, Anders, RA, Fu, YX, and Diehl, AM. "Natural killer T cells regulate liver regeneration." October 2004.
Source
wos-lite
Published In
Hepatology
Volume
40
Issue
4
Publish Date
2004
Start Page
182A
End Page
182A

Obesity and alcoholic liver disease.

Obesity potentiates the severity of alcohol-induced liver damage. Ethanol influences adipose tissue production of hormones and cytokines. The mechanisms by which adiposity and ethanol interact to produce hepatic steatosis and steatohepatitis are beginning to be studied. Exacerbation of the proinflammatory state that induces tumor necrosis factor activity and hepatic insulin resistance seems to be involved. However, the precise cellular signals that culminate in hepatocyte dysfunction and death remain controversial. Both hepatocyte apoptosis and necrosis are likely, but further study is needed to develop optimal hepatoprotective strategies. It is currently unclear whether the hepatotoxic consequences of obesity and ethanol ingestion are additive or synergistic. This information has important prognostic implications and might be useful to formulate body mass index-based guidelines for "safe" alcohol consumption. Findings of studies in experimental animals also raise questions about the relation between steatohepatitis and cirrhosis. Despite overwhelming evidence that obesity promotes alcohol-induced steatosis and steatohepatitis, most obese human beings (and mice) who drink alcohol do not become cirrhotic. Moreover, at least in mice, even severe steatohepatitis leads to cirrhosis relatively infrequently. Thus, it is conceivable that, although steatohepatitis is a permissive factor for cirrhosis, it is neither necessary nor sufficient for cirrhosis to occur. The quest to identify the proximal mediators of hepatic fibrosis should probably include an investigation of how various adipokines, neurotransmitters, and cytokines interact to regulate hepatic stellate cells. Armed with such knowledge, further modifying actions of ethanol on these mechanisms can be explored by investigators.

Authors
Diehl, AM
MLA Citation
Diehl, AM. "Obesity and alcoholic liver disease." Alcohol 34.1 (August 2004): 81-87. (Review)
PMID
15670669
Source
pubmed
Published In
Alcohol
Volume
34
Issue
1
Publish Date
2004
Start Page
81
End Page
87
DOI
10.1016/j.alcohol.2004.07.010

Tumor necrosis factor and its potential role in insulin resistance and nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of hepatic pathology that resembles alcohol-induced fatty liver disease(AFLD), but which develops in individuals who are not heavy drinkers. In people, NAFLD is associated strongly with obesity,insulin resistance, and dysmetabolic syndrome, but the exact mechanisms that promote liver disease in this clinical context remain poorly understood. The proinflammatory cytokine, funor necrosis factor alpha is known to be a key mediator of AFLD. This article discusses clinical and experimental evidence that tumor necrosis factor plays a role in the pathogenesis of insulin resistance syndromes, including nonalcoholic fatty syndromes, including nonalcoholic fatty liver disease.

Authors
Diehl, AM
MLA Citation
Diehl, AM. "Tumor necrosis factor and its potential role in insulin resistance and nonalcoholic fatty liver disease." Clin Liver Dis 8.3 (August 2004): 619-x. (Review)
PMID
15331067
Source
pubmed
Published In
Clinics in Liver Disease
Volume
8
Issue
3
Publish Date
2004
Start Page
619
End Page
x
DOI
10.1016/j.cld.2004.04.012

Alcoholic liver disease

Authors
Koteish, A; Diehl, AM
MLA Citation
Koteish, A, and Diehl, AM. "Alcoholic liver disease." (April 23, 2004): 85-94. (Chapter)
Source
scopus
Publish Date
2004
Start Page
85
End Page
94
DOI
10.1016/B978-0-443-06633-7.50011-9

Oxidative DNA damage and DNA repair enzyme expression are inversely related in murine models of fatty liver disease

Mitochondrial generation of reactive oxygen species (ROS) is increased in mice with fatty livers induced by genetic obesity, chronic consumption of ethanol, or methionine/choline-deficient diets. Both nuclear and mitochondrial (mt) DNA are targets for ROS-induced damage and accumulate hydroxylated bases, such as 8-hydroxy-2′-deoxyguanosine (8-oxoG) and base substitution of adenine with 8-oxoG (A*8-oxoG), that introduce mutations that promote cancer as well as cell death. The mammalian homolog of the bacterial DNA mismatch repair enzyme MutY (MYH) removes A*8-oxoG from nuclear and mtDNA, reduces 8-oxoG accumulation, and restores genomic stability after ROS exposure. Cumulative damage to mtDNA occurs as fatty liver disease progresses. Therefore, differences in hepatic MYH activity may influence the severity of fatty liver disease. To evaluate this hypothesis, we compared mtH2O2 production, MYH expression, oxidative DNA damage, and hepatocyte death in healthy mice and different mouse models of fatty liver disease. The results show that diverse causes of steatohepatitis increase mtROS production, limit repair of mtDNA, and oxidatively damage DNA. However, there are important differences in the DNA repair response to oxidant stress among mouse models of fatty liver disease. Independent of the degree of mtROS generation, models with the least MYH exhibit the greatest accumulation of 8-oxoG and the most hepatocyte death. These findings raise the intriguing possibility that inherited or acquired differences in DNA repair enzyme activity may underlie some of the interindividual differences in fatty liver disease outcomes.

Authors
Gao, D; Wei, C; Chen, L; Huang, J; Yang, S; Diehl, AM
MLA Citation
Gao, D, Wei, C, Chen, L, Huang, J, Yang, S, and Diehl, AM. "Oxidative DNA damage and DNA repair enzyme expression are inversely related in murine models of fatty liver disease." American Journal of Physiology - Gastrointestinal and Liver Physiology 287.5 50-5 (2004): G1070-G1077.
PMID
15231485
Source
scival
Published In
American Journal of Physiology - Gastrointestinal and Liver Physiology
Volume
287
Issue
5 50-5
Publish Date
2004
Start Page
G1070
End Page
G1077
DOI
10.1152/ajpgi.00228.2004

Dietary composition and nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a common and potentially serious form of chronic liver disease that occurs in patients who do not abuse alcohol. Present dietary recommendations for all Americans, including those with NAFLD, endorse a low-calorie, low-fat diet. However, little is known about the effect of diet composition on liver histopathology in patients with NAFLD. The aim of this study was to determine whether overall calorie intake and diet composition are associated with the severity of NAFLD histopathology. Seventy-four consecutive morbidly obese patients presenting for bariatric surgery from January 2001 to March 2002 were retrospectively reviewed. In addition to a standard surgical and psychological evaluation, all patients underwent a preoperative dietary evaluation using a standardized 24-hr food recall. Food intake was evaluated for total calories and macronutrients and compared to liver histopathology from biopsies routinely obtained during surgery. Associations with the severity of steatosis and the presence of inflammation or fibrosis were assessed separately using chi-square for categorical variables and ANOVA for continuous variables. Further, we conducted multiple logistic regression analyses for each histological outcome. There were no significant associations between either total caloric intake or protein intake and either steatosis, fibrosis, or inflammation. However, higher CHO intake was associated with significantly higher odds of inflammation, while higher fat intake was associated with significantly lower odds of inflammation. In conclusion, present dietary recommendations may worsen NAFLD histopathology.

Authors
Solga, S; Alkhuraishe, AR; Clark, JM; Torbenson, M; Greenwald, A; Diehl, AM; Magnuson, T
MLA Citation
Solga, S, Alkhuraishe, AR, Clark, JM, Torbenson, M, Greenwald, A, Diehl, AM, and Magnuson, T. "Dietary composition and nonalcoholic fatty liver disease." Digestive Diseases and Sciences 49.10 (2004): 1578-1583.
PMID
15573908
Source
scival
Published In
Digestive Diseases and Sciences
Volume
49
Issue
10
Publish Date
2004
Start Page
1578
End Page
1583
DOI
10.1023/B:DDAS.0000043367.69470.b7

Sympathetic nervous system regulation of liver repair

This chapter reviews recent evidence that the sympathetic nervous system (SNS) regulates liver repair by modulating the phenotypes of hepatic stellate cells (HSCs), the liver's principal fibrogenic cells, and hepatic epithelial progenitors, i.e., oval cells. SNS nerve fibers touch HSCs and these cells express adrenoceptors, suggesting that HSCs may be targets for SNS neurotransmitters. HSCs also contain catecholamine biosynthetic enzymes, release norepinephrine (NE), and are growth-inhibited by adrenoceptor antagonists. In addition, HSCs from mice with reduced levels of NE grow poorly in culture and exhibit inhibited activation during liver injury. Finally, growth and injury-related fibrogenic responses are rescued by adrenoceptor agonists. Thus, certain SNS inhibitors (SNSIs) protect experimental animals from cirrhosis. Conversely, SNSIs enhance the hepatic accumulation of oval cells (OCs) in injured livers. This response is associated with improved liver injury. Because SNSIs do not affect the expression of cytokines, growth factors, or growth factor receptors that are known to regulate OCs, and OCs express adrenoceptors, it is conceivable that catecholamines influence OCs by direct interaction with OC adrenoceptors. Given evidence that the SNS regulates the viability and activation of HSCs and OCs differentially, SNSIs may be novel therapies to improve the repair of damaged livers. © 2004 Wiley-Liss, Inc.

Authors
Oben, JA; Diehl, AM
MLA Citation
Oben, JA, and Diehl, AM. "Sympathetic nervous system regulation of liver repair." Anatomical Record - Part A Discoveries in Molecular, Cellular, and Evolutionary Biology 280.1 (2004): 874-883.
PMID
15382023
Source
scival
Published In
Anatomical Record - Part A Discoveries in Molecular, Cellular, and Evolutionary Biology
Volume
280
Issue
1
Publish Date
2004
Start Page
874
End Page
883
DOI
10.1002/ar.a.20081

Erratum: Overexpression of caspase-3 in hepatocellular carcinomas (Modern Pathology (2004) 17 (861-867) doi:10.1038/modpathol.3800146

Authors
Persad, R; Liu, C; Wu, T-T; Houlihan, PS; Hamilton, SR; Diehl, AM; Rashid, A
MLA Citation
Persad, R, Liu, C, Wu, T-T, Houlihan, PS, Hamilton, SR, Diehl, AM, and Rashid, A. "Erratum: Overexpression of caspase-3 in hepatocellular carcinomas (Modern Pathology (2004) 17 (861-867) doi:10.1038/modpathol.3800146." Modern Pathology 17.8 (2004): 1026--.
Source
scival
Published In
Modern Pathology
Volume
17
Issue
8
Publish Date
2004
Start Page
1026-
DOI
10.1038/modpathol.3800215

Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis

It is not known why natural killer T (NKT) cells, which modulate liver injury by regulating local cytokine production, are reduced in leptin-deficient ob/ob mice. NKT cells express adrenoceptors. Thus, we hypothesize that the low norepinephrine (NE) activity of ob/ob mice promotes depletion of liver NKT cells, thereby sensitizing ob/ob livers to lipopolysaccharide (LPS) toxicity. To evaluate this hypothesis, hepatic NKT cells were quantified in wild-type mice before and after treatment with NE inhibitors, and in dopamine β-hydroxylase knockout mice (which cannot synthesize NE) and ob/ob mice before and after 4 weeks of NE supplementation. Decreasing NE activity consistently reduces liver NKT cells, while increasing NE has the opposite effect. Analysis of hepatic and thymic NKT cells in mice of different ages demonstrate an age-related accumulation of hepatic NKT cells in normal mice, while liver NKT cells become depleted after birth in ob/ob mice, which have increased apoptosis of hepatic NKT cells. NE treatment inhibits apoptosis and restores hepatic NKT cells. In ob/ob mice with reduced hepatic NKT cells, hepatic T and NKT cells produce excessive T helper (Th)-1 proinflammatory cytokines and the liver is sensitized to LPS toxicity. NE treatment decreases Th-1 cytokines, increases production of Th-2 cytokines, and reduces hepatotoxicity. Studies of CD1d-deficient mice, which lack the receptor required for NKT cell development, demonstrate that they are also unusually sensitive to LPS hepatotoxicity. In conclusion, low NE activity increases hepatic NKT cell apoptosis and depletes liver NKT cells, promoting proinflammatory polarization of hepatic cytokine production that sensitizes the liver to LPS toxicity.

Authors
Li, Z; Oben, JA; Yang, S; Lin, H; Stafford, EA; Soloski, MJ; Thomas, SA; Diehl, AM
MLA Citation
Li, Z, Oben, JA, Yang, S, Lin, H, Stafford, EA, Soloski, MJ, Thomas, SA, and Diehl, AM. "Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis." Hepatology 40.2 (2004): 434-441.
PMID
15368448
Source
scival
Published In
Hepatology
Volume
40
Issue
2
Publish Date
2004
Start Page
434
End Page
441
DOI
10.1002/hep.20320

Overexpression of caspase-3 hepatocellular carcinomas

Caspase-3 is a downstream effector cysteine protease in the apoptotic pathway. It is ubiquitously expressed in normal human tissues including the liver. Overexpression and loss of expression of caspase-3 has been reported in diverse human malignancies. However, expression of caspase-3 in hepatocellular carcinoma (HCC) has not been studied. Therefore, we studied its expression in four hepatoma cell lines and 22 HCCs by Western blot, and correlated the findings with in vitro caspase-3 activity and apoptosis. In addition, 47 surgically resected HCCs and 29 metastatic colorectal carcinomas were evaluated for caspase-3 expression by immunohistochemistry on formalin-fixed, paraffin-embedded tissue sections, and the staining intensity was correlated with the clinicopathological features. Caspase-3 overexpression was present in all four hepatoma cell lines, and 68% (15/22) of HCCs in comparison to the non-neoplastic liver parenchyma by Western blot, and in 52% (36/69) of HCCs by immunohistochemistry. Caspase-3 overexpression in HCCs by Western blot correlated with caspase-3 overexpression by immunohistochemistry (P=0.002), and in vitro caspase-3 activity (P=0.01). Caspase-3 overexpression in HCCs by immunohistochemistry was associated with serum ocfetoprotein (AFP) levels (P=0.01). In conclusion, caspase-3 is frequently overexpressed in HCCs and is associated with high serum levels of AFP.

Authors
Persad, R; Liu, C; Wu, T-T; Houlihan, PS; Hamilton, SR; Diehl, AM; Rashid, A
MLA Citation
Persad, R, Liu, C, Wu, T-T, Houlihan, PS, Hamilton, SR, Diehl, AM, and Rashid, A. "Overexpression of caspase-3 hepatocellular carcinomas." Modern Pathology 17.7 (2004): 861-867.
PMID
15098015
Source
scival
Published In
Modern Pathology
Volume
17
Issue
7
Publish Date
2004
Start Page
861
End Page
867
DOI
10.1038/modpathol.3800146

Metformin in the treatment of non-alcoholic steatohepatitis: A pilot open label trial

Background: Insulin sensitizing agents may be useful in treatment of non-alcoholic fatty liver disease. Aim: A pilot study to evaluate the efficacy and safety of metformin in non-alcoholic fatty liver disease. Methods: In an open labelled study, patients with histologically confirmed non-alcoholic fatty liver disease were given metformin (20 mg/kg) for 1 year. Insulin resistance (by log homeostasis assessment model analysis for insulin resistance and Quantitative Insulin Sensitivity Check Index) and post-treatment hepatic histology were compared with pre-treatment histology. Results: Fifteen patients completed 1 year of treatment. During the initial 3 months, there was improvement in alanine aminotransferase and aspartate aminotransferase (P-value 0.01 and 0.02, respectively) along with improvement in insulin sensitivity. However, after 3 months, there was no further improvement in insulin sensitivity and there was gradual rise in aspartate aminotransferase and alanine aminotransferase back to pre-treatment levels. Among the 10 patients with post-treatment biopsy, three (33%), showed improvement in steatosis, two (20%) showed improvement in inflammation score and one (10%) showed improvement in fibrosis. Conclusion: Metformin treatment was associated with only a transient improvement in liver chemistries. A progressive, sustainable reduction in insulin sensitivity was not noted during treatment.

Authors
Nair, S; Diehl, AM; Wiseman, M; Jr, GHF; Perrillo, RP
MLA Citation
Nair, S, Diehl, AM, Wiseman, M, Jr, GHF, and Perrillo, RP. "Metformin in the treatment of non-alcoholic steatohepatitis: A pilot open label trial." Alimentary Pharmacology and Therapeutics 20.1 (2004): 23-28.
PMID
15225167
Source
scival
Published In
Alimentary Pharmacology & Therapeutics
Volume
20
Issue
1
Publish Date
2004
Start Page
23
End Page
28
DOI
10.1111/j.1365-2036.2004.02025.x

Fatty liver, hypertension, and the metabolic syndrome

Authors
Diehl, AM
MLA Citation
Diehl, AM. "Fatty liver, hypertension, and the metabolic syndrome." Gut 53.7 (2004): 923-924.
PMID
15194635
Source
scival
Published In
Gut
Volume
53
Issue
7
Publish Date
2004
Start Page
923
End Page
924
DOI
10.1136/gut.2003.037309

Gut Flora-Based Therapy in Liver Disease? The Liver Cares about the Gut

Authors
Solga, SF; Diehl, AM
MLA Citation
Solga, SF, and Diehl, AM. "Gut Flora-Based Therapy in Liver Disease? The Liver Cares about the Gut." Hepatology 39.5 (2004): 1197-1200.
PMID
15122746
Source
scival
Published In
Hepatology
Volume
39
Issue
5
Publish Date
2004
Start Page
1197
End Page
1200
DOI
10.1002/hep.20220

Hematopoietic stem cells convert into liver cells within days without fusion

Both plasticity and cell fusion have been suggested to have a role in germ-layer switching. To understand the mechanisms underlying cell fate changes, we have examined a highly enriched population of hematopoietic stem cells (HSCs) in vitro or in vivo in response to injury for liver-specific phenotypic and functional changes. Here we show that HSCs become liver cells when cocultured with injured liver separated by a barrier. Chromosomal analyses and tissue-specific gene and/or protein expression show that microenvironmental cues rather than fusion are responsible for conversion in vitro. We transplanted HSCs into liver-injured mice and observed that HSCs convert into viable hepatocytes with increasing injury. Notably, liver function was restored 2-7 d after transplantation. We conclude that HSCs contribute to the regeneration of injured liver by converting into functional hepatocytes without fusion.

Authors
Jang, Y-Y; Collector, MI; Baylin, SB; Diehl, AM; Sharkis, SJ
MLA Citation
Jang, Y-Y, Collector, MI, Baylin, SB, Diehl, AM, and Sharkis, SJ. "Hematopoietic stem cells convert into liver cells within days without fusion." Nature Cell Biology 6.6 (2004): 532-539.
PMID
15133469
Source
scival
Published In
Nature Cell Biology
Volume
6
Issue
6
Publish Date
2004
Start Page
532
End Page
539
DOI
10.1038/ncb1132

Oval Cells Compensate for Damage and Replicative Senescence of Mature Hepatocytes in Mice with Fatty Liver Disease

Hepatic steatosis may have a generally benign prognosis, either because most hepatocytes are not significantly injured or mechanisms to replace damaged hepatocytes are induced. To determine the relative importance of these mechanisms, we compared hepatocyte damage and replication in ethanol-fed and ob/ob mice with very indolent fatty liver disease to that of healthy control mice and PARP-1-/- mice with targeted disruption of the DNA repair enzyme, poly(ADP-ribose) polymerase. Compared to the healthy controls, both groups with fatty livers had significantly higher serum alanine aminotransferase values, hepatic mitochondrial H202 production, and hepatocyte oxidative DNA damage. A significantly smaller proportion of the hepatocytes from fatty livers entered S phase when cultured with mitogens. Moreover, this replicative senescence was not reversed by treating cultured hepatocytes with agents (i.e., betaine or leptin) that improve liver disease in intact ethanol-fed or leptin-deficient mice. Hepatocytes from PARP1-/- mice also had more DNA damage and reduced DNA synthesis in response to mitogens. However, neither mice with fatty livers nor PARP1-deficient mice had atrophic livers. All of the mice with senescent mature hepatocytes exhibited hepatic accumulation of liver progenitor (oval) cells and oval cell numbers increased with the demand for hepatocyte replacement. Therefore, although hepatic oxidant production and damage are generally increased in fatty livers, expansion of hepatic progenitor cell populations helps to compensate for the increased turnover of damaged mature hepatocytes. In conclusion, these results demonstrate that induction of mechanisms to replace damaged hepatocytes is important for limiting the progression of fatty liver disease.

Authors
Yang, S; Koteish, A; Lin, H; Huang, J; Roskams, T; Dawson, V; Diehl, AM
MLA Citation
Yang, S, Koteish, A, Lin, H, Huang, J, Roskams, T, Dawson, V, and Diehl, AM. "Oval Cells Compensate for Damage and Replicative Senescence of Mature Hepatocytes in Mice with Fatty Liver Disease." Hepatology 39.2 (2004): 403-411.
PMID
14767993
Source
scival
Published In
Hepatology
Volume
39
Issue
2
Publish Date
2004
Start Page
403
End Page
411
DOI
10.1002/hep.20082

Hepatic fibrogenesis requires sympathetic neurotransmitters

Background and aims: Hepatic stellate cells (HSC) are activated by liver injury to become proliferate fibrogenic myofibroblasts. This process may be regulated by the sympathetic nervous system (SNS) but the mechanisms involved are unclear. Methods: We studied cultured HSC and intact mice with liver injury to test the hypothesis that HSC respond to and produce SNS neurotransmitters to promote fibrogenesis. Results: HSC expressed adrenoceptors, catecholamine biosynthetic enzymes, released norepinephrine (NE), and were growth inhibited by α- and β-adrenoceptor antagonists. HSC from dopamine β-hydroxylase deficient (Dbh-/-) mice, which cannot make NE, grew poorly in culture and were rescued by NE. Inhibitor studies demonstrated that this effect was mediated via G protein coupled adrenoceptors, mitogen activated kinases, and phosphatidylinositol 3-kinase. Injury related fibrogenic responses were inhibited in Dbh-/- mice, as evidenced by reduced hepatic accumulation of α-smooth muscle actin+ve HSC and decreased induction of transforming growth factor β1 (TGF-β1) and collagen. Treatment with isoprenaline rescued HSC activation. HSC were also reduced in leptin deficient ob/ob mice which have reduced NE levels and are resistant to hepatic fibrosis. Treating ob/ob mice with NE induced HSC proliferation, upregulated hepatic TGF-β1 and collagen, and increased liver fibrosis. Conclusions: HSC are hepatic neuroglia that produce and respond to SNS neurotransmitters to promote hepatic fibrosis.

Authors
Oben, JA; Roskams, T; Yang, S; Lin, H; Sinelli, N; Torbenson, M; Smedh, U; Moran, TH; Li, Z; Huang, J; Thomas, SA; Diehl, AM
MLA Citation
Oben, JA, Roskams, T, Yang, S, Lin, H, Sinelli, N, Torbenson, M, Smedh, U, Moran, TH, Li, Z, Huang, J, Thomas, SA, and Diehl, AM. "Hepatic fibrogenesis requires sympathetic neurotransmitters." Gut 53.3 (2004): 438-445.
PMID
14960531
Source
scival
Published In
Gut
Volume
53
Issue
3
Publish Date
2004
Start Page
438
End Page
445
DOI
10.1136/gut.2003.026658

Innate immunity in the liver

Purpose of review: The liver is constantly exposed to large varieties of antigens that are derived from the gastrointestinal tract, including dietary antigens, pathogens, and toxins. Its function as a major immune organ is now being appreciated. The liver lymphocyte population is enriched in macrophages (ie, Kupffer cells), natural killer and natural killer T cells, which constitute the innate immune system. This review will focus on recent advances in the understanding of mechanisms that regulate the hepatic innate immune system because the innate immune system may mediate many chronic liver diseases, including nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis. Recent findings: Hepatic natural killer T cells modulate liver injury by balancing local production of proinflammatory (Th-1) and antiinflammatory (Th-2) cytokines. Hepatic natural killer T cell depletion leads to Th-1 polarization of hepatic cytokine production, increasing tumor necrosis factor alpha and interferon gamma. This potentates lipopolysaccharide-induced hepatotoxicity. The hepatic natural killer T cells themselves are regulated by Kupffer-cell-produced cytokines, dietary factors, and certain neurotransmitters, such as norepinephrine. In leptin-deficient ob/ob mice, an animal model for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, insufficient norepinephrine increases hepatic natural killer T cell apoptosis, depleting hepatic natural killer T cells and inducing proinflammatory cytokine polarization. This contributes to chronic inflammation, increased lipopolysaccharide-induced hepatotoxicity, and insulin resistance in ob/ob mice. Summary: Assuming that defects in the hepatic innate immune system that promote Th-1 cytokine polarization are common pathogenic mechanisms for hepatic insulin resistance and nonalcoholic steatohepatitis, therapies that inhibit inflammatory activity may be beneficial for these disorders.

Authors
Li, Z; Diehl, AM
MLA Citation
Li, Z, and Diehl, AM. "Innate immunity in the liver." Current Opinion in Gastroenterology 19.6 (2003): 565-571.
PMID
15703606
Source
scival
Published In
Current Opinion in Gastroenterology
Volume
19
Issue
6
Publish Date
2003
Start Page
565
End Page
571
DOI
10.1097/00001574-200311000-00009

Diagnosis of Nonalcoholic Fatty Liver Disease [2] (multiple letters)

Authors
Yanai, H; Morimoto, M; Mascitelli, L; Pezzetta, F; Clark, JM; Diehl, AM
MLA Citation
Yanai, H, Morimoto, M, Mascitelli, L, Pezzetta, F, Clark, JM, and Diehl, AM. "Diagnosis of Nonalcoholic Fatty Liver Disease [2] (multiple letters)." Journal of the American Medical Association 290.12 (2003): 1577-1578.
PMID
14506112
Source
scival
Published In
Journal of the American Medical Association
Volume
290
Issue
12
Publish Date
2003
Start Page
1577
End Page
1578
DOI
10.1001/jama.290.12.1577-a

Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease

In animals, the combination of oxidative liver damage and inhibited hepatocyte proliferation increases the numbers of hepatic progenitors (oval cells). We studied different murine models of fatty liver disease and patients with nonalcoholic fatty liver disease or alcoholic liver disease to determine whether oval cells increase in fatty livers and to clarify the mechanisms for this response. To varying degrees, all mouse models exhibit excessive hepatic mitochondrial production of H2O2, a known inducer of cell-cycle inhibitors. In mice with the greatest H2O2 production, mature hepatocyte proliferation is inhibited most, and the greatest number of oval cells accumulates. These cells differentiate into intermediate hepatocyte-like cells after a regenerative challenge. Hepatic oval cells are also increased significantly in patients with nonalcoholic fatty liver disease and alcoholic liver disease. In humans, fibrosis stage and oval cell numbers, as well as the number of intermediate hepatocyte-like cells, are strongly correlated. However, cirrhosis is not required for oval cell accumulation in either species. Rather, as in mice, progenitor cell activation in human fatty liver diseases is associated with inhibited replication of mature hepatocytes. The activation of progenitor cells during fatty liver disease may increase the risk for hepatocellular cancer, similar to that observed in the Soft-Farber model of hepatocarcinogenesis in rats.

Authors
Roskams, T; Yang, SQ; Koteish, A; Durnez, A; DeVos, R; Huang, X; Achten, R; Verslype, C; Diehl, AM
MLA Citation
Roskams, T, Yang, SQ, Koteish, A, Durnez, A, DeVos, R, Huang, X, Achten, R, Verslype, C, and Diehl, AM. "Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease." American Journal of Pathology 163.4 (2003): 1301-1311.
PMID
14507639
Source
scival
Published In
American Journal of Pathology
Volume
163
Issue
4
Publish Date
2003
Start Page
1301
End Page
1311
DOI
10.1016/S0002-9440(10)63489-X

Sympathetic nervous system inhibition increases hepatic progenitors and reduces liver injury

Recovery from liver damage might be enhanced by encouraging repopulation of the liver by endogenous hepatic progenitor cells. Oval cells are resident hepatic stem cells that promote liver regeneration and repair. Little is known about the mediators that regulate the accumulation of these cells in the liver. Parasympathetic nervous system inhibition reduces the number of oval cells in injured livers. The effect of sympathetic nervous system (SNS) inhibition on oval cell number is not known. Adrenergic inhibition mobilizes hematopoietic precursors into the circulation and has also been shown to promote liver regeneration. Thus, we hypothesized that SNS inhibition would promote hepatic accumulation of oval cells and reduce liver damage in mice fed antioxidant-depleted diets to induce liver injury. Our results confirm this hypothesis. Compared with control mice that were fed only the antioxidant-depleted diets, mice fed the same diets with prazosin (PRZ, an α-1 adrenoceptor antagonist) or 6-hydroxydopamine (6-OHDA, an agent that induces chemical sympathectomy) had significantly increased numbers of oval cells. Increased oval cell accumulation was accompanied by less hepatic necrosis and steatosis, lower serum aminotransferases, and greater liver and whole body weights. Neither PRZ nor 6-OHDA affected the expression of cytokines, growth factors, or growth factor receptors that are known to regulate progenitor cells. In conclusion, stress-related sympathetic activity modulates progenitor cell accumulation in damaged livers and SNS blockade with α-adrenoceptor antagonists enhances hepatic progenitor cell accumulation.

Authors
Oben, JA; Roskams, T; Yang, S; Lin, H; Sinelli, N; Li, Z; Torbenson, M; Huang, J; Guarino, P; Kafrouni, M; Diehl, AM
MLA Citation
Oben, JA, Roskams, T, Yang, S, Lin, H, Sinelli, N, Li, Z, Torbenson, M, Huang, J, Guarino, P, Kafrouni, M, and Diehl, AM. "Sympathetic nervous system inhibition increases hepatic progenitors and reduces liver injury." Hepatology 38.3 (2003): 664-673.
PMID
12939593
Source
scival
Published In
Hepatology
Volume
38
Issue
3
Publish Date
2003
Start Page
664
End Page
673
DOI
10.1053/jhep.2003.50371

Norepinephrine induces hepatic fibrogenesis in leptin deficient ob/ob mice

Leptin's actions on certain cells require a leptin-inducible neurotransmitter, norepinephrine (NE). NE modulates hepatic fibrosis. Therefore, decreased NE may explain why leptin deficiency inhibits hepatic fibrosis. We manipulated adrenergic activity in leptin-deficient ob/ob mice, leptin-sufficient, dopamine β-hydroxylase deficient (Dbh-/-) mice, and HSC cultures to determine if leptin requires NE to activate HSC and induce hepatic fibrosis. ob/ob mice have chronic liver injury, but reduced numbers of HSC. Supplemental leptin increases HSC, suggesting that leptin-dependent, injury-related factors permit expansion of HSC populations. NE also increases HSC numbers and activation, normalizing fibrogenesis. When fed hepatotoxic diets, NE-deficient Dbh-/- mice fail to accumulate activated HSC and have impaired fibrogenesis unless treated with adrenergic agonists. NE acts directly on HSC to modulate leptin's actions because leptin increases HSC proliferation and prazosin, an α-adrenoceptor antagonist, inhibits this. Thus, leptin permits injury-related increases in adrenergic activity and requires NE to activate HSC and induce hepatic fibrogenesis. © 2003 Elsevier Inc. All rights reserved.

Authors
Oben, JA; Roskams, T; Yang, S; Lin, H; Sinelli, N; Li, Z; Torbenson, M; Thomas, SA; Diehl, AM
MLA Citation
Oben, JA, Roskams, T, Yang, S, Lin, H, Sinelli, N, Li, Z, Torbenson, M, Thomas, SA, and Diehl, AM. "Norepinephrine induces hepatic fibrogenesis in leptin deficient ob/ob mice." Biochemical and Biophysical Research Communications 308.2 (2003): 284-292.
PMID
12901866
Source
scival
Published In
Biochemical and Biophysical Research Communications
Volume
308
Issue
2
Publish Date
2003
Start Page
284
End Page
292
DOI
10.1016/S0006-291X(03)01360-3

Insulin resistance syndrome and nonalcoholic fatty liver disease.

Authors
Diehl, AM; Clarke, J; Brancati, F
MLA Citation
Diehl, AM, Clarke, J, and Brancati, F. "Insulin resistance syndrome and nonalcoholic fatty liver disease." Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 9.Suppl 2 (2003): 93-96.
PMID
14698985
Source
scival
Published In
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists
Volume
9
Issue
Suppl 2
Publish Date
2003
Start Page
93
End Page
96

In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats

Background & Aims: Orthotopic liver transplantation is currently the only curative therapy for chronic end-stage liver disease and acute liver failure. However, a scarcity of cadaveric donors has led to a critical shortage of organs available for transplant. This is further complicated by the prevalence of steatosis in about 13%-50% of donor livers, which is associated with a high risk of dysfunction and primary nonfunction. Methods: Steatotic Zucker rat livers and livers from alcohol-fed rats were transplanted into lean control rats. Liver injury, activation of survival signals, and hepatic microcirculation were compared in nontreated and interleukin-6 (IL6)-treated steatotic isografts. Results: IL-6 pretreatment of steatotic Zucker rat liver isografts dramatically reduces mortality and liver injury following transplantation. Reperfusion after transplantation induces significant sinusoidal endothelial cell necrapoptosis in steatotic Zucker rat liver isografts, which is prevented by in vitro IL-6 pretreatment. IL-6 treatment activates cell survival signal transducer and activator of transcription factor 3 (STAT3) in hepatocytes and sinusoidal endothelial cells. Laser Doppler imaging and microsphere analyses demonstrate that IL-6 treatment markedly improves hepatic microcirculation, which is impaired in steatotic Zucker rat liver transplants. Finally, in vitro IL-6 treatment of donor livers also markedly reduces mortality associated with fatty liver transplants from alcohol-fed rats. Conclusions: IL-6 induces hepatoprotection of steatotic liver isografts via preventing sinusoidal endothelial cell necrapoptosis and consequent amelioration of hepatic microcirculation, and protecting against hepatocyte death. IL-6 pretreatment of steatotic livers may render such allografts useable for clinical transplantation.

Authors
Sun, Z; Klein, AS; Radaeva, S; Hong, F; El-Assal, O; Pan, H-N; Jaruga, B; Batkai, S; Hoshino, S; Tian, Z; Kunos, G; Diehl, AM; Gao, B
MLA Citation
Sun, Z, Klein, AS, Radaeva, S, Hong, F, El-Assal, O, Pan, H-N, Jaruga, B, Batkai, S, Hoshino, S, Tian, Z, Kunos, G, Diehl, AM, and Gao, B. "In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats." Gastroenterology 125.1 (2003): 202-215.
PMID
12851884
Source
scival
Published In
Gastroenterology
Volume
125
Issue
1
Publish Date
2003
Start Page
202
End Page
215
DOI
10.1016/S0016-5085(03)00696-6

Cytokine network during NASH and possible treatment selection [1] (multiple letters)

Authors
Perrella, A; Tarantino, G; Borgia, G; Conca, P; Sorrentino, P; Ragucci, P; Vecchione, R; Perrella, O; Li, Z; Yang, S; Lin, H; Huang, J; Watkins, PA; Moser, AB; DeSimone, C; Song, X-Y; Diehl, AM
MLA Citation
Perrella, A, Tarantino, G, Borgia, G, Conca, P, Sorrentino, P, Ragucci, P, Vecchione, R, Perrella, O, Li, Z, Yang, S, Lin, H, Huang, J, Watkins, PA, Moser, AB, DeSimone, C, Song, X-Y, and Diehl, AM. "Cytokine network during NASH and possible treatment selection [1] (multiple letters)." Hepatology 38.2 (2003): 530-531.
PMID
12883498
Source
scival
Published In
Hepatology
Volume
38
Issue
2
Publish Date
2003
Start Page
530
End Page
531
DOI
10.1053/jhep.2003.50272

Elevated hepatocyte levels of the Forkhead box A2 (HNF-3β) transcription factor cause postnatal steatosis and mitochondrial damage

The Forkhead box (Fox) transcription factor Foxa2 (HNF-3β) and related family members Foxa1 (HNF-3α) and Foxa3 (HNF-3γ) act in concert with other hepatocyte nuclear factors (HNF) to coordinately regulate liver-specific gene expression. To circumvent the hepatic functional redundancy of the Foxa proteins, we used the T-77 transgenic (TG) mouse line in which the -3-kb transthyretin (TTR) promoter functioned to increase hepatocyte expression of the Foxa2 cDNA. Adult TG mice exhibited reduced hepatic glycogen and progressive liver injury, but maintained normal serum levels of glucose, insulin, and glucagon. In this study, we further characterized the postnatal liver defect in TTR-FoxA2 TG mice. The postnatal TG mice displayed significant reduction in serum glucose levels and in hepatocyte glycogen storage without increased serum levels of ketone bodies and free fatty acid suggesting that they are not undergoing a starvation response. We show that TG liver developed a substantial transient steatosis, which reached a maximum at postnatal day 5 and is associated with increased expression of hepatic genes involved in fatty acid and triglyceride synthesis, lipid β-oxidation, and amino acid biosynthesis. Furthermore, transmission electron microscopy analysis of postnatal TG liver revealed extensive mitochondrial membrane damage, which is likely due to reactive oxygen species generated from lipid β-oxidation. In conclusion, our model proposes that in response to reduction in hepatocyte glycogen storage, the TTR-Foxa2 TG mice survive by maintaining sufficient serum levels of glucose through gluconeogenesis using deaminated amino acids with dicarboxylate products of peroxisomal lipid β-oxidation shuttled through the tricarboxylic acid cycle.

Authors
Hughes, DE; Stolz, DB; Yu, S; Tan, Y; Reddy, JK; Watkins, SC; Diehl, AM; Costa, RH
MLA Citation
Hughes, DE, Stolz, DB, Yu, S, Tan, Y, Reddy, JK, Watkins, SC, Diehl, AM, and Costa, RH. "Elevated hepatocyte levels of the Forkhead box A2 (HNF-3β) transcription factor cause postnatal steatosis and mitochondrial damage." Hepatology 37.6 (2003): 1414-1424.
PMID
12774021
Source
scival
Published In
Hepatology
Volume
37
Issue
6
Publish Date
2003
Start Page
1414
End Page
1424
DOI
10.1053/jhep.2003.50253

Nonalcoholic Fatty Liver Disease: An Underrecognized Cause of Cryptogenic Cirrhosis

Cryptogenic cirrhosis is a common cause of liver-related morbidity and mortality in the United States. Nonalcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of cryptogenic cirrhosis. However, the diagnosis of cirrhosis in patients with NAFLD appears to be delayed compared with those with other chronic liver diseases and thus carries a higher mortality rate. This delay in diagnosis is illustrated in our case of a 53-year-old man who presented with hepatic hydrothorax and ascites, whose workup revealed cirrhosis due to NAFLD. Although a diagnosis of presumed NAFLD can be made noninvasively, a definitive diagnosis requires a liver biopsy specimen. A biopsy specimen is also important for detecting histologically advanced disease, which may be clinically silent and undetected by amino-transferases or diagnostic imaging. Although there are no proven treatments, recommendations for patients with NAFLD include avoidance of hepatotoxins and aggressive management of associated conditions, such as hypertriglyceridemia and type 2 diabetes mellitus.

Authors
Clark, JM; Diehl, AM
MLA Citation
Clark, JM, and Diehl, AM. "Nonalcoholic Fatty Liver Disease: An Underrecognized Cause of Cryptogenic Cirrhosis." Journal of the American Medical Association 289.22 (2003): 3000-3004.
PMID
12799409
Source
scival
Published In
Journal of the American Medical Association
Volume
289
Issue
22
Publish Date
2003
Start Page
3000
End Page
3004
DOI
10.1001/jama.289.22.3000

Hyperlactataemia syndromes associated with HIV therapy

Hypedactataemia is seen in 8-18.3% of HIV-infected patients taking nucleoside analogue reverse transcriptase inhibitors (NRTIs). Recent epidemiological studies suggest that most episodes are transient and subclinical. However, symptomatic and occasionally life-threatening cases accompanied by metabolic acidosis and hepatic steatosis (ie, lactic acidosis syndrome) have also been described. Though yet to be fully elucidated, the proposed mechanism is NRTI-induced inhibition of mitochondrial DNA polymerase culminating in derangements in oxidative phosphorylation and lactate homeostasis. Signs and symptoms range from mild hyperlactataemia accompanied by nausea, abdominal discomfort, and weight loss to severe, intractable lactic acidosis complicated by coma and multi-organ failure. Significant progress has recently been made with regard to the natural history of NRTI-related hyperlactataemia. However, other important aspects of the disorder, such as its pathogenesis, predisposing conditions, and management, remain poorly understood. This article reviews the current published work on these issues, identifies areas of controversy, and addresses directions for future research.

Authors
Ogedegbe, A-EO; Thomas, DL; Diehl, AM
MLA Citation
Ogedegbe, A-EO, Thomas, DL, and Diehl, AM. "Hyperlactataemia syndromes associated with HIV therapy." Lancet Infectious Diseases 3.6 (2003): 329-337.
PMID
12781504
Source
scival
Published In
Lancet Infectious Diseases
Volume
3
Issue
6
Publish Date
2003
Start Page
329
End Page
337
DOI
10.1016/S1473-3099(03)00654-6

The prevalence and etiology of elevated aminotransferase levels in the United States

OBJECTIVES: Chronic liver disease is a major cause of morbidity and mortality in the United States. Although often used to detect liver disease, the prevalence and etiology of elevated aminotransferases are unknown. METHODS: We analyzed data on adults ages 17 yr and older (N = 15,676) from the Third National Health and Nutrition Examination Survey (1988-1994). Participants were classified as having elevated aminotransferase levels if either aspartate aminotransferase or alanine aminotransferase was elevated above normal. Aminotransferase elevation was classified as "explained" if there was laboratory evidence of hepatitis B or C infection, iron overload, or if there was a history of alcohol consumption. Analyses were weighted to provide national estimates. RESULTS: The prevalence of aminotransferase elevation in the United States was 7.9%. Aminotransferase elevation was more common in men compared to womefi (9.3% vs 6.6%, p = 0.002), in Mexican Americans (14.9%) and non-Hispanic blacks (8.1%) compared to non-Hispanic whites (7.1%, p < 0.001). High alcohol consumption, hepatitis B or C infection and high transferrin saturation were found in only 31.0% of cases. Aminotransferase elevation was unexplained in the majority (69.0%). In both men and women, unexplained aminotransferase elevation was significantly associated with higher body mass index, waist circumference, triglycerides, fasting insulin, and lower HDL; and with type 2 diabetes and hypertension in women (all p < 0.05). CONCLUSIONS: Aminotransferase elevation was common in the United States, and the majority could not be unexplained by alcohol consumption, viral hepatitis or hemochromatosis. Unexplained aminotransferase elevation was strongly associated with adiposity and other features of the metabolic syndrome, and thus may represent nonalcoholic fatty liver disease. © 2003 by Am. Coll. of Gastroenterology.

Authors
Clark, JM; Brancati, FL; Diehl, AM
MLA Citation
Clark, JM, Brancati, FL, and Diehl, AM. "The prevalence and etiology of elevated aminotransferase levels in the United States." American Journal of Gastroenterology 98.5 (2003): 960-967.
PMID
12809815
Source
scival
Published In
American Journal of Gastroenterology
Volume
98
Issue
5
Publish Date
2003
Start Page
960
End Page
967
DOI
10.1111/j.1572-0241.2003.07486.x

Non-alcoholic fatty liver disease: Lumen-liver interactions and possible role for probiotics

NAFLD is a common and serious disease. The pathogenesis of NAFLD continues to be elaborated. Recent progress suggests some commonality with the pathogenesis of AFLD; specifically, the importance of lumen-liver interactions and increased activity of TNF-α. Such understanding furthers interest in the intestinal flora, which may be an appropriate target for therapy. Such therapy should be safe, well-tolerated, inexpensive, appropriate for long term use, and optimally, work at multiple levels to down-regulate inflammatory mediators. Probiotics could be an option.

Authors
Solga, SF; Diehl, AM
MLA Citation
Solga, SF, and Diehl, AM. "Non-alcoholic fatty liver disease: Lumen-liver interactions and possible role for probiotics." Journal of Hepatology 38.5 (2003): 681-687.
PMID
12713883
Source
scival
Published In
Journal of Hepatology
Volume
38
Issue
5
Publish Date
2003
Start Page
681
End Page
687
DOI
10.1016/S0168-8278(03)00097-7

Norepinephrine and neuropeptide Y promote proliferation and collagen gene expression of hepatic myofibroblastic stellate cells

The mechanisms initiating and perpetuating the fibrogenic response in the injured liver are not well understood. Hepatic stellate cells are activated by liver injury to become proliferative and fibrogenic myofibroblasts. Emerging evidence suggests that the sympathetic nervous system may play a role in the development of cirrhosis. It is not known, however, whether this requires a direct interaction between sympathetic neurotransmitters and stellate cell receptors, or results indirectly, from sympathetic effects on the vasculature. Using cultured hepatic stellate cells, we show that the sympathetic neurotransmitters, norepinephrine and neuropeptide Y, markedly stimulate the proliferation of activated, myofibroblastic, hepatic stellate cells. Norepinephrine, but not neuropeptide Y, also induces collagen gene expression. In conclusion, physiologically relevant concentrations of sympathetic neurotransmitters directly modulate the phenotype of hepatic stellate cells. This suggests that targeted interruption of sympathetic nervous system signaling in hepatic stellate cells may be useful in constraining the fibrogenic response to liver injury. © 2003 Elsevier Science (USA). All rights reserved.

Authors
Oben, JA; Yang, S; Lin, H; Ono, M; Diehl, AM
MLA Citation
Oben, JA, Yang, S, Lin, H, Ono, M, and Diehl, AM. "Norepinephrine and neuropeptide Y promote proliferation and collagen gene expression of hepatic myofibroblastic stellate cells." Biochemical and Biophysical Research Communications 302.4 (2003): 685-690.
PMID
12646223
Source
scival
Published In
Biochemical and Biophysical Research Communications
Volume
302
Issue
4
Publish Date
2003
Start Page
685
End Page
690
DOI
10.1016/S0006-291X(03)00232-8

Hepatic allograft-derived Kupffer cells regulate T cell response in rats

In liver transplantation, the development of tolerance is associated with an increased rate of apoptosis of T lymphocytes in the portal inflammatory infiltrate and the presence of an intragraft Th2-like T cell population. Underlying mechanisms are poorly understood. Kupffer cells (KC), which reside in the hepatic sinosoids, can directly interact with circulating T lymphocytes and thus are uniquely positioned to play a role in immunomodulation. In this study, the immunoregulatory effects of KC were investigated. We show that KC can significantly suppress T cell proliferation in mixed leukocyte reaction (MLR). Furthermore, KC express functional Fas ligand (FasL) and can induce apoptosis of Fas+ cells. This process can be blocked by addition of neutralizing anti-FaSL antibody. Moreover, using an allogeneic liver transplant model we have determined that 1. KC recovered from chronically accepted hepatic allografts have increased FasL messenger RNA (mRNA) and protein expression and a greater ability to induce apoptosis of alloreactive T cells compared with KC recovered from an acute rejection model; 2. KC not only induce apoptosis of T cells, but also regulate cytokine production and Th2/Th3-like cytokine (interleukin [IL]-10 / transforming growth factor [TGF]-β mRNA expression in allogeneic MLR in vitro; and 3. administration of KC derived from chronically accepted liver allografts significantly prolongs the survival of hepatic allografts in an acute rejection model in an alloantigen-specific manner. In conclusion, these data implicate the possible role of KC-mediated regulation of T cell response in the induction of immune tolerance in liver allografts.

Authors
Sun, Z; Wada, T; Maemura, K; Uchikura, K; Hoshino, S; Diehl, AM; Klein, AS
MLA Citation
Sun, Z, Wada, T, Maemura, K, Uchikura, K, Hoshino, S, Diehl, AM, and Klein, AS. "Hepatic allograft-derived Kupffer cells regulate T cell response in rats." Liver Transplantation 9.5 (2003): 489-497.
PMID
12740792
Source
scival
Published In
Liver Transplantation
Volume
9
Issue
5
Publish Date
2003
Start Page
489
End Page
497
DOI
10.1053/jlts.2003.50091

Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease

Ob/ob mice, a model for nonalcoholic fatty liver disease (NAFLD), develop intestinal bacterial overgrowth and overexpress tumor necrosis factor α (TNF-α). In animal models for alcoholic fatty liver disease (AFLD), decontaminating the or intestine or inhibiting TNF-α improves AFLD. Because AFLD and NAFLD may have a similar pathogenesis, treatment with a probiotic (to modify the intestinal flora) or anti-TNF antibodies (to inhibit TNF-α activity) may improve NAFLD in ob/ob mice. To evaluate this hypothesis, 48 ob/ob mice were given either a high-fat diet alone (ob/ob controls) or the same diet + VSL#3 probiotic or anti-TNF antibodies for 4 weeks. Twelve lean littermates fed a high-fat diet served as controls. Treatment with VSL#3 or anti-TNF antibodies improved liver histology, reduced hepatic total fatty acid content, and decreased serum alanine aminotransferase (ALT) levels. These benefits were associated with decreased hepatic expression of TNF-α messenger RNA (mRNA) in mice treated with anti-TNF antibodies but not in mice treated with VSL#3. Nevertheless, both treatments reduced activity of Jun N-terminal kinase (JNK), a TNF-regulated kinase that promotes insulin resistance, and decreased the DNA binding activity of nuclear factor κB (NF-κB), the target of IKKβ, another TNF-regulated enzyme that causes insulin resistance. Consistent with treatment-related improvements in hepatic insulin resistance, fatty acid β-oxidation and uncoupling protein (UCP)-2 expression decreased after treatment with VSL#3 or anti-TNF antibodies. In conclusion, these results support the concept that intestinal bacteria induce endogenous signals that play a pathogenic role in hepatic insulin resistance and NAFLD and suggest novel therapies for these common conditions.

Authors
Li, Z; Yang, S; Lin, H; Huang, J; Watkins, PA; Moser, AB; DeSimone, C; Song, X-Y; Diehl, AM
MLA Citation
Li, Z, Yang, S, Lin, H, Huang, J, Watkins, PA, Moser, AB, DeSimone, C, Song, X-Y, and Diehl, AM. "Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease." Hepatology 37.2 (2003): 343-350.
PMID
12540784
Source
scival
Published In
Hepatology
Volume
37
Issue
2
Publish Date
2003
Start Page
343
End Page
350
DOI
10.1053/jhep.2003.50048

Hepatic ATP reserve and efficiency of replenishing: Comparison between obese and nonobese normal individuals

OBJECTIVE: Although obesity-associated fatty liver disease is emerging as one of the most common diseases in hepatology practice, it is unclear why liver disease prevalence increases with obesity. Because impaired energy homeostasis enhances the susceptibility of hepatocytes to injury, the aim of this study was to determine whether increased body mass index (BMI) is associated with decreased basal hepatic adenosine triphosphate (ATP) stores or impaired recovery from fructose-induced hepatic ATP depletion. METHODS: Hepatic ATP stores were assessed by nuclear magnetic resonance spectroscopy in 19 healthy subjects with varying BMI. After obtaining the baseline spectra, 0.5 ml/kg of 50% fructose solution was administered to all subjects to deplete the ATP reserve, and follow-up nuclear magnetic resonance spectra was obtained at 5-min intervals for the ensuing hour. AST and ALT were determined at 24 h to assess whether ATP depletion caused any appreciable hepatocyte injury. RESULTS: Among the 19 subjects who participated in the study, five had BMI of ≤25, seven had BMI between 25-30, and seven had BMI of >30. The baseline ATP content was inversely related to BMI (correlation coefficient -0.63, p = 0.02), decreasing steadily with increasing BMI. Fructose injection decreased hepatic ATP stores in all subjects and did not increase transaminases in anyone. Neither the postfructose ATP nadir values nor the extent of ATP recovery correlated with BMI. CONCLUSIONS: Reduced hepatic ATP stores are more prevalent in overweight and obese subjects than in lean subjects. However, a cause-effect relationship between these abnormalities was not demonstrated by our study. © 2003 by Am. Coll. of Gastroenterology.

Authors
Nair, S; Chacko, VP; Arnold, C; Diehl, AM
MLA Citation
Nair, S, Chacko, VP, Arnold, C, and Diehl, AM. "Hepatic ATP reserve and efficiency of replenishing: Comparison between obese and nonobese normal individuals." American Journal of Gastroenterology 98.2 (2003): 466-470.
PMID
12591070
Source
scival
Published In
American Journal of Gastroenterology
Volume
98
Issue
2
Publish Date
2003
Start Page
466
End Page
470
DOI
10.1016/S0002-9270(02)05889-6

Defining nonalcoholic fatty liver disease: Implications for epidemiologic studies

Authors
Clark, JM; Diehl, AM
MLA Citation
Clark, JM, and Diehl, AM. "Defining nonalcoholic fatty liver disease: Implications for epidemiologic studies." Gastroenterology 124.1 (2003): 248-250.
PMID
12512048
Source
scival
Published In
Gastroenterology
Volume
124
Issue
1
Publish Date
2003
Start Page
248
End Page
250
DOI
10.1053/gast.2003.50032

Acetylcholine promotes the proliferation and collagen gene expression of myofibroblastic hepatic stellate cells

The mechanisms that initiate and perpetuate the fibrogenic response, during liver injury, are unclear. Animal studies, however, strongly support a role for the autonomic nervous system (ANS) in wound healing. Therefore, the ANS may also mediate the development of cirrhosis. Hepatic stellate cells (HSC), the liver's major matrix-producing cells, are activated by injury to become proliferative, fibrogenic myofibroblasts. HSC respond to sympathetic neurotransmitters by changing phenotype, suggesting that HSC may be the cellular effectors of ANS signals that modulate hepatic fibrogenesis during recovery from liver damage. We show here that the parasympathetic neurotransmitter acetylcholine markedly stimulates the proliferation of myofibroblastic HSC and induces HSC collagen gene expression in these cells. By extending evidence that HSC are direct targets of the ANS, these results support the proposed neuroglial role of HSC in the liver and suggest that interrupting ANS signalling may be useful in constraining the fibrogenic response to liver injury. © 2002 Elsevier Science (USA). All rights reserved.

Authors
Oben, JA; Yang, S; Lin, H; Ono, M; Diehl, AM
MLA Citation
Oben, JA, Yang, S, Lin, H, Ono, M, and Diehl, AM. "Acetylcholine promotes the proliferation and collagen gene expression of myofibroblastic hepatic stellate cells." Biochemical and Biophysical Research Communications 300.1 (2003): 172-177.
PMID
12480538
Source
scival
Published In
Biochemical and Biophysical Research Communications
Volume
300
Issue
1
Publish Date
2003
Start Page
172
End Page
177
DOI
10.1016/S0006-291X(02)02773-0

Fat and the liver - A molecular overview

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that occurs in nondrinkers but which cannot be distinguished from alcohol-induced liver disease histologically. There are no diagnostic blood tests for NAFLD but the disease is associated with several insulin-resistant states, including obesity, type 2 diabetes mellitus and dyslipidemia. Most of the liver-related morbidity and mortality that accompany NAFLD occur in patients who develop cirrhosis. The latter is most likely to occur in individuals who have progressed from simple steatosis (fatty liver) to steatohepatitis, a chronic inflammatory liver lesion. The mechanisms that promote the transition from steatosis to nonalcoholic steatohepatitis appear to involve multiple cellular adaptations to the oxidative stress that occurs when fatty acid metabolism is deranged during insulin resistance. A better understanding of these mechanisms is desired to target treatments to prevent and/or reverse nonalcoholic steatohepatitis, thereby aborting the evolution of cirrhosis. Copyright 2002, Elsevier Science (USA). All rights reserved.

Authors
Harrison, SA; Diehl, AM
MLA Citation
Harrison, SA, and Diehl, AM. "Fat and the liver - A molecular overview." Seminars in Gastrointestinal Disease 13.1 (2002): 3-16.
PMID
11944631
Source
scival
Published In
Seminars in Gastrointestinal Disease
Volume
13
Issue
1
Publish Date
2002
Start Page
3
End Page
16

Stat-3 overexpression and p21 up-regulation accompany impaired regeneration of fatty livers

Fatty liver is an important cause of morbidity in humans and is linked to impaired liver regeneration after liver injury, but the mechanisms for impaired liver regeneration remain unknown. In the normal liver, the interleukin (IL)-6/STAT-3 pathway is thought to play a central role in regeneration because this pathway is disrupted in IL-6-deficient mice that exhibit impaired liver regeneration after 70% partial hepatectomy (PH). To determine whether inhibition of STAT-3 is involved in fatty liver-related mitoinhibition, regenerative induction of STAT-3 was compared in normal mice and leptin-deficient ob/ob mice that have fatty livers and markedly impaired liver regeneration after PH. In both groups, two waves of STAT-3 activation were observed, the first in endothelia and the second in hepatocytes. Before PH, a significantly higher percentage of ob/ob endothelial and hepatocyte nuclei expressed phosphorylated (activated) STAT-3. After PH, phospho-STAT-3 accumulated in liver nuclei of lean mice and this response was markedly exaggerated in ob/ob mice. Moreover, a striking inverse correlation was noted between hepatocyte nuclear accumulation of phospho-STAT-3 and DNA synthesis (as assessed by bromodeoxyuridine labeling), as well as cyclin D1 mRNA induction and protein expression. In contrast, STAT-3 activation was positively correlated with p21 protein expression in both groups of mice. Because these results link exaggerated STAT-3 activation with impaired hepatocyte proliferation, STAT-3 inhibition cannot be a growth-arrest mechanism in ob/ob fatty livers. Rather, hyperinduction of this factor may promote mitoinhibition by up-regulating mechanisms that impede cell cycle progression.

Authors
Torbenson, M; Yang, SQ; Liu, HZ; Huang, J; Gage, W; Diehl, AM
MLA Citation
Torbenson, M, Yang, SQ, Liu, HZ, Huang, J, Gage, W, and Diehl, AM. "Stat-3 overexpression and p21 up-regulation accompany impaired regeneration of fatty livers." American Journal of Pathology 161.1 (2002): 155-161.
PMID
12107100
Source
scival
Published In
The American journal of pathology
Volume
161
Issue
1
Publish Date
2002
Start Page
155
End Page
161
DOI
10.1016/S0002-9440(10)64167-3

Liver regeneration in obese mice with fatty livers: Does the impairment have relevance for other types of fatty liver disease? [2] (multiple letters)

Authors
Farrell, GC; Robertson, GR; Leclercq, I; Horsman, Y; Diehl, AM
MLA Citation
Farrell, GC, Robertson, GR, Leclercq, I, Horsman, Y, and Diehl, AM. "Liver regeneration in obese mice with fatty livers: Does the impairment have relevance for other types of fatty liver disease? [2] (multiple letters)." Hepatology 35.3 (2002): 731-732.
PMID
11870394
Source
scival
Published In
Hepatology
Volume
35
Issue
3
Publish Date
2002
Start Page
731
End Page
732
DOI
10.1053/jhep.2002.31786

Nonalcoholic fatty liver disease: An agenda for clinical research

Authors
Younossi, ZM; Diehl, AM; Ong, JP
MLA Citation
Younossi, ZM, Diehl, AM, and Ong, JP. "Nonalcoholic fatty liver disease: An agenda for clinical research." Hepatology 35.4 (2002): 746-752.
PMID
11915019
Source
scival
Published In
Hepatology
Volume
35
Issue
4
Publish Date
2002
Start Page
746
End Page
752
DOI
10.1053/jhep.2002.32483

Molecular pathology and clinical aspects of alcohol-induced tissue injury

Proceedings of a symposium at the 2001 RSA Meeting in Montreal, Canada; organized and co-chaired by Patricia E. Molina and Manuela Neuman. The presentations were (1) Mechanisms of alcohol-induced cell injury by Craig McClain; (2) Cytokines in alcoholic steatohepatitis and non-alcoholic steatohepatitis by Manuela Neuman; (3) Combination of alcohol and hepatitis C virus and liver injury by Dominique Valla; (4) Chronic ethanol exposure potentiates lipopolysaccharide liver injury, despite inhibiting Jun N-Terminal kinase and caspase 3 activation by Anna Mae Diehl; (5) Glutathione homeostasis in alcoholism: Role in alveolar epithelial barrier and lung injury by David M. Guidot; (6) Metabolic and inflammatory contribution of alcohol to trauma-induced tissue injury by Patricia E. Molina; (7) Growth factor and protein synthesis dysregulation: Role in alcoholic myopathy by Charles H. Lang.

Authors
Molina, PE; McClain, C; Valla, D; Guidot, D; Diehl, AM; Lang, CH; Neuman, M
MLA Citation
Molina, PE, McClain, C, Valla, D, Guidot, D, Diehl, AM, Lang, CH, and Neuman, M. "Molecular pathology and clinical aspects of alcohol-induced tissue injury." Alcoholism: Clinical and Experimental Research 26.1 (2002): 120-128.
PMID
11821662
Source
scival
Published In
Alcoholism: Clinical and Experimental Research
Volume
26
Issue
1
Publish Date
2002
Start Page
120
End Page
128

Murine leptin deficiency alters Kupffer cell production of cytokines that regulate the innate immune system

Background & Aims: ob/ob mice are used to study the mechanisms that regulate the progression from steatosis to nonalcoholic steatohepatitis. The livers of ob/ob mice are depleted of CD4-positive natural killer cells, components of the innate immune system that induce anti-inflammatory cytokines. Although this may explain the sensitivity of fatty livers to lipopolysaccharide, why such hepatic CD4-positive natural killer cell depletion occurs is uncertain. Because leptin regulates macrophages, our hypothesis is that leptin deficiency alters Kupffer cell production of cytokines that inhibit (e.g., interleukin [IL]-12) or enhance (e.g., IL-15) hepatic CD4-positive natural killer cell viability. Methods: Kupffer cell cytokine production and the hepatic content of CD4-positive natural killer cells were compared in ob/ob and lean mice. ob/ob mice were then treated with IL-15 or leptin to determine whether either factor improved their immunologic abnormalities. Results: Compared with control Kupffer cells, ob/ob Kupffer cells produced less IL-15 basally and more IL-12 after lipopolysaccharide stimulation. Treatment of ob/ob mice with IL-15 for 1 week normalizes their hepatic CD4-positive natural killer cell content. Leptin increases the hepatic expression of IL-15 in ob/ob mice and partially replenishes their hepatic CD4-positive natural killer cells. Conclusions: Leptin deficiency increases hepatic IL-12 and reduces hepatic IL-15 expression. The abnormal production of these Kupffer cell factors promotes hepatic CD4-positive natural killer cell depletion in ob/ob livers.

Authors
Li, Z; Lin, H; Yang, S; Diehl, AM
MLA Citation
Li, Z, Lin, H, Yang, S, and Diehl, AM. "Murine leptin deficiency alters Kupffer cell production of cytokines that regulate the innate immune system." Gastroenterology 123.4 (2002): 1304-1310.
PMID
12360490
Source
scival
Published In
Gastroenterology
Volume
123
Issue
4
Publish Date
2002
Start Page
1304
End Page
1310
DOI
10.1053/gast.2002.35997

The liver in obesity and type 2 diabetes mellitus

Obesity and type 2 diabetes are associated strongly with NAFLD. It is not clear if one of these conditions causes the others, or if all are consequences of another process. Although NAFLD is known to occur in overly lean individuals, which indicates that excessive adiposity is not required for the development of NAFLD, the severities of insulin resistance and NAFLD tend to parallel each other, and the greatest prevalence of type 2 diabetes occurs in patients with NAFLD and cirrhosis. This observation suggests that insulin resistance and NAFLD may be related pathogenically. Experiments in mice demonstrate that insulin resistance and NAFLD result from a chronic inflammatory state that is characterized by increased levels of TNFα The mechanisms that drive this chronic inflammation are unknown but might involve the oxidative stress that develops during fatty acid metabolism or when products from intestinal bacteria escape into the mesenteric blood to trigger a sustained hepatic inflammatory cytokine response in genetically susceptible individuals, promoting a positive feedback loop that reinforces insulin resistance and inflammation. This hypothesis is supported by some animal and human studies; however, more research is needed to evaluate this theory. Additional studies also are required to determine the benefits of treatments that interrupt this pathogenic cascade at various points. Preliminary work in animal and human studies suggests that diverse strategies that inhibit production of TNFα and improve insulin resistance also ameliorate NAFLD.

Authors
Li, Z; Clark, J; Diehl, AM
MLA Citation
Li, Z, Clark, J, and Diehl, AM. "The liver in obesity and type 2 diabetes mellitus." Clinics in Liver Disease 6.4 (2002): 867-877.
PMID
12516196
Source
scival
Published In
Clinics in Liver Disease
Volume
6
Issue
4
Publish Date
2002
Start Page
867
End Page
877
DOI
10.1016/S1089-3261(02)00060-0

Ethanol induces redox-sensitive cell-cycle inhibitors and inhibits liver regeneration after partial hepatectomy

Background: Doses of ethanol (EtOH) that are not overtly cytotoxic inhibit mitogen-induced hepatocyte proliferation and delay liver regeneration after 70% partial hepatectomy (PH). The mechanisms for this are poorly understood. This study evaluates the hypothesis that EtOH inhibits hepatocyte proliferation after PH by inducing redox-sensitive factors, such as p38 mitogen-activated protein kinase (MAPK) and p21 (WAF1/CIP1), that protect cells from oxidative stress but prevent cell-cycle progression by inhibiting cyclin D1. Methods: Mechanisms that regulate the transition from the prereplicative G1 phase of the cell cycle into S phase were compared in EtOH-fed mice and normal pair-fed mice after PH. Results: Prior EtOH exposure significantly increases p38 MAPK and p21 after PH. This is accompanied by reduced expression of cyclin D1 messenger RNA and protein, increases in other cell-cycle regulators (such as signal transducer and activator of transcription-3 and p27) that are normally inhibited by cyclin D1, and hepatocyte G1 arrest. Conclusions: EtOH amplifies G1 checkpoint mechanisms that are induced by oxidative stress and promotes hepatic accumulation of factors, including p38 MAPK, p21, and signal transducer and activator of transcription-3, that enhance cellular survival after oxidant exposure. Therefore, cell-cycle inhibition may be an adaptive response that helps EtOH-exposed livers survive situations, such as PH, that acutely increase reactive oxygen species in hepatocytes.

Authors
Koteish, A; Yang, S; Lin, H; Huang, J; Diehl, AM
MLA Citation
Koteish, A, Yang, S, Lin, H, Huang, J, and Diehl, AM. "Ethanol induces redox-sensitive cell-cycle inhibitors and inhibits liver regeneration after partial hepatectomy." Alcoholism: Clinical and Experimental Research 26.11 (2002): 1710-1718.
PMID
12436061
Source
scival
Published In
Alcoholism: Clinical and Experimental Research
Volume
26
Issue
11
Publish Date
2002
Start Page
1710
End Page
1718

Animal models of steatohepatitis

Animal models of hepatic steatosis and steatohepatitis have improved our understanding of the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Three models, genetically obese ob/ob mice, lipoatrophic mice and normal rats fed choline-deficient, methionine-restricted diets, have been particularly informative. All support the multiple 'hit' hypothesis for NAFLD pathogenesis that suggests that fatty livers are unusually vulnerable to oxidants and develop steatohepatitis when secondary insults generate sufficient oxidants to cause liver cell death and inflammation. Steatohepatitis, in turn, increases sensitivity to other insults that induce hepatic fibrosis, promoting the evolution of cirrhosis. Early during NAFLD pathogenesis, inhibitor kappa kinase beta (IKKβ), an enzyme that induces tumour necrosis factor alpha (TNFα) and other proinflammatory cytokines, is activated and this causes insulin resistance. Inhibition of IKKβ or TNFα improves insulin sensitivity, steatosis and steatohepatitis in animals, suggesting novel strategies to prevent and treat early NAFLD in humans.

Authors
Koteish, A; Diehl, AM
MLA Citation
Koteish, A, and Diehl, AM. "Animal models of steatohepatitis." Bailliere's Best Practice and Research in Clinical Gastroenterology 16.5 (2002): 679-690.
PMID
12406439
Source
scival
Published In
Bailliere's Best Practice and Research in Clinical Gastroenterology
Volume
16
Issue
5
Publish Date
2002
Start Page
679
End Page
690
DOI
10.1053/bega.2002.0332

Hepatic steatosis and type 2 diabetes mellitus.

Type 2 diabetes is strongly associated with nonalcoholic fatty liver disease (NAFLD), a spectrum of liver damage that ranges from relatively benign hepatic steatosis to potentially fatal cirrhosis. The severities of insulin resistance and liver damage parallel each other, with the greatest prevalence of cirrhosis occurring in cirrhotics. However, it is unknown whether one of these conditions causes the other, or if both are consequences of another process. Experimental evidence suggests that both insulin resistance and NAFLD result from a chronic inflammatory state. The mechanisms driving this chronic inflammation are unknown but might include the egress of products from intestinal bacteria into the portal blood, liver, and systemic circulation to trigger a sustained inflammatory cytokine response in genetically susceptible individuals. More research is needed to evaluate this hypothesis and to determine the benefits of treatments that interrupt this pathogenic cascade.

Authors
Clark, JM; Diehl, AM
MLA Citation
Clark, JM, and Diehl, AM. "Hepatic steatosis and type 2 diabetes mellitus." Curr Diab Rep 2.3 (2002): 210-215.
PMID
12643175
Source
scival
Published In
Curr Diab Rep
Volume
2
Issue
3
Publish Date
2002
Start Page
210
End Page
215

Liver regeneration.

Unlike other vital organs, the liver typically regenerates after injury. Indeed, the very factors that cause liver injury initiate a reparative process in the residual liver that includes the induction of cytoprotective mechanisms, deletion of mortally wounded cells, repair of less damaged survivors, liver cell proliferation to replace the cells that died, the deposition of new matrix, and tissue remodeling to restore normal hepatic mass and architecture. During liver regeneration, the liver normally continues to perform vital, liver-specific functions. Unfortunately, the hepatic regenerative response sometimes becomes disrupted--either failing to occur or occurring in a disordered, or incomplete fashion. Abnormal regeneration contributes to the pathogenesis of fulminate liver failure, cirrhosis, and primary liver cancers. Research in the field of regenerative biology has identified several events that are required for liver regeneration. These include injury-induced changes in the hepatic microenvironment, the ability of surviving liver cells and/or their progenitors to proliferate, and a temporary suspension of homeostatic mechanisms that normally couple cell proliferation to programmed cell death. The signals that mediate these complex biologic responses are being detailed. A better understanding of the extra- and intracellular signals that prompt the injured liver to regenerate should suggest treatments to promote liver regeneration in patients with otherwise fatal liver diseases.

Authors
Diehl, AM
MLA Citation
Diehl, AM. "Liver regeneration." Front Biosci 7 (2002): e301-e314.
PMID
12086922
Source
scival
Published In
Front Biosci
Volume
7
Publish Date
2002
Start Page
e301
End Page
e314

Chronic ethanol exposure potentiates lipopolysaccharide liver injury despite inhibiting Jun N-terminal kinase and caspase 3 activation

Although ethanol is known to sensitize hepatocytes to tumor necrosis factor (TNF) lethality, the mechanisms involved remain controversial. Recently, others have shown that adding TNFα to cultures of ethanol-pretreated hepatocytes provokes the mitochondrial permeability transition, cytochrome c release, procaspase 3 activation, and apoptosis. Although this demonstrates that ethanol can sensitize hepatocytes to TNF-mediated apoptosis, the hepatic inflammation and ballooning hepatocyte degeneration that typify alcohol-induced liver injury suggest that other mechanisms might predominate in vivo. To evaluate this possibility, acute responses to lipopolysaccharide (LPS), a potent inducer of TNFα, were compared in mice that had been fed either an ethanol-containing or control diet for 5 weeks. Despite enhanced induction of cytokines such as interleukin (IL)-10, IL-15, and IL-6 that protect hepatocytes from apoptosis, ethanol-fed mice exhibited a 4-5-fold increase in serum alanine aminotransferase after LPS, confirming increased liver injury. Six h post-LPS histology also differed notably in the two groups, with control livers demonstrating only scattered apoptotic hepatocytes, whereas ethanol-exposed livers had large foci of ballooned hepatocytes, inflammation, and scattered hemorrhage. No caspase 3 activity was noted during the initial 6 h after LPS in ethanol-fed mice, but this tripled by 1.5 h after LPS in controls. Procaspase 8 cleavage and activity of the apoptosis-associated kinase, Jun N-terminal kinase, were also greater in controls. In contrast, ethanol exposure did not inhibit activation of cytoprotective mitogen-activated protein kinases and AKT or attenuate induction of the anti-apoptotic factors NF-κB and inducible nitric oxide synthase. Consistent with these responses, neither cytochrome c release, an early apoptotic response, nor hepatic oligonucleosomal DNA fragmentation, the ultimate consequence of apoptosis, was increased by ethanol. Thus, ethanol exacerbates TNF-related hepatotoxicity in vivo without enhancing caspase 3-dependent apoptosis.

Authors
Koteish, A; Yang, S; Lin, H; Huang, X; Diehl, AM
MLA Citation
Koteish, A, Yang, S, Lin, H, Huang, X, and Diehl, AM. "Chronic ethanol exposure potentiates lipopolysaccharide liver injury despite inhibiting Jun N-terminal kinase and caspase 3 activation." Journal of Biological Chemistry 277.15 (2002): 13037-13044.
PMID
11812769
Source
scival
Published In
The Journal of biological chemistry
Volume
277
Issue
15
Publish Date
2002
Start Page
13037
End Page
13044
DOI
10.1074/jbc.M101632200

Nonalcoholic fatty liver disease

Authors
Clark, JM; Brancati, FL; Diehl, AM
MLA Citation
Clark, JM, Brancati, FL, and Diehl, AM. "Nonalcoholic fatty liver disease." Gastroenterology 122.6 (2002): 1649-1657.
PMID
12016429
Source
scival
Published In
Gastroenterology
Volume
122
Issue
6
Publish Date
2002
Start Page
1649
End Page
1657

Nonalcoholic steatosis and steatohepatitis IV. Nonalcoholic fatty liver disease abnormalities in macrophage function and cytokines