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Liddle, Rodger Alan

Overview:

Our laboratory has two major research interests:

Enteroendocrine Cell Biology

Enteroendocrine cells (EECs) are sensory cells of the gut that send signals throughout the body.  They have the ability to sense food and nutrients in the lumen of the intestine and secrete hormones into the blood.  Our laboratory has had a longstanding interest in two types of EECs that regulate satiety and signal the brain to stop eating.   Cholecystokinin (CCK) is secreted from EECs of the upper small intestine and regulates the ingestion and digestion of food through effects on the stomach, gallbladder, pancreas and brain.  Peptide YY (PYY) is secreted from EECs of the small intestine and colon and regulates satiety.  We recently demonstrated that CCK and PYY cells not only secrete hormones but are directly connected to nerves through unique cellular processes called ‘neuropods’.  Our laboratory is devoted to understanding EECs signaling and its role in disease.

Pancreatitis


Pancreatitis is an inflammatory disease of the pancreas compounded by intrapancreaatic activation of digestive enzymes.  Our laboratory is studying the influence of nerves on the development of pancreatitis. Neurogenic inflammation results from the release of bioactive substances from sensory neurons in the pancreas causing vasodilatation, edema, and inflammatory cell infiltration producing tissue necrosis. Our goal is to identify the agents that activate sensory neurons, characterize the receptors on sensory nerves that mediate these actions, and determine the effects of neural stimulation on pancreatic injury with the long-term objective of developing strategies to reduce neurogenic inflammation to treat pancreatitis. 

https://medicine.duke.edu/divisions/gastroenterology/research/basic-and-... our lab page.

Positions:

Professor of Medicine

Medicine, Gastroenterology
School of Medicine

Member of the Duke Institute for Brain Sciences

Duke Institute for Brain Sciences
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1972

B.S. — University of Utah

M.D. 1978

M.D. — Vanderbilt University

Internship, General Internal Medicine

University of California - San Francisco

Residency, Generalinternal Medicine

University of California - San Francisco

Gastroenterology Fellowship, Gastroenterology

University of California - San Francisco

News:

Grants:

Duke Training Grant in Digestive Diseases and Nutrition

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

The role of gut endocrine cells in Parkinson's Disease

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2016
End Date
August 31, 2020

Gut-Brain Neurocircuit Modulating Eating Behavior

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
January 19, 2015
End Date
December 31, 2019

Receptor Regulation of CCK Cell Function

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 18, 2013
End Date
August 31, 2018

Functional mapping of efferent gut neuroepithelial circuits

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 28, 2016
End Date
July 31, 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

Pathogenic Mechanisms of Pancreatitis

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2003
End Date
February 28, 2018

Carnitine Acetyltransferase and Metabolic Regulation in the Exocrine Pancreas

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Co-Sponsor
Start Date
September 30, 2015
End Date
September 29, 2017

Mechanisms Regulating Gastrointestinal Hormone Secretion

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 17, 2011
End Date
August 31, 2016

Effects of BCX4161 on the Pancreas

Administered By
Medicine, Gastroenterology
AwardedBy
Biocryst Corporation
Role
Principal Investigator
Start Date
January 26, 2016
End Date
February 17, 2016

Regulation of Intestinal PYY cell function

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 2012
End Date
December 31, 2014

Role of Pancreatic Trypsin Inhibitor in Pancreatitis

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2006
End Date
March 31, 2011

The Role of transcription factor Sox2 in the homeostasis of the adult esophagus

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
April 01, 2010
End Date
September 30, 2010

CCK Cell Function

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 14, 1988
End Date
June 30, 2010

Regulation of Gut Substance P Receptors

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
April 01, 1996
End Date
December 31, 2007

IPA - Chieh-Chun HSU

Administered By
Medicine, Gastroenterology
AwardedBy
Veterans Administration Medical Center
Role
Principal Investigator
Start Date
November 01, 2005
End Date
October 31, 2007

Duke/NIDDK Functional Genomics Center

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Administrative Assistant
Start Date
September 30, 2000
End Date
August 31, 2003

Surgical Approach to Experimental Pancreatitis

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2000
End Date
August 31, 2002

Duke Training Grant In Digestive Diseases And Nutrition

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1988
End Date
August 31, 1999

Duke Training Grant In Digestive Diseases And Nutrition

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1988
End Date
August 31, 1999

Second Messenger Signaling In Cholecystokinin Cells

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 14, 1988
End Date
June 30, 1999

Second Messenger Signalling In Cholecystokinin Cells

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 14, 1988
End Date
June 30, 1995

Integrated Role Of Cck On The Gastrointestinal Tract

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1990
End Date
June 01, 1991
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Publications:

Editorial introductions

MLA Citation
"Editorial introductions." Current Opinion in Gastroenterology 33.5 (September 2017): v-v.
Source
crossref
Published In
Current Opinion in Gastroenterology
Volume
33
Issue
5
Publish Date
2017
Start Page
v
End Page
v
DOI
10.1097/MOG.0000000000000391

Gastrointestinal hormones and the gut connectome.

Provision of adequate nutrients by the gut is essential for survival and essential behaviors are linked to the proper ingestion and digestion of food. Recently, a new neural connection has been reported between sensory cells of the gut epithelium and the nervous system that mediates signals from the gut to the brain.This review describes how the gut senses its environment, relays those signals to the brain, and how the brain influences the gut.This gut-brain connection provides a pathway for how the body handles food.

Authors
Ye, L; Liddle, RA
MLA Citation
Ye, L, and Liddle, RA. "Gastrointestinal hormones and the gut connectome." Current opinion in endocrinology, diabetes, and obesity 24.1 (February 2017): 9-14.
PMID
27820704
Source
epmc
Published In
Current Opinion in Endocrinology, Diabetes and Obesity
Volume
24
Issue
1
Publish Date
2017
Start Page
9
End Page
14
DOI
10.1097/med.0000000000000299

Location, Location, Location . . . It Is Important in Pancreatitis, Too.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Location, Location, Location . . . It Is Important in Pancreatitis, Too." Cellular and molecular gastroenterology and hepatology 3.1 (January 2017): 6-7.
PMID
28174753
Source
epmc
Published In
Cellular and molecular gastroenterology and hepatology
Volume
3
Issue
1
Publish Date
2017
Start Page
6
End Page
7
DOI
10.1016/j.jcmgh.2016.10.005

Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain.

TRPV4 ion channels represent osmo-mechano-TRP channels with pleiotropic function and wide-spread expression. One of the critical functions of TRPV4 in this spectrum is its involvement in pain and inflammation. However, few small-molecule inhibitors of TRPV4 are available. Here we developed TRPV4-inhibitory molecules based on modifications of a known TRPV4-selective tool-compound, GSK205. We not only increased TRPV4-inhibitory potency, but surprisingly also generated two compounds that potently co-inhibit TRPA1, known to function as chemical sensor of noxious and irritant signaling. We demonstrate TRPV4 inhibition by these compounds in primary cells with known TRPV4 expression - articular chondrocytes and astrocytes. Importantly, our novel compounds attenuate pain behavior in a trigeminal irritant pain model that is known to rely on TRPV4 and TRPA1. Furthermore, our novel dual-channel blocker inhibited inflammation and pain-associated behavior in a model of acute pancreatitis - known to also rely on TRPV4 and TRPA1. Our results illustrate proof of a novel concept inherent in our prototype compounds of a drug that targets two functionally-related TRP channels, and thus can be used to combat isoforms of pain and inflammation in-vivo that involve more than one TRP channel. This approach could provide a novel paradigm for treating other relevant health conditions.

Authors
Kanju, P; Chen, Y; Lee, W; Yeo, M; Lee, SH; Romac, J; Shahid, R; Fan, P; Gooden, DM; Simon, SA; Spasojevic, I; Mook, RA; Liddle, RA; Guilak, F; Liedtke, WB
MLA Citation
Kanju, P, Chen, Y, Lee, W, Yeo, M, Lee, SH, Romac, J, Shahid, R, Fan, P, Gooden, DM, Simon, SA, Spasojevic, I, Mook, RA, Liddle, RA, Guilak, F, and Liedtke, WB. "Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain." Scientific Reports 6 (June 2016): 26894-.
Website
http://hdl.handle.net/10161/12075
PMID
27247148
Source
epmc
Published In
Scientific Reports
Volume
6
Publish Date
2016
Start Page
26894
DOI
10.1038/srep26894

Mechanism, assessment and management of pain in chronic pancreatitis: Recommendations of a multidisciplinary study group.

Pain in patients with chronic pancreatitis (CP) remains the primary clinical complaint and source of poor quality of life. However, clear guidance on evaluation and treatment is lacking.Pancreatic Pain working groups reviewed information on pain mechanisms, clinical pain assessment and pain treatment in CP. Levels of evidence were assigned using the Oxford system, and consensus was based on GRADE. A consensus meeting was held during PancreasFest 2012 with substantial post-meeting discussion, debate, and manuscript refinement.Twelve discussion questions and proposed guidance statements were presented. Conference participates concluded: Disease Mechanism: Pain etiology is multifactorial, but data are lacking to effectively link symptoms with pathologic feature and molecular subtypes. Assessment of Pain: Pain should be assessed at each clinical visit, but evidence to support an optimal approach to assessing pain character, frequency and severity is lacking.There was general agreement on the roles for endoscopic and surgical therapies, but less agreement on optimal patient selection for medical, psychological, endoscopic, surgical and other therapies.Progress is occurring in pain biology and treatment options, but pain in patients with CP remains a major problem that is inadequately understood, measured and managed. The growing body of information needs to be translated into more effective clinical care.

Authors
Anderson, MA; Akshintala, V; Albers, KM; Amann, ST; Belfer, I; Brand, R; Chari, S; Cote, G; Davis, BM; Frulloni, L; Gelrud, A; Guda, N; Humar, A; Liddle, RA; Slivka, A; Gupta, RS; Szigethy, E; Talluri, J; Wassef, W; Wilcox, CM; Windsor, J; Yadav, D; Whitcomb, DC
MLA Citation
Anderson, MA, Akshintala, V, Albers, KM, Amann, ST, Belfer, I, Brand, R, Chari, S, Cote, G, Davis, BM, Frulloni, L, Gelrud, A, Guda, N, Humar, A, Liddle, RA, Slivka, A, Gupta, RS, Szigethy, E, Talluri, J, Wassef, W, Wilcox, CM, Windsor, J, Yadav, D, and Whitcomb, DC. "Mechanism, assessment and management of pain in chronic pancreatitis: Recommendations of a multidisciplinary study group." Pancreatology : official journal of the International Association of Pancreatology (IAP) .. [et al.] 16.1 (January 2016): 83-94.
PMID
26620965
Source
epmc
Published In
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]
Volume
16
Issue
1
Publish Date
2016
Start Page
83
End Page
94
DOI
10.1016/j.pan.2015.10.015

Correlative Confocal and 3D Electron Microscopy of a Specific Sensory Cell.

Delineation of a cell's ultrastructure is important for understanding its function. This can be a daunting project for rare cell types diffused throughout tissues made of diverse cell types, such as enteroendocrine cells of the intestinal epithelium. These gastrointestinal sensors of food and bacteria have been difficult to study because they are dispersed among other epithelial cells at a ratio of 1:1,000. Recently, transgenic reporter mice have been generated to identify enteroendocrine cells by means of fluorescence. One of those is the peptide YY-GFP mouse. Using this mouse, we developed a method to correlate confocal and serial block-face scanning electron microscopy. We named the method cocem3D and applied it to identify a specific enteroendocrine cell in tissue and unveil the cell's ultrastructure in 3D. The resolution of cocem3D is sufficient to identify organelles as small as secretory vesicles and to distinguish cell membranes for volume rendering. Cocem3D can be easily adapted to study the 3D ultrastructure of other specific cell types in their native tissue.

Authors
Bohórquez, D; Haque, F; Medicetty, S; Liddle, RA
MLA Citation
Bohórquez, D, Haque, F, Medicetty, S, and Liddle, RA. "Correlative Confocal and 3D Electron Microscopy of a Specific Sensory Cell." Journal of visualized experiments : JoVE 101 (July 19, 2015): e52918-.
PMID
26273796
Source
epmc
Published In
Journal of Visualized Experiments
Issue
101
Publish Date
2015
Start Page
e52918
DOI
10.3791/52918

The gut connectome: making sense of what you eat.

The enteric nervous system has been studied thus far as an isolated unit. As researchers probe deeper into the function of this system, it is evident that the neural network stretches beyond enteric neurons. It is formed by both intrinsic and extrinsic neurons innervating the gut, enteric glia, and innervated sensory epithelial cells, such as enteroendocrine cells. This Review series summarizes recent knowledge on function and disease of nerves, glia, and sensory epithelial cells of the gut in eight distinctive articles. The timing and growing knowledge for each individual field calls for an appropriate term encompassing the entire system. We call this neuronal ensemble the "gut connectome" and summarize the work from a food sensory perspective.

Authors
Bohórquez, DV; Liddle, RA
MLA Citation
Bohórquez, DV, and Liddle, RA. "The gut connectome: making sense of what you eat." The Journal of clinical investigation 125.3 (March 2, 2015): 888-890.
PMID
25729849
Source
epmc
Published In
Journal of Clinical Investigation
Volume
125
Issue
3
Publish Date
2015
Start Page
888
End Page
890
DOI
10.1172/jci81121

Endogenous elevation of plasma cholecystokinin does not prevent gallstones.

Regular gall bladder contraction reduces bile stasis and prevents gallstone formation. Intraduodenal administration of exogenous pancreatic secretory trypsin inhibitor-I (PSTI-I, also known as monitor peptide) causes cholecystokinin (CCK) secretion.We proposed that stimulation of CCK release by PSTI would produce gall bladder contraction and prevent gallstones in mice fed a lithogenic diet. Therefore, we tested the effect of overexpression of rat PSTI-I in pancreatic acinar cells on plasma CCK levels and gall bladder function in a transgenic mouse line (TgN[Psti1]; known hereafter as PSTI-I tg).Importantly, PSTI tg mice had elevated fasting and fed plasma CCK levels compared to wild-type (WT) mice. Only mice fed the lithogenic diet developed gallstones. Both fasting and stimulated plasma CCK levels were substantially reduced in both WT and PSTI-I tg mice on the lithogenic diet. Moreover, despite higher CCK levels PSTI-I tg animals developed more gallstones than WT animals.Together with the previously observed decrease in CCK-stimulated gall bladder emptying in mice fed a lithogenic diet, our findings suggest that a lithogenic diet causes gallstone formation by impaired CCK secretion in addition to reduced gall bladder sensitivity to CCK.

Authors
Shahid, RA; Wang, DQ-H; Fee, BE; McCall, SJ; Romac, JM-J; Vigna, SR; Liddle, RA
MLA Citation
Shahid, RA, Wang, DQ-H, Fee, BE, McCall, SJ, Romac, JM-J, Vigna, SR, and Liddle, RA. "Endogenous elevation of plasma cholecystokinin does not prevent gallstones." European journal of clinical investigation 45.3 (March 2015): 237-246.
PMID
25641074
Source
epmc
Published In
European Journal of Clinical Investigation
Volume
45
Issue
3
Publish Date
2015
Start Page
237
End Page
246
DOI
10.1111/eci.12400

ILDR1 null mice, a model of human deafness DFNB42, show structural aberrations of tricellular tight junctions and degeneration of auditory hair cells.

In the mammalian inner ear, bicellular and tricellular tight junctions (tTJs) seal the paracellular space between epithelial cells. Tricellulin and immunoglobulin-like (Ig-like) domain containing receptor 1 (ILDR1, also referred to as angulin-2) localize to tTJs of the sensory and non-sensory epithelia in the organ of Corti and vestibular end organs. Recessive mutations of TRIC (DFNB49) encoding tricellulin and ILDR1 (DFNB42) cause human nonsyndromic deafness. However, the pathophysiology of DFNB42 deafness remains unknown. ILDR1 was recently reported to be a lipoprotein receptor mediating the secretion of the fat-stimulated cholecystokinin (CCK) hormone in the small intestine, while ILDR1 in EpH4 mouse mammary epithelial cells in vitro was shown to recruit tricellulin to tTJs. Here we show that two different mouse Ildr1 mutant alleles have early-onset severe deafness associated with a rapid degeneration of cochlear hair cells (HCs) but have a normal endocochlear potential. ILDR1 is not required for recruitment of tricellulin to tTJs in the cochlea in vivo; however, tricellulin becomes mislocalized in the inner ear sensory epithelia of ILDR1 null mice after the first postnatal week. As revealed by freeze-fracture electron microscopy, ILDR1 contributes to the ultrastructure of inner ear tTJs. Taken together, our data provide insight into the pathophysiology of human DFNB42 deafness and demonstrate that ILDR1 is crucial for normal hearing by maintaining the structural and functional integrity of tTJs, which are critical for the survival of auditory neurosensory HCs.

Authors
Morozko, EL; Nishio, A; Ingham, NJ; Chandra, R; Fitzgerald, T; Martelletti, E; Borck, G; Wilson, E; Riordan, GP; Wangemann, P; Forge, A; Steel, KP; Liddle, RA; Friedman, TB; Belyantseva, IA
MLA Citation
Morozko, EL, Nishio, A, Ingham, NJ, Chandra, R, Fitzgerald, T, Martelletti, E, Borck, G, Wilson, E, Riordan, GP, Wangemann, P, Forge, A, Steel, KP, Liddle, RA, Friedman, TB, and Belyantseva, IA. "ILDR1 null mice, a model of human deafness DFNB42, show structural aberrations of tricellular tight junctions and degeneration of auditory hair cells." Human molecular genetics 24.3 (February 2015): 609-624.
PMID
25217574
Source
epmc
Published In
Human Molecular Genetics
Volume
24
Issue
3
Publish Date
2015
Start Page
609
End Page
624
DOI
10.1093/hmg/ddu474

Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells.

Satiety and other core physiological functions are modulated by sensory signals arising from the surface of the gut. Luminal nutrients and bacteria stimulate epithelial biosensors called enteroendocrine cells. Despite being electrically excitable, enteroendocrine cells are generally thought to communicate indirectly with nerves through hormone secretion and not through direct cell-nerve contact. However, we recently uncovered in intestinal enteroendocrine cells a cytoplasmic process that we named neuropod. Here, we determined that neuropods provide a direct connection between enteroendocrine cells and neurons innervating the small intestine and colon. Using cell-specific transgenic mice to study neural circuits, we found that enteroendocrine cells have the necessary elements for neurotransmission, including expression of genes that encode pre-, post-, and transsynaptic proteins. This neuroepithelial circuit was reconstituted in vitro by coculturing single enteroendocrine cells with sensory neurons. We used a monosynaptic rabies virus to define the circuit's functional connectivity in vivo and determined that delivery of this neurotropic virus into the colon lumen resulted in the infection of mucosal nerves through enteroendocrine cells. This neuroepithelial circuit can serve as both a sensory conduit for food and gut microbes to interact with the nervous system and a portal for viruses to enter the enteric and central nervous systems.

Authors
Bohórquez, DV; Shahid, RA; Erdmann, A; Kreger, AM; Wang, Y; Calakos, N; Wang, F; Liddle, RA
MLA Citation
Bohórquez, DV, Shahid, RA, Erdmann, A, Kreger, AM, Wang, Y, Calakos, N, Wang, F, and Liddle, RA. "Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells." Journal of Clinical Investigation 125.2 (February 2015): 782-786.
Website
http://hdl.handle.net/10161/9363
PMID
25555217
Source
epmc
Published In
Journal of Clinical Investigation
Volume
125
Issue
2
Publish Date
2015
Start Page
782
End Page
786
DOI
10.1172/jci78361

Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells

Authors
Bohorquez, DV; Shahid, RA; Erdmann, A; Kreger, AM; Wang, Y; Calakos, N; Wang, F; Liddle, RA
MLA Citation
Bohorquez, DV, Shahid, RA, Erdmann, A, Kreger, AM, Wang, Y, Calakos, N, Wang, F, and Liddle, RA. "Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells." JOURNAL OF CLINICAL INVESTIGATION 125.2 (February 2015): 782-786.
Website
http://hdl.handle.net/10161/13005
Source
wos-lite
Published In
Journal of Clinical Investigation
Volume
125
Issue
2
Publish Date
2015
Start Page
782
End Page
786
DOI
10.1172/JCI78361

Acinar Cell Production of Leukotriene B4 Contributes to Development of Neurogenic Pancreatitis in Mice.

In the pancreas, activation of primary sensory nerves through the transient receptor potential ion channel TRPV1 contributes to the early stages of development of pancreatitis. Little is known about the mechanism by which this occurs. We investigated whether leukotriene B4 (LTB4) is an endogenous agonist of TRPV1 and mediates pancreatitis.Acute inflammation was induced in the pancreata of Trpv1(-/-) mice and their wild-type littermates by retrograde infusion of the main pancreatic duct with 2% sodium taurocholate (NaT) or intraperitoneal injections of caerulein. Mice were also given injections of resiniferatoxin (an excitotoxin that desensitizes TRPV1) or MK886 (a drug that inhibits LTB4 biosynthesis). Pancreatic tissues and plasma were collected and analyzed.Retrograde perfusion of the main pancreatic ducts of wild-type mice with NaT caused severe acute pancreatitis; severity was reduced by co-administration of resiniferatoxin. Trpv1(-/-) mice developed a less severe pancreatitis following NaT administration than controls. Administration of MK886 before perfusion with NaT also significantly reduced the severity of pancreatitis in wild-type mice. Pancreatic tissues from mice given NaT had a marked increase in the level of 5-lipoxygenase immunoreactivity specifically in acinar cells. Bile acid and caerulein induced secretion of LTB4 by cultured pancreatic acinar cells; MK886 inhibited this process.Administration of caerulein or intraductal bile acids in mice causes production of LTB4 by pancreatic acinar cells. This activates TRPV1 on primary sensory nerves to induce acute pancreatitis.

Authors
Shahid, RA; Vigna, SR; Layne, AC; Romac, JM-J; Liddle, RA
MLA Citation
Shahid, RA, Vigna, SR, Layne, AC, Romac, JM-J, and Liddle, RA. "Acinar Cell Production of Leukotriene B4 Contributes to Development of Neurogenic Pancreatitis in Mice." Cellular and molecular gastroenterology and hepatology 1.1 (January 2015): 75-86.
PMID
25729765
Source
epmc
Published In
Cellular and molecular gastroenterology and hepatology
Volume
1
Issue
1
Publish Date
2015
Start Page
75
End Page
86
DOI
10.1016/j.jcmgh.2014.11.002

Minutes of the Business Meeting of the American Pancreatic Association, Friday, November 1, 2013, Miami, Florida

Authors
Freeman, M; Pandol, SJ; Liddle, RA; Saluja, AK; Fernandez-del Castillo, C; Maitra, A; Sahin-Toth, M; Go, VLW
MLA Citation
Freeman, M, Pandol, SJ, Liddle, RA, Saluja, AK, Fernandez-del Castillo, C, Maitra, A, Sahin-Toth, M, and Go, VLW. "Minutes of the Business Meeting of the American Pancreatic Association, Friday, November 1, 2013, Miami, Florida." Pancreas 43.8 (November 2014): 1141-1142.
Source
crossref
Published In
Pancreas
Volume
43
Issue
8
Publish Date
2014
Start Page
1141
End Page
1142
DOI
10.1097/MPA.0000000000000227

Recent advances in the regulation of pancreatic secretion.

This review highlights recent progress made in the field of pancreatic secretion.This review summarizes a number of recent studies demonstrating the intracellular pathways by which hormones and neural inputs regulate pancreatic exocrine and endocrine secretion. In particular, the effects of vasoactive intestinal peptide and secretin on intra-acinar cell adenosine 3',5'-cyclic monophosphate are explored. Considerable attention is paid to regulation of β-cell function and includes studies detailing the mechanisms of regulation of insulin by somatostatin, serotonin, and melanocortins. These studies emphasize the critical role that hormonal, paracrine, and neural factors play in glucose homeostasis.Exocrine and endocrine pancreatic secretions are regulated by hormonal and neural mechanisms, and understanding these pathways will enable the discovery and design of new and improved therapies for prevention and control of diabetes and perhaps exocrine insufficiency.

Authors
Chandra, R; Liddle, RA
MLA Citation
Chandra, R, and Liddle, RA. "Recent advances in the regulation of pancreatic secretion." Current opinion in gastroenterology 30.5 (September 2014): 490-494. (Review)
PMID
25003603
Source
epmc
Published In
Current Opinion in Gastroenterology
Volume
30
Issue
5
Publish Date
2014
Start Page
490
End Page
494
DOI
10.1097/mog.0000000000000099

Ethanol contributes to neurogenic pancreatitis by activation of TRPV1.

Alcohol abuse is a major cause of pancreatitis in people, but the mechanism is unknown. It has been recently demonstrated that transient receptor potential vanilloid 1 (TRPV1) activation causes neurogenic inflammation and plays an important role in acute pancreatitis. Moreover, TRPV1 is activated by ethanol. We examined the direct effects of ethanol on acute pancreatitis. Acute inflammation of the pancreas was produced by injection of ethanol and palmitoleic acid (POA), a nonoxidative metabolite of ethanol, in wild-type C57BL/6J mice and Trpv1-knockout C57BL/6J mice. Inflammatory indexes were analyzed 24 h later. Injection of ethanol + POA produced acute pancreatitis indicated by significant increases in histopathological damage, serum amylase levels, and pancreatic MPO concentrations (P<0.05-0.001). All parameters of pancreatitis were blocked by pretreatment with the TRPV1 antagonist drug AMG9810. In addition, ethanol + POA administration to Trpv1knockout mice did not produce pancreatic inflammation. Treatment with vehicle, ethanol alone, or POA alone had no inflammatory effects. TRPV1 partially mediates inflammation induced by ethanol + POA in the mouse pancreas, consistent with the ability of ethanol to activate TRPV1. We propose that ethanol may contribute to alcohol-induced pancreatitis by a neurogenic mechanism.

Authors
Vigna, SR; Shahid, RA; Liddle, RA
MLA Citation
Vigna, SR, Shahid, RA, and Liddle, RA. "Ethanol contributes to neurogenic pancreatitis by activation of TRPV1." FASEB J 28.2 (February 2014): 891-896.
PMID
24221085
Source
pubmed
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
28
Issue
2
Publish Date
2014
Start Page
891
End Page
896
DOI
10.1096/fj.13-236208

An enteroendocrine cell-enteric glia connection revealed by 3D electron microscopy.

The enteroendocrine cell is the cornerstone of gastrointestinal chemosensation. In the intestine and colon, this cell is stimulated by nutrients, tastants that elicit the perception of flavor, and bacterial by-products; and in response, the cell secretes hormones like cholecystokinin and peptide YY--both potent regulators of appetite. The development of transgenic mice with enteroendocrine cells expressing green fluorescent protein has allowed for the elucidation of the apical nutrient sensing mechanisms of the cell. However, the basal secretory aspects of the enteroendocrine cell remain largely unexplored, particularly because a complete account of the enteroendocrine cell ultrastructure does not exist. Today, the fine ultrastructure of a specific cell can be revealed in the third dimension thanks to the invention of serial block face scanning electron microscopy (SBEM). Here, we bridged confocal microscopy with SBEM to identify the enteroendocrine cell of the mouse and study its ultrastructure in the third dimension. The results demonstrated that 73.5% of the peptide-secreting vesicles in the enteroendocrine cell are contained within an axon-like basal process. We called this process a neuropod. This neuropod contains neurofilaments, which are typical structural proteins of axons. Surprisingly, the SBEM data also demonstrated that the enteroendocrine cell neuropod is escorted by enteric glia--the cells that nurture enteric neurons. We extended these structural findings into an in vitro intestinal organoid system, in which the addition of glial derived neurotrophic factors enhanced the development of neuropods in enteroendocrine cells. These findings open a new avenue of exploration in gastrointestinal chemosensation by unveiling an unforeseen physical relationship between enteric glia and enteroendocrine cells.

Authors
Bohórquez, DV; Samsa, LA; Roholt, A; Medicetty, S; Chandra, R; Liddle, RA
MLA Citation
Bohórquez, DV, Samsa, LA, Roholt, A, Medicetty, S, Chandra, R, and Liddle, RA. "An enteroendocrine cell-enteric glia connection revealed by 3D electron microscopy." PLoS ONE 9.2 (January 2014): e89881-.
Website
http://hdl.handle.net/10161/9382
PMID
24587096
Source
epmc
Published In
PloS one
Volume
9
Issue
2
Publish Date
2014
Start Page
e89881
DOI
10.1371/journal.pone.0089881

Recent advances in the regulation of pancreatic secretion

PURPOSE OF REVIEW: This review highlights recent progress made in the field of pancreatic secretion. RECENT FINDINGS: This review summarizes a number of recent studies demonstrating the intracellular pathways by which hormones and neural inputs regulate pancreatic exocrine and endocrine secretion. In particular, the effects of vasoactive intestinal peptide and secretin on intra-acinar cell adenosine 3',5'-cyclic monophosphate are explored. Considerable attention is paid to regulation of β-cell function and includes studies detailing the mechanisms of regulation of insulin by somatostatin, serotonin, and melanocortins. These studies emphasize the critical role that hormonal, paracrine, and neural factors play in glucose homeostasis. SUMMARY: Exocrine and endocrine pancreatic secretions are regulated by hormonal and neural mechanisms, and understanding these pathways will enable the discovery and design of new and improved therapies for prevention and control of diabetes and perhaps exocrine insufficiency. © 2014 Wolters Kluwer Health.

Authors
Chandra, R; Liddle, RA
MLA Citation
Chandra, R, and Liddle, RA. "Recent advances in the regulation of pancreatic secretion." Current Opinion in Gastroenterology 30.5 (2014): 490-494.
Source
scival
Published In
Current Opinion in Gastroenterology
Volume
30
Issue
5
Publish Date
2014
Start Page
490
End Page
494
DOI
10.1097/MOG.0000000000000099

Modulation of taste responsiveness by the satiation hormone peptide YY

It has been hypothesized that the peripheral taste system may be modulated in the context of an animal's metabolic state. One purported mechanism for this phenomenon is that circulating gastrointestinal peptides modulate the functioning of the peripheral gustatory system. Recent evidence suggests endocrine signaling in the oral cavity can influence food intake (FI) and satiety. We hypothesized that these hormones may be affecting FI by influencing taste perception. We used immunohistochemistry along with genetic knockout models and the specific reconstitution of peptide YY (PYY) in saliva using gene therapy protocols to identify a role for PYY signaling in taste. We show that PYY is expressed in subsets of taste cells in murine taste buds. We also show, using brief-access testing with PYY knockouts, that PYY signaling modulates responsiveness to bitter-tasting stimuli, as well as to lipid emulsions. We show that salivary PYY augmentation, via viral vector therapy, rescues behavioral responsiveness to a lipid emulsion but not to bitter stimuli and that this response is likely mediated via activation of Y2 receptors localized apically in taste cells. Our findings suggest distinct functions for PYY produced locally in taste cells vs. that circulating systemically.-La Sala, M. S., Hurtado, M. D., Brown, A. R., Bohórquez, D. V., Liddle, R. A., Herzog, H., Zolotukhin, S., Dotson, C. D. Modulation of taste responsiveness by the satiation hormone peptide YY. © FASEB.

Authors
Sala, MSL; Hurtado, MD; Brown, AR; Bohórquez, DV; Liddle, RA; Herzog, H; Zolotukhin, S; Dotson, CD
MLA Citation
Sala, MSL, Hurtado, MD, Brown, AR, Bohórquez, DV, Liddle, RA, Herzog, H, Zolotukhin, S, and Dotson, CD. "Modulation of taste responsiveness by the satiation hormone peptide YY." FASEB Journal 27.12 (December 1, 2013): 5022-5033.
PMID
24043261
Source
scopus
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
27
Issue
12
Publish Date
2013
Start Page
5022
End Page
5033
DOI
10.1096/fj.13-228064

Minutes of the business meeting of the American Pancreatic Association, Friday, November 2, 2012, Miami, Florida.

Authors
Liddle, RA; Freeman, M; Simeone, DM; Saluja, AK; Castillo, CF-D; Maitra, A; Pandol, SJ; Go, VLW
MLA Citation
Liddle, RA, Freeman, M, Simeone, DM, Saluja, AK, Castillo, CF-D, Maitra, A, Pandol, SJ, and Go, VLW. "Minutes of the business meeting of the American Pancreatic Association, Friday, November 2, 2012, Miami, Florida." Pancreas 42.8 (November 2013): 1333-1334.
PMID
24152959
Source
epmc
Published In
Pancreas
Volume
42
Issue
8
Publish Date
2013
Start Page
1333
End Page
1334
DOI
10.1097/mpa.0b013e3182a99936

Modulation of pancreatic exocrine and endocrine secretion.

PURPOSE OF REVIEW: Recent advances in the regulation of pancreatic secretion by secretagogues, modulatory proteins and neural pathways are discussed. RECENT FINDINGS: Downstream events involved in secretagogue stimulation of pancreatic secretion have been elucidated through characterization of the Src kinase pathway. An additional mechanism regulating vagus nerve effects on the pancreas involves Group II and III metabotropic glutamate receptors that are located presynaptically on certain vagal pancreas-projecting neurons. Hypothalamic neurons perceive glucose and regulate insulin release by direct communication with islets, and activation of proopiomelanocortin neurons by leptin enhances insulin secretion and modulates glucose but not energy homeostasis. Ghrelin and somatostatin mediate glucose-stimulated insulin secretion by differential receptor signaling that is dependent on the amount of ghrelin and state of receptor heterodimerization. Endoplasmic reticulum (ER) stress and loss-of-function mutations of a key ER stress protein are associated with disruption of membrane translocation and reduction in insulin secretion. The importance of hormones, neuropeptides, amino acids, cytokines and regulatory proteins in pancreatic secretion and the pathophysiology of type 2 diabetes are also discussed. SUMMARY: The biomolecular pathways regulating pancreatic secretions are still not fully understood. New secretagogues and mechanisms continue to be identified and this information will aid in drug discovery and development of new and improved therapy for pancreatic disorders.

Authors
Chandra, R; Liddle, RA
MLA Citation
Chandra, R, and Liddle, RA. "Modulation of pancreatic exocrine and endocrine secretion." Curr Opin Gastroenterol 29.5 (September 2013): 517-522. (Review)
PMID
23817137
Source
pubmed
Published In
Current Opinion in Gastroenterology
Volume
29
Issue
5
Publish Date
2013
Start Page
517
End Page
522
DOI
10.1097/MOG.0b013e3283639326

Immunoglobulin-like domain containing receptor 1 mediates fat-stimulated cholecystokinin secretion.

Cholecystokinin (CCK) is a satiety hormone produced by discrete enteroendocrine cells scattered among absorptive cells of the small intestine. CCK is released into blood following a meal; however, the mechanisms inducing hormone secretion are largely unknown. Ingested fat is the major stimulant of CCK secretion. We recently identified a novel member of the lipoprotein remnant receptor family known as immunoglobulin-like domain containing receptor 1 (ILDR1) in intestinal CCK cells and postulated that this receptor conveyed the signal for fat-stimulated CCK secretion. In the intestine, ILDR1 is expressed exclusively in CCK cells. Orogastric administration of fatty acids elevated blood levels of CCK in wild-type mice but not Ildr1-deficient mice, although the CCK secretory response to trypsin inhibitor was retained. The uptake of fluorescently labeled lipoproteins in ILDR1-transfected CHO cells and release of CCK from isolated intestinal cells required a unique combination of fatty acid plus HDL. CCK secretion secondary to ILDR1 activation was associated with increased [Ca2+]i, consistent with regulated hormone release. These findings demonstrate that ILDR1 regulates CCK release through a mechanism dependent on fatty acids and lipoproteins and that absorbed fatty acids regulate gastrointestinal hormone secretion.

Authors
Chandra, R; Wang, Y; Shahid, RA; Vigna, SR; Freedman, NJ; Liddle, RA
MLA Citation
Chandra, R, Wang, Y, Shahid, RA, Vigna, SR, Freedman, NJ, and Liddle, RA. "Immunoglobulin-like domain containing receptor 1 mediates fat-stimulated cholecystokinin secretion." J Clin Invest 123.8 (August 2013): 3343-3352.
PMID
23863714
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
123
Issue
8
Publish Date
2013
Start Page
3343
End Page
3352
DOI
10.1172/JCI68587

CD36-dependent signaling mediates fatty acid-induced gut release of secretin and cholecystokinin

Authors
Sundaresan, S; Shahid, R; Riehl, TE; Chandra, R; Nassir, F; Stenson, WF; Liddle, RA; Abumrad, NA
MLA Citation
Sundaresan, S, Shahid, R, Riehl, TE, Chandra, R, Nassir, F, Stenson, WF, Liddle, RA, and Abumrad, NA. "CD36-dependent signaling mediates fatty acid-induced gut release of secretin and cholecystokinin." FASEB JOURNAL 27.3 (March 2013): 1191-1202.
PMID
23233532
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
27
Issue
3
Publish Date
2013
Start Page
1191
End Page
1202
DOI
10.1096/fj.12-217703

Modulation of pancreatic exocrine and endocrine secretion

PURPOSE OF REVIEW: Recent advances in the regulation of pancreatic secretion by secretagogues, modulatory proteins and neural pathways are discussed. RECENT FINDINGS: Downstream events involved in secretagogue stimulation of pancreatic secretion have been elucidated through characterization of the Src kinase pathway. An additional mechanism regulating vagus nerve effects on the pancreas involves Group II and III metabotropic glutamate receptors that are located presynaptically on certain vagal pancreas-projecting neurons. Hypothalamic neurons perceive glucose and regulate insulin release by direct communication with islets, and activation of proopiomelanocortin neurons by leptin enhances insulin secretion and modulates glucose but not energy homeostasis. Ghrelin and somatostatin mediate glucose-stimulated insulin secretion by differential receptor signaling that is dependent on the amount of ghrelin and state of receptor heterodimerization. Endoplasmic reticulum (ER) stress and loss-of-function mutations of a key ER stress protein are associated with disruption of membrane translocation and reduction in insulin secretion. The importance of hormones, neuropeptides, amino acids, cytokines and regulatory proteins in pancreatic secretion and the pathophysiology of type 2 diabetes are also discussed. SUMMARY: The biomolecular pathways regulating pancreatic secretions are still not fully understood. New secretagogues and mechanisms continue to be identified and this information will aid in drug discovery and development of new and improved therapy for pancreatic disorders. Copyright © 2013 Lippincott Williams & Wilkins.

Authors
Chandra, R; Liddle, RA
MLA Citation
Chandra, R, and Liddle, RA. "Modulation of pancreatic exocrine and endocrine secretion." Current Opinion in Gastroenterology 29.5 (2013): 517-522.
Source
scival
Published In
Current Opinion in Gastroenterology
Volume
29
Issue
5
Publish Date
2013
Start Page
517
End Page
522
DOI
10.1097/MOG.0b013e3283639326

Pilot study of aprepitant for prevention of post-ERCP pancreatitis in high risk patients: a phase II randomized, double-blind placebo controlled trial.

CONTEXT: Animal studies have demonstrated a role for substance P binding to neurokinin-1 receptor in the pathogenesis of acute pancreatitis. OBJECTIVE: Our aim was to assess the efficacy of a neurokinin-1 receptor antagonist (aprepitant) at preventing post-ERCP pancreatitis in high risk patients. DESIGN: Randomized, double-blind, placebo controlled trial at a single academic medical center. INTERVENTION: Patients at high risk for post-ERCP pancreatitis received either placebo or oral aprepitant administered 4 hours prior to ERCP, 80 mg 24 hours after the first dose, and then 80 mg 24 hours after the second dose. PATIENTS: Thirty-four patients received aprepitant and 39 patients received placebo. STATISTICS: Fisher's exact test was used to compare incidence of post-ERCP pancreatitis in the two groups. RESULTS: Baseline characteristics were similar between the two groups. Incidence of acute pancreatitis was 7 in the aprepitant group and 7 in the placebo group. Hospitalization within 7 days post-procedure for abdominal pain that did not meet criteria for acute pancreatitis occurred in 6 and 9 patients in the aprepitant and placebo groups respectively (P=0.772). CONCLUSIONS: Aprepitant did not lower incidence of post-ERCP pancreatitis in this preliminary human study. Larger studies potentially using the recently available intravenous formulation are necessary to conclusively clarify the efficacy of aprepitant in this setting.  

Authors
Shah, TU; Liddle, R; Branch, MS; Jowell, P; Obando, J; Poleski, M
MLA Citation
Shah, TU, Liddle, R, Branch, MS, Jowell, P, Obando, J, and Poleski, M. "Pilot study of aprepitant for prevention of post-ERCP pancreatitis in high risk patients: a phase II randomized, double-blind placebo controlled trial. (Published online)" JOP 13.5 (September 10, 2012): 514-518.
PMID
22964958
Source
pubmed
Published In
JOP : Journal of the pancreas
Volume
13
Issue
5
Publish Date
2012
Start Page
514
End Page
518

Neurohormonal regulation of pancreatic secretion.

PURPOSE OF REVIEW: Recent advances in the regulation of pancreatic secretion by neural and hormonal mechanisms are discussed in this review. RECENT FINDINGS: It has been shown that the multidrug-resistance protein MRP4 may play a role in the efflux of cAMP from exocrine cells and neurokinin receptors are important in substance P-mediated inhibition of ductal bicarbonate secretion. Leptin attenuates glucagon secretion by downregulating glucagon gene expression, whereas ghrelin upregulates glucagon release by elevating intracellular calcium and phosphorylation of extracellular signal-regulated kinase (ERK). Cytokine interleukin 6 is secreted from muscles during exercise and induces the release of GLP-1 that stimulates insulin secretion. Osteocalcin and 17β-estradiol mediate their effects through G protein-coupled receptors, resulting in ERK phosphorylation and activation of protein kinase-dependent signaling pathways. Melatonin and ghrelin inhibit insulin secretion through inhibitory G proteins, whereas aldosterone may attenuate insulin secretion by increasing oxidative stress in islets cells. Finally, the pattern of innervation of human pancreatic islets has been examined and demonstrated to be very different from that in the mouse. SUMMARY: Many different receptors and signaling pathways govern the complex biology of pancreatic secretion. Elucidation of these cellular mechanisms will aid in drug discovery and treatment as well as prevention of pancreatic diseases.

Authors
Chandra, R; Liddle, RA
MLA Citation
Chandra, R, and Liddle, RA. "Neurohormonal regulation of pancreatic secretion." Curr Opin Gastroenterol 28.5 (September 2012): 483-487. (Review)
PMID
22782019
Source
pubmed
Published In
Current Opinion in Gastroenterology
Volume
28
Issue
5
Publish Date
2012
Start Page
483
End Page
487
DOI
10.1097/MOG.0b013e3283567f16

Pancreatic secretory trypsin inhibitor I reduces the severity of chronic pancreatitis in mice overexpressing interleukin-1β in the pancreas.

IL-1β is believed to play a pathogenic role in the development of pancreatitis. Expression of human IL-1β in pancreatic acinar cells produces chronic pancreatitis, characterized by extensive intrapancreatic inflammation, atrophy, and fibrosis. To determine if activation of trypsinogen is important in the pathogenesis of chronic pancreatitis in this model, we crossed IL-1β transgenic [Tg(IL1β)] mice with mice expressing a trypsin inhibitor that is normally produced in rat pancreatic acinar cells [pancreatic secretory trypsin inhibitor (PTSI) I]. We previously demonstrated that transgenic expression of PSTI-I [Tg(Psti1)] increased pancreatic trypsin inhibitor activity by 190%. Tg(IL1β) mice were found to have marked pancreatic inflammation, characterized by histological changes, including acinar cell loss, inflammatory cell infiltration, and fibrosis, as well as elevated myeloperoxidase activity and elevated pancreatic trypsin activity, as early as 6 wk of age. In contrast to Tg(IL1β) mice, pancreatitis was significantly less severe in dual-transgenic [Tg(IL1β)-Tg(Psti1)] mice expressing IL-1β and PSTI-I in pancreatic acinar cells. These findings indicate that overexpression of PSTI-I reduces the severity of pancreatitis and that pancreatic trypsin activity contributes to the pathogenesis of an inflammatory model of chronic pancreatitis.

Authors
Romac, JM-J; Shahid, RA; Choi, SS; Karaca, GF; Westphalen, CB; Wang, TC; Liddle, RA
MLA Citation
Romac, JM-J, Shahid, RA, Choi, SS, Karaca, GF, Westphalen, CB, Wang, TC, and Liddle, RA. "Pancreatic secretory trypsin inhibitor I reduces the severity of chronic pancreatitis in mice overexpressing interleukin-1β in the pancreas." Am J Physiol Gastrointest Liver Physiol 302.5 (March 1, 2012): G535-G541.
PMID
22173919
Source
pubmed
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
302
Issue
5
Publish Date
2012
Start Page
G535
End Page
G541
DOI
10.1152/ajpgi.00287.2011

2012 American pancreatic association presidential address: Fostering translation

Authors
Liddle, RA
MLA Citation
Liddle, RA. "2012 American pancreatic association presidential address: Fostering translation." Pancreas 41.8 (2012): 1165-1166.
PMID
23086240
Source
scival
Published In
Pancreas
Volume
41
Issue
8
Publish Date
2012
Start Page
1165
End Page
1166
DOI
10.1097/MPA.0b013e31826b49ce

Factors associated with survival of veterans with gastrointestinal neuroendocrine tumors.

Background. Gastrointestinal (GI) neuroendocrine tumor (NET) incidence has been increasing; however, GI NET within the national Veterans Affairs (VA) health system has not been described. Methods. We used the VA Central Cancer Registry to identify the cohort of patients diagnosed with GI NET in 1995-2009. Cox regression models were constructed to explore factors associated with survival. Results. We included 1793 patients with NET of the stomach (9%), duodenum (10%), small intestine (24%), colon (19%) or rectum (38%). Twenty percent were diagnosed in 1995-1999, 35% in 2000-2004, and 45% in 2005-2009. Unadjusted 5-year survival rates were: stomach 56%, duodenum 66%, small intestine 52%, colon 67%, and rectum 84%. Factors associated with shorter survival were increasing age, hazard ratio (HR) 1.05 (95% CI 1.04-1.06), NET location [compared to rectum: stomach HR 2.26 (95% CI 1.68-3.05), duodenum HR 1.70 (95% CI 1.26-2.28), small intestine HR 1.85 (95% CI 1.42-2.42), and colon 1.83 (95% CI 1.41-2.39)], stage [compared to in situ/local: regional HR 1.15 (95% CI 0.90-1.47), distant HR 2.38 (95% CI 1.87-3.05)], and earlier period of diagnosis [compared to 1995-1999: 2000-2004 HR 0.70 (95% CI 0.59-0.85), 2005-2009 HR 0.43 (95% CI 0.34-0.54)]. Conclusions. The incidence of GI NET has also increased over time in the VA system with similar survival rates to those observed in non-VA settings. Worsened survival was associated with older age, tumor site, advanced stage, and earlier year of diagnosis.

Authors
Balmadrid, BL; Thomas, CM; Coffman, CJ; Liddle, RA; Fisher, DA
MLA Citation
Balmadrid, BL, Thomas, CM, Coffman, CJ, Liddle, RA, and Fisher, DA. "Factors associated with survival of veterans with gastrointestinal neuroendocrine tumors." J Cancer Epidemiol 2012 (2012): 986708-.
PMID
22693504
Source
pubmed
Published In
Journal of Cancer Epidemiology
Volume
2012
Publish Date
2012
Start Page
986708
DOI
10.1155/2012/986708

The challenging task of treating painful chronic pancreatitis

Authors
Forsmark, CE; Liddle, RA
MLA Citation
Forsmark, CE, and Liddle, RA. "The challenging task of treating painful chronic pancreatitis." Gastroenterology 143.3 (2012): 533-535.
PMID
22841737
Source
scival
Published In
Gastroenterology
Volume
143
Issue
3
Publish Date
2012
Start Page
533
End Page
535
DOI
10.1053/j.gastro.2012.07.029

Regulation of Pancreatic Secretion

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Regulation of Pancreatic Secretion." Physiology of the Gastrointestinal Tract 2 (2012): 1425-1460.
Source
scival
Published In
Physiology of the Gastrointestinal Tract
Volume
2
Publish Date
2012
Start Page
1425
End Page
1460
DOI
10.1016/B978-0-12-382026-6.00052-X

Axon-like basal processes in enteroendocrine cells: characteristics and potential targets.

Enteroendocrine cells (EECs) play a key role in nutrient digestion and absorption, and are essential for normal life. Recently, EEC function has received considerable attention because several gastrointestinal hormones modulate insulin secretion and food intake; and, gut hormone-based therapies have been developed to treat diabetes mellitus. Despite these advances, the regulation of EECs remains poorly understood. The development of transgenic mouse models that express green fluorescent proteins (GFP) under specific hormone promoters (e.g., peptide YY-GFP) is shedding light onto previously overlooked features of EECs. These cells have prominent cytoplasmic processes that extend underneath enterocytes, and in some EECs, such as the L cell of the distal ileum, the basal process can be over 50 μm long. These basal cytoplasmic processes resemble axons and end in synaptic-like bouton. The location and anatomy of these processes suggest two functions: (1) to monitor absorbed nutrients at the base of enterocytes; and (2) to convey electrochemical information through cell-cell connections with subepithelial myofibroblasts and/or nerves located directly beneath in the lamina propria. Understanding how EECs communicate with cells in the lamina propria may provide novel ways to treat metabolic disorders such as obesity and diabetes.

Authors
Bohórquez, DV; Liddle, RA
MLA Citation
Bohórquez, DV, and Liddle, RA. "Axon-like basal processes in enteroendocrine cells: characteristics and potential targets." Clin Transl Sci 4.5 (October 2011): 387-391. (Review)
PMID
22029814
Source
pubmed
Published In
Clinical and Translational Science
Volume
4
Issue
5
Publish Date
2011
Start Page
387
End Page
391
DOI
10.1111/j.1752-8062.2011.00299.x

Recent advances in pancreatic endocrine and exocrine secretion.

PURPOSE OF REVIEW: This review presents recent advancements in the mechanisms by which integrated signaling mechanisms elicit and regulate pancreatic endocrine and exocrine secretion. RECENT FINDINGS: Cholecystokinin (CCK) can stimulate exocrine secretion by acting directly on neurons located in the dorsal motor of the vagus or indirectly by acting on pancreatic stellate cells. The importance of small GTPases such as RhoA and Rac1 in CCK-induced pancreatic secretion is also described. Ghrelin attenuates insulin secretion through the AMP-activated protein kinase-uncoupling protein 2 pathway. An exciting new report describes that leptin can influence insulin release by osteoclastin, a hormone produced by osteoblasts. This finding adds a new layer of complexity in the regulation of insulin secretion with implications for glucose and energy homeostasis. In addition, leptin also mediates insulin secretion through the sympathetic system and via pro-opiomelanocortin neurons, which could serve as the cross-road for leptin and melanocortin signaling pathways. Recent reports on the action of numerous other regulators such as atrial natriuretic peptide, neurotensin, and orexin B are also discussed. SUMMARY: The pancreas is an extremely complex gland. Elucidation of the secretory and regulatory pathways that control pancreatic secretion will aid in the development of treatment for diseases such as pancreatitis, diabetes, and obesity.

Authors
Chandra, R; Liddle, RA
MLA Citation
Chandra, R, and Liddle, RA. "Recent advances in pancreatic endocrine and exocrine secretion." Curr Opin Gastroenterol 27.5 (September 2011): 439-443. (Review)
PMID
21778879
Source
pubmed
Published In
Current Opinion in Gastroenterology
Volume
27
Issue
5
Publish Date
2011
Start Page
439
End Page
443
DOI
10.1097/MOG.0b013e328349e2e1

Leukotriene B4 mediates inflammation via TRPV1 in duct obstruction-induced pancreatitis in rats.

OBJECTIVES: We tested the hypothesis that leukotriene B4 (LTB4) mediates pancreatic inflammation in rats via activation of the transient receptor potential vanilloid 1 (TRPV1). METHODS: Leukotriene B4 or a vehicle was administered to adult rats via celiac axis injection after pretreatment with the TRPV1 antagonist, capsazepine, or vehicle, and the severity of subsequent pancreatitis was assessed by measuring pancreatic edema, myeloperoxidase (MPO) activity, and histological grading. In a second experiment, acute pancreatitis was induced by common pancreaticobiliary duct ligation. Six hours after surgery, pancreatic tissue levels of LTB4 were determined by enzyme-linked immunosorbent assay. Also, the effects of inhibition of LTB4 biosynthesis by pretreatment with the 5-lipoxygenase-activating peptide inhibitor, MK-886, were determined. RESULTS: Celiac axis administration of LTB4 significantly increased pancreatic edema and MPO activity, and produced histological evidence of pancreatic edema, neutrophil infiltration, and necrosis. Capsazepine pretreatment significantly reduced all inflammatory parameters in LTB4-induced pancreatitis. Pancreatic tissue levels of LTB4 were significantly elevated in rats that underwent common pancreaticobiliary duct ligation compared with control rats. MK-886 pretreatment significantly inhibited pancreatic edema, histological damage, and pancreatic MPO concentrations. CONCLUSIONS: Common pancreaticobiliary duct obstruction causes an increase in pancreatic LTB4 concentrations that in turn mediates activation of TRPV1 resulting in acute pancreatitis.

Authors
Vigna, SR; Shahid, RA; Nathan, JD; McVey, DC; Liddle, RA
MLA Citation
Vigna, SR, Shahid, RA, Nathan, JD, McVey, DC, and Liddle, RA. "Leukotriene B4 mediates inflammation via TRPV1 in duct obstruction-induced pancreatitis in rats." Pancreas 40.5 (July 2011): 708-714.
PMID
21602738
Source
pubmed
Published In
Pancreas
Volume
40
Issue
5
Publish Date
2011
Start Page
708
End Page
714
DOI
10.1097/MPA.0b013e318214c8df

Amino acids stimulate cholecystokinin release through the Ca2+-sensing receptor.

Cholecystokinin (CCK) is produced by discrete endocrine cells in the proximal small intestine and is released following the ingestion of food. CCK is the primary hormone responsible for gallbladder contraction and has potent effects on pancreatic secretion, gastric emptying, and satiety. In addition to fats, digested proteins and aromatic amino acids are major stimulants of CCK release. However, the cellular mechanism by which amino acids affect CCK secretion is unknown. The Ca(2+)-sensing receptor (CaSR) that was originally identified on parathyroid cells is not only sensitive to extracellular Ca(2+) but is activated by extracellular aromatic amino acids. It has been postulated that this receptor may be involved in gastrointestinal hormone secretion. Using transgenic mice expressing a CCK promoter driven/enhanced green fluorescent protein (GFP) transgene, we have been able to identify and purify viable intestinal CCK cells. Intestinal mucosal CCK cells were enriched >200-fold by fluorescence-activated cell sorting. These cells were then used for real-time PCR identification of CaSR. Immunohistochemical staining with an antibody specific for CaSR confirmed colocalization of CaSR to CCK cells. In isolated CCK cells loaded with a Ca(2+)-sensitive dye, the amino acids phenylalanine and tryptophan, but not nonaromatic amino acids, caused an increase in intracellular Ca(2+) ([Ca(2+)](i)). The increase in [Ca(2+)](i) was blocked by the CaSR inhibitor Calhex 231. Phenylalanine and tryptophan stimulated CCK release from intestinal CCK cells, and this stimulation was also blocked by CaSR inhibition. Electrophysiological recordings from isolated CCK-GFP cells revealed these cells to possess a predominant outwardly rectifying potassium current. Administration of phenylalanine inhibited basal K(+) channel activity and caused CCK cell depolarization, consistent with changes necessary for hormone secretion. These findings indicate that amino acids have a direct effect on CCK cells to stimulate CCK release by activating CaSR and suggest that CaSR is the physiological mechanism through which amino acids regulate CCK secretion.

Authors
Wang, Y; Chandra, R; Samsa, LA; Gooch, B; Fee, BE; Cook, JM; Vigna, SR; Grant, AO; Liddle, RA
MLA Citation
Wang, Y, Chandra, R, Samsa, LA, Gooch, B, Fee, BE, Cook, JM, Vigna, SR, Grant, AO, and Liddle, RA. "Amino acids stimulate cholecystokinin release through the Ca2+-sensing receptor." Am J Physiol Gastrointest Liver Physiol 300.4 (April 2011): G528-G537.
PMID
21183662
Source
pubmed
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
300
Issue
4
Publish Date
2011
Start Page
G528
End Page
G537
DOI
10.1152/ajpgi.00387.2010

The enteroendocrine PYY cell interacts with neurites of the enteric nervous system through axon-like basal process

Authors
Bohorquez, DV; Samsa, LA; Vigna, SR; Liddle, RA
MLA Citation
Bohorquez, DV, Samsa, LA, Vigna, SR, and Liddle, RA. "The enteroendocrine PYY cell interacts with neurites of the enteric nervous system through axon-like basal process." 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

Characterization of basal pseudopod-like processes in ileal and colonic PYY cells.

The peptide tyrosine tyrosine (PYY) is produced and secreted from L cells of the gastrointestinal mucosa. To study the anatomy and function of PYY-secreting L cells, we developed a transgenic PYY-green fluorescent protein mouse model. PYY-containing cells exhibited green fluorescence under UV light and were immunoreactive to antibodies against PYY and GLP-1 (glucagon-like peptide-1, an incretin hormone also secreted by L cells). PYY-GFP cells from 15 μm thick sections were imaged using confocal laser scanning microscopy and three-dimensionally (3D) reconstructed. Results revealed unique details of the anatomical differences between ileal and colonic PYY-GFP cells. In ileal villi, the apical portion of PYY cells makes minimal contact with the lumen of the gut. Long pseudopod-like basal processes extend from these cells and form an interface between the mucosal epithelium and the lamina propria. Some basal processes are up to 50 μm in length. Multiple processes can be seen protruding from one cell and these often have a terminus resembling a synapse that appears to interact with neighboring cells. In colonic crypts, PYY-GFP cells adopt a spindle-like shape and weave in between epithelial cells, while maintaining contact with the lumen and lamina propria. In both tissues, cytoplasmic granules containing the hormones PYY and GLP-1 are confined to the base of the cell, often filling the basal process. The anatomical arrangement of these structures suggests a dual function as a dock for receptors to survey absorbed nutrients and as a launching platform for hormone secretion in a paracrine fashion.

Authors
Bohórquez, DV; Chandra, R; Samsa, LA; Vigna, SR; Liddle, RA
MLA Citation
Bohórquez, DV, Chandra, R, Samsa, LA, Vigna, SR, and Liddle, RA. "Characterization of basal pseudopod-like processes in ileal and colonic PYY cells." J Mol Histol 42.1 (February 2011): 3-13.
Website
http://hdl.handle.net/10161/9383
PMID
21061049
Source
pubmed
Published In
Journal of Molecular Histology
Volume
42
Issue
1
Publish Date
2011
Start Page
3
End Page
13
DOI
10.1007/s10735-010-9302-6

Pseudopod-like basal cell processes in intestinal cholecystokinin cells.

Cholecystokinin (CCK) is secreted by neuroendocrine cells comprising 0.1%-0.5% of the mucosal cells in the upper small intestine. Using CCK promoter-driven green fluorescent protein (GFP) expression in transgenic mice, we have applied immunofluorescence techniques to analyze the morphology of CCK cells. GFP and CCK colocalize in neuroendocrine cells with little aberrant GFP expression. CCK-containing cells are either flask- or spindle-shaped, and in some cells, we have found dendritic processes similar to pseudopods demonstrated for gut somatostatin-containing D cells. Most pseudopods are short, the longest process visualized extending across three cells. Pseudopods usually extend to adjacent cells but some weave between neighboring cells. Dual processes have also been observed. Three-dimensional reconstructions suggest that processes are not unidirectional and thus are unlikely to be involved in migration of CCK cells from the crypt up the villus. Abundant CCK immunostaining is present in the pseudopods, suggesting that they release CCK onto the target cell. In order to identify the type of cells being targeted, we have co-stained sections with antibodies to chromogranin A, trefoil factor-3, and sucrase-isomaltase. CCK cell processes almost exclusively extend to sucrase-isomaltase-positive enterocytes. Thus, CCK cells have cellular processes possibly involved in paracrine secretion.

Authors
Chandra, R; Samsa, LA; Vigna, SR; Liddle, RA
MLA Citation
Chandra, R, Samsa, LA, Vigna, SR, and Liddle, RA. "Pseudopod-like basal cell processes in intestinal cholecystokinin cells." Cell Tissue Res 341.2 (August 2010): 289-297.
PMID
20582553
Source
pubmed
Published In
Cell and Tissue Research
Volume
341
Issue
2
Publish Date
2010
Start Page
289
End Page
297
DOI
10.1007/s00441-010-0997-1

Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype.

Endogenous trypsin inhibitors are synthesized, stored, and secreted by pancreatic acinar cells. It is believed that they play a protective role in the pancreas by inhibiting trypsin within the cell should trypsinogen become prematurely activated. Rodent trypsin inhibitors are highly homologous to human serine protease inhibitor Kazal-type 1 (SPINK1). The mouse has one pancreatic trypsin inhibitor known as SPINK3, and the rat has two trypsin inhibitors commonly known as pancreatic secretory trypsin inhibitors I and II (PSTI-I and -II). Rat PSTI-I is a 61-amino acid protein that shares 65% sequence identity with mouse SPINK3. It was recently demonstrated that mice with genetic deletion of the Spink3 gene (Spink3(-/-)) do not survive beyond 15 days and lack normal pancreata because of pancreatic autophagy. We have shown that targeted transgenic expression of the rat Psti1 gene to acinar cells in mice [TgN(Psti1)] protects mice against caerulein-induced pancreatitis. To determine whether the autophagic phenotype and lethality in Spink3(-/-) mice were due to lack of pancreatic trypsin inhibitor, we conducted breeding studies with Spink3(+/-) heterozygous mice and TgN(Psti1) mice. We observed that, whereas Spink3(+/+), Spink3(+/-), and Spink3(-/-)/TgN(Psti1) mice had similar survival rates, no Spink3(-/-) mice survived longer than 1 wk. The level of expression of SPINK3 protein in acini was reduced in heterozygote mice compared with wild-type mice. Furthermore, endogenous trypsin inhibitor capacity was reduced in the pancreas of heterozygote mice compared with wild-type or knockout mice rescued with the rat Psti1 gene. Surprisingly, the lesser amount of SPINK3 present in the pancreata of heterozygote mice did not predispose animals to increased susceptibility to caerulein-induced acute pancreatitis. We propose that a threshold level of expression is sufficient to protect against pancreatitis.

Authors
Romac, JM-J; Ohmuraya, M; Bittner, C; Majeed, MF; Vigna, SR; Que, J; Fee, BE; Wartmann, T; Yamamura, K-I; Liddle, RA
MLA Citation
Romac, JM-J, Ohmuraya, M, Bittner, C, Majeed, MF, Vigna, SR, Que, J, Fee, BE, Wartmann, T, Yamamura, K-I, and Liddle, RA. "Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype." Am J Physiol Gastrointest Liver Physiol 298.4 (April 2010): G518-G524.
PMID
20110462
Source
pubmed
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
298
Issue
4
Publish Date
2010
Start Page
G518
End Page
G524
DOI
10.1152/ajpgi.00431.2009

Protection against chronic pancreatitis and pancreatic fibrosis in mice overexpressing pancreatic secretory trypsin inhibitor.

OBJECTIVES: Mutations in the gene encoding for pancreatic secretory trypsin inhibitor (PSTI) can contribute to chronic pancreatitis. In the current study, we tested whether overexpression of PSTI-I in mice protects against chronic pancreatitis and pancreatic fibrosis. METHODS: Rat PSTI-I expression was targeted to pancreatic acinar cells in transgenic mice. Chronic pancreatitis was achieved by intraperitoneal injection of cerulein for 10 weeks. Pancreatitis severity was assessed by histological grading of inflammatory infiltrate, atrophy, and fibrosis; quantitation of myeloperoxidase (MPO) activity; quantitative morphometric analysis of collagen content; and measurements of type I collagen, fibronectin, and transforming growth factor beta mRNA expression. RESULTS: Cerulein administration to nontransgenic mice produced histological evidence of inflammatory infiltrate, glandular atrophy, and parenchymal fibrosis and increased collagen production, MPO activity, and collagen I and fibronectin mRNA levels. In cerulein-treated PSTI transgenic mice, there were significant reductions in inflammatory infiltrate, MPO activity, fibrosis, and collagen I and fibronectin mRNA levels. Transgenic mice treated with cerulein had significantly less collagen than nontransgenic mice. CONCLUSIONS: The severity of chronic pancreatitis and pancreatic fibrosis is significantly reduced in mice expressing rat PSTI-I. We propose that pancreatic trypsin inhibitors play a protective role in the pancreatic response to repeated injurious events.

Authors
Nathan, JD; Romac, J; Peng, RY; Peyton, M; Rockey, DC; Liddle, RA
MLA Citation
Nathan, JD, Romac, J, Peng, RY, Peyton, M, Rockey, DC, and Liddle, RA. "Protection against chronic pancreatitis and pancreatic fibrosis in mice overexpressing pancreatic secretory trypsin inhibitor." Pancreas 39.1 (January 2010): e24-e30.
PMID
19904222
Source
pubmed
Published In
Pancreas
Volume
39
Issue
1
Publish Date
2010
Start Page
e24
End Page
e30
DOI
10.1097/MPA.0b013e3181bc45e9

Pancreatitis: The acid test

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Pancreatitis: The acid test." Gastroenterology 139.5 (2010): 1457-1460.
PMID
20875788
Source
scival
Published In
Gastroenterology
Volume
139
Issue
5
Publish Date
2010
Start Page
1457
End Page
1460
DOI
10.1053/j.gastro.2010.09.021

A Tribute to Gary M. Green (1940-2008) IN MEMORIAM

Authors
Jr, RJR; Liddle, RA
MLA Citation
Jr, RJR, and Liddle, RA. "A Tribute to Gary M. Green (1940-2008) IN MEMORIAM." PANCREAS 38.7 (October 2009): 719-720.
Source
wos-lite
Published In
Pancreas
Volume
38
Issue
7
Publish Date
2009
Start Page
719
End Page
720
DOI
10.1097/MPA.0b013e3181b13795

Neural and hormonal regulation of pancreatic secretion.

PURPOSE OF REVIEW: The biology of the pancreas is exquisitely complex and involves both endocrine and exocrine functions that are regulated by an integrated array of neural and hormonal processes. This review discusses recent developments in the regulation of both endocrine and exocrine secretion from the pancreas. RECENT FINDINGS: New data suggest that cholecystokinin can stimulate neurons located in the dorsal motor nucleus of the vagus. Addressing a controversial topic, recent evidence suggests a direct secretory action of cholecystokinin on human acinar cells. An emerging concept is that some hormones and peptides such as melatonin, ghrelin, obestatin and leptin perform dual functions in the pancreas by regulating secretion and maintaining metabolic homeostasis. The regulation of pancreatic secretion by several appetite-controlling neuropeptides such as ghrelin, orexin A and neuropeptide Y is also discussed. Recent data highlight findings that mechanisms of hormone action may be different between species possibly due to a divergence in signaling pathways during evolution. SUMMARY: The regulation of the secretory function of the pancreas by numerous hormones suggests that there are multiple and perhaps redundant signals governing the control of this important organ. Understanding these diverse pathways is essential to the treatment of pancreatitis, diabetes and obesity.

Authors
Chandra, R; Liddle, RA
MLA Citation
Chandra, R, and Liddle, RA. "Neural and hormonal regulation of pancreatic secretion." Curr Opin Gastroenterol 25.5 (September 2009): 441-446. (Review)
PMID
19535978
Source
pubmed
Published In
Current Opinion in Gastroenterology
Volume
25
Issue
5
Publish Date
2009
Start Page
441
End Page
446
DOI
10.1097/MOG.0b013e32832e9c41

A pH-sensitive, neurogenic pathway mediates disease severity in a model of post-ERCP pancreatitis.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) has a high risk of pancreatitis although the underlying mechanisms are unclear. Transient receptor potential vanilloid 1 (TRPV1) is a cation channel expressed on C and Adelta fibres of primary sensory neurons and is activated by low pH. TRPV1 activation causes release of inflammatory mediators that produce oedema and neutrophil infiltration. We previously demonstrated that neurogenic factors contribute to the pathogenesis of pancreatitis. Resiniferatoxin (RTX) is a TRPV1 agonist that, in high doses, defunctionalises C and Adelta fibres. When we discovered that the pH of radio-opaque contrast solutions used for ERCP was 6.9, we hypothesised that low pH may contribute to the development of contrast-induced pancreatitis via activation of TRPV1. METHODS: Rats underwent equal pressure pancreatic ductal injection of contrast solutions at varying pH with or without RTX. RESULTS: Contrast solution (pH 6.9) injected into the pancreatic duct caused a significant increase in pancreatic oedema, serum amylase, neutrophil infiltration, and histological damage. Solutions of pH 7.3 injected at equal pressure caused little damage. The severity of the pancreatitis was significantly increased by injection of solutions at pH 6.0. To determine if the effects of low pH were mediated by TRPV1, RTX was added to the contrast solutions. At pH levels of 6.0 and 6.9, RTX significantly reduced the severity of pancreatitis. CONCLUSIONS: Contrast solutions with low pH contribute to the development of pancreatitis through a TRPV1-dependent mechanism. It is possible that increasing the pH of contrast solution and/or adding an agent that inhibits primary sensory nerve activation may reduce the risk of post-ERCP pancreatitis.

Authors
Noble, MD; Romac, J; Vigna, SR; Liddle, RA
MLA Citation
Noble, MD, Romac, J, Vigna, SR, and Liddle, RA. "A pH-sensitive, neurogenic pathway mediates disease severity in a model of post-ERCP pancreatitis." Gut 57.11 (November 2008): 1566-1571.
PMID
18625695
Source
pubmed
Published In
Gut
Volume
57
Issue
11
Publish Date
2008
Start Page
1566
End Page
1571
DOI
10.1136/gut.2008.148551

Pharmacologic disruption of TRPV1-expressing primary sensory neurons but not genetic deletion of TRPV1 protects mice against pancreatitis.

OBJECTIVES: Transient receptor potential subtype vanilloid 1 (TRPV1) is an ion channel that is primarily expressed by primary sensory neurons where it mediates pain and heat sensation and participates in neurogenic inflammation. In this study, we examined the role of TRPV1 during neurogenic activation of pancreatic inflammation using a secretagogue-induced model in mice. METHODS: A supramaximal dose of caerulein (50 microg/kg) was injected hourly for 12 hours. Mice lacking TRPV1 were compared to wild-type animals. RESULTS: All the parameters: serum amylase, pancreatic myeloperoxidase activity, histological scoring, pancreatic wet weight/body weight ratio, and quantification of neurokinin-1 receptor internalization indicated that null mice were not protected from acute pancreatitis. However, when primary sensory neurons were ablated by injection of the neurotoxin and TRPV1 agonist, resiniferatoxin, pancreatitis was ameliorated in wild-type mice but not in null mice, indicating that nerves bearing TRPV1 are part of the inflammatory pathway in acute pancreatitis because disappearance significantly reduced the inflammatory response. CONCLUSIONS: Nerves expressing TRPV1 participate in the neurogenic inflammation during acute pancreatitis. The lack of protection in TRPV1 null mice suggests that an alternate pathway to TRPV1 coexists in the same neurons.

Authors
Romac, JMJ; McCall, SJ; Humphrey, JE; Heo, J; Liddle, RA
MLA Citation
Romac, JMJ, McCall, SJ, Humphrey, JE, Heo, J, and Liddle, RA. "Pharmacologic disruption of TRPV1-expressing primary sensory neurons but not genetic deletion of TRPV1 protects mice against pancreatitis." Pancreas 36.4 (May 2008): 394-401.
PMID
18437086
Source
pubmed
Published In
Pancreas
Volume
36
Issue
4
Publish Date
2008
Start Page
394
End Page
401
DOI
10.1097/MPA.0b013e318160222a

Clinical features and physiological response to a test meal in purging disorder and bulimia nervosa.

CONTEXT: Recent data suggest that purging disorder, a recently characterized form of eating disorder not otherwise specified, may be worthy of specific delineation in nosological schemes. However, more data are needed to determine how purging disorder differs from bulimia nervosa. OBJECTIVE: To examine clinical features and subjective as well as objective physiological responses to a standardized test meal in purging disorder compared with bulimia nervosa and controls. DESIGN: Study visit 1 included psychological assessments with structured clinical interviews and questionnaires. Study visit 2 included assessment of test-meal responses. SETTING: Participants recruited from the community completed test-meal studies in a General Clinical Research Center. PARTICIPANTS: Women with DSM-IV bulimia nervosa-purging subtype (n = 37) and purging disorder (n = 20) and non-eating disorder controls (n = 33) with a body mass index (calculated as weight in kilograms divided by height in meters squared) between 18.5 and 26.5 who were free of psychotropic medications. MAIN OUTCOME MEASURES: Assessments of eating disorder severity, postprandial cholecystokinin response, and subjective responses to test meals. RESULTS: Eating abnormalities were significantly elevated in participants with purging disorder and bulimia nervosa compared with controls but did not differ between eating disorder groups. Participants with purging disorder demonstrated significantly greater postprandial cholecystokinin release compared with participants with bulimia nervosa (t(76.44) = 2.51; P = .01) and did not differ significantly from controls (t(75.93) = 0.03; P = .98). Participants with purging disorder reported significantly greater postprandial fullness and gastrointestinal distress compared with participants with bulimia nervosa and controls. CONCLUSIONS: Purging disorder is a clinically significant disorder of eating that appears to be distinct from bulimia nervosa on subjective and physiological responses to a test meal. Findings support further consideration of purging disorder for inclusion in the classification of eating disorders. Future studies on the psychobiology of purging disorder are needed to understand the propensity to purge in the absence of binge eating.

Authors
Keel, PK; Wolfe, BE; Liddle, RA; De Young, KP; Jimerson, DC
MLA Citation
Keel, PK, Wolfe, BE, Liddle, RA, De Young, KP, and Jimerson, DC. "Clinical features and physiological response to a test meal in purging disorder and bulimia nervosa." Arch Gen Psychiatry 64.9 (September 2007): 1058-1066.
PMID
17768271
Source
pubmed
Published In
Archives of General Psychiatry
Volume
64
Issue
9
Publish Date
2007
Start Page
1058
End Page
1066
DOI
10.1001/archpsyc.64.9.1058

The role of Transient Receptor Potential Vanilloid 1 (TRPV1) channels in pancreatitis.

Premature activation of digestive enzymes within the pancreas which leads to autodigestion of the gland is an early step in the pathogenesis of pancreatitis. Pancreatic injury is followed by other manifestations of inflammation including plasma extravasation, edema, and neutrophil infiltration which constitute the features of pancreatitis. Recent studies indicate that neural innervation of the pancreas may play an important role in the initiation and maintenance of the inflammatory response to injury. The pancreas is innervated by vagal, sympathetic and parasympathetic neurons, as well as sensory neurons. Activation of pancreatic primary sensory neurons causes the release of inflammatory neuropeptides both in the spinal cord to signal pain and in the pancreas itself where they produce plasma extravasation and neutrophil infiltration. Recent studies indicate that primary sensory neurons of the pancreas express transient receptor potential V1 (TRPV1) channels whose activation induces pancreatic inflammation. Moreover, blockade of these TRP channels significantly ameliorates experimental pancreatitis. This review describes our current understanding of the role of TRPV1 channels in pancreatitis and illustrates how this mechanism might be used to direct future treatments of pancreatic diseases.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "The role of Transient Receptor Potential Vanilloid 1 (TRPV1) channels in pancreatitis." Biochim Biophys Acta 1772.8 (August 2007): 869-878. (Review)
PMID
17428642
Source
pubmed
Published In
Biochimica et Biophysica Acta: international journal of biochemistry and biophysics
Volume
1772
Issue
8
Publish Date
2007
Start Page
869
End Page
878
DOI
10.1016/j.bbadis.2007.02.012

Cholecystokinin.

PURPOSE OF REVIEW: The hormone cholecystokinin was discovered in 1928 because of its ability to induce gallbladder contraction. Since then, cholecystokinin has been shown to possess multiple functions in the gastrointestinal tract and brain. This review discusses several significant developments in cholecystokinin biology that show how it plays a role in gastrointestinal diseases, including control of appetite. RECENT FINDINGS: Cholecystokinin was shown to induce satiety by interacting through CCK-1 receptors located in specialized regions of the hindbrain. Cholecystokinin also inhibits expression of orexigenic peptides in the hypothalamus and prevents stimulation of specialized neurons by ghrelin. In the pancreas, cholecystokinin increased the proliferation of insulin-producing beta cells and reduced insulin-induced hyperphagia. Elevated cholecystokinin levels decreased appetite and reduced intestinal inflammation caused by parasites and bacterial toxins. SUMMARY: Understanding the mechanisms by which cholecystokinin regulates orexigenic pathways in the body may lead to strategies for controlling appetite-related disorders such as obesity and bulimia. The reduction of intestinal inflammation by dietary fats (by elevating cholecystokinin) suggests that the hormone plays an integrated role in regulating the ingestion and digestion of food that may be relevant to inflammatory diseases of the gastrointestinal tract.

Authors
Chandra, R; Liddle, RA
MLA Citation
Chandra, R, and Liddle, RA. "Cholecystokinin." Curr Opin Endocrinol Diabetes Obes 14.1 (February 2007): 63-67. (Review)
PMID
17940422
Source
pubmed
Published In
Current Opinion in Endocrinology, Diabetes and Obesity
Volume
14
Issue
1
Publish Date
2007
Start Page
63
End Page
67
DOI
10.1097/MED.0b013e3280122850

Epigenetic silencing of genes in human colon cancer.

Authors
Liddle, RA; Jirtle, RL
MLA Citation
Liddle, RA, and Jirtle, RL. "Epigenetic silencing of genes in human colon cancer." Gastroenterology 131.3 (September 2006): 960-962.
PMID
16952566
Source
pubmed
Published In
Gastroenterology
Volume
131
Issue
3
Publish Date
2006
Start Page
960
End Page
962
DOI
10.1053/j.gastro.2006.07.028

Local disruption of the celiac ganglion inhibits substance P release and ameliorates caerulein-induced pancreatitis in rats.

Primary sensory neurons of the C and Adelta subtypes express the vanilloid capsaicin receptor TRPV1 and contain proinflammatory peptides such as substance P (SP) that mediate neurogenic inflammation. Pancreatic injury stimulates these neurons causing the release of SP in the pancreas resulting in pancreatic edema and neutrophil infiltration that contributes to pancreatitis. Axons of primary sensory neurons innervating the pancreas course through the celiac ganglion. We hypothesized that disruption of the celiac ganglion by surgical excision or inhibition of C and Adelta fibers through blockade of TRPV1 would reduce the severity of experimental pancreatitis by inhibiting neurogenic inflammation. Resiniferatoxin (RTX) is a specific TRPV1 agonist that, in high doses, selectively destroys C and Adelta fibers. Sprague-Dawley rats underwent surgical ganglionectomy or application of 10 microg RTX (vs. vehicle alone) to the celiac ganglion. One week later, pancreatitis was induced by six hourly intraperitoneal injections of caerulein (50 microg/kg). The severity of pancreatitis was assessed by serum amylase, pancreatic edema, and pancreatic myeloperoxidase (MPO) activity. SP receptor (neurokinin-1 receptor, NK-1R) internalization in acinar cells, used as an index of endogenous SP release, was assessed by immunocytochemical quantification of NK-1R endocytosis. Caerulein administration caused significant increases in pancreatic edema, serum amylase, MPO activity, and NK-1R internalization. RTX treatment and ganglionectomy significantly reduced pancreatic edema by 46% (P < 0.001) and NK-1R internalization by 80% and 51% (P < 0.001 and P < 0.05, respectively). RTX administration also significantly reduced MPO activity by 47% (P < 0.05). Neither treatment affected serum amylase, consistent with a direct effect of caerulein. These results demonstrate that disruption of or local application of RTX to the celiac ganglion inhibits SP release in the pancreas and reduces the severity of acute secretagogue-induced pancreatitis. It is possible that selectively disrupting TRPV1-bearing neurons could be used to reduce pancreatitis severity.

Authors
Noble, MD; Romac, J; Wang, Y; Hsu, J; Humphrey, JE; Liddle, RA
MLA Citation
Noble, MD, Romac, J, Wang, Y, Hsu, J, Humphrey, JE, and Liddle, RA. "Local disruption of the celiac ganglion inhibits substance P release and ameliorates caerulein-induced pancreatitis in rats." Am J Physiol Gastrointest Liver Physiol 291.1 (July 2006): G128-G134.
PMID
16769810
Source
pubmed
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
291
Issue
1
Publish Date
2006
Start Page
G128
End Page
G134
DOI
10.1152/ajpgi.00442.2005

Pathophysiology of SPINK mutations in pancreatic development and disease.

The endogenous pancreatic trypsin inhibitor, SPINK, is believed to limit enzyme activity in the pancreas and reduce the risk of pancreatitis. Recently, mutations in the SPINK1 gene have been associated with development of both acute and chronic pancreatitis. In most patients with SPINK1 mutations, the genetic variants do not cause the disease independently, but may act in concert with other genetic or environmental factors. Recent studies, using mice in which the trypsin inhibitor gene has been deleted or overexpressed, provide novel insights into the role of SPINK in pancreatic development and pancreatitis.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Pathophysiology of SPINK mutations in pancreatic development and disease." Endocrinol Metab Clin North Am 35.2 (June 2006): 345-x. (Review)
PMID
16632097
Source
pubmed
Published In
Endocrinology & Metabolism Clinics of North America
Volume
35
Issue
2
Publish Date
2006
Start Page
345
End Page
x
DOI
10.1016/j.ecl.2006.02.012

Sequence variation outside the "active" region of dog and rabbit cholecystokinin-58 results in bioactivity differences.

OBJECTIVES: We propose that regions outside the bioactive 7-amino acid carboxyl terminus of cholecystokinin (CCK)-58 influence its biological activity. Here we evaluate if sequence variation of the N-terminal regions of rabbit and canine CCK-58 changes their biological activities. METHODS: Cholecystokinin-like immunoreactivity was purified from rabbit intestinal extracts by reverse phase and ion-exchange high-performance liquid chromatography steps. The peptide was characterized by microsequence and mass spectral characterizations of the intact and tryptic peptides. Canine and rabbit CCK-58 were evaluated for their CCK1 and CCK2 receptor binding, receptor activation, and immunologic properties. RESULTS: The sequence of rabbit CCK-58 differs from that of canine CCK-58 in 9 of the amino terminal 40 residues. Canine CCK-58 was approximately 3-fold more potent than rabbit CCK-58 for CCK1 receptor binding and CCK2 receptor binding, but about the same potency for stimulation of amylase release from purified acinar cells. The canine peptide was 9-fold more immunoreactive than rabbit CCK-58. CONCLUSIONS: Canine and rabbit CCK-58 have different biological and immunologic properties that can only result from differences in their N-terminal sequences which influence the properties of their identical carboxyl termini. These results are the first direct demonstration that amino acids outside the C-terminus of CCK-58 influence CCK biological activity.

Authors
Reeve, JR; Liddle, RA; Shively, JE; Lee, TD; Keire, DA; Chew, P; Vigna, SR
MLA Citation
Reeve, JR, Liddle, RA, Shively, JE, Lee, TD, Keire, DA, Chew, P, and Vigna, SR. "Sequence variation outside the "active" region of dog and rabbit cholecystokinin-58 results in bioactivity differences." Pancreas 32.3 (April 2006): 306-313.
PMID
16628087
Source
pubmed
Published In
Pancreas
Volume
32
Issue
3
Publish Date
2006
Start Page
306
End Page
313
DOI
10.1097/01.mpa.0000218315.04954.77

Lack of trophic pancreatic effects in humans with long-term administration of ximelagatran.

OBJECTIVES: Negative feedback regulation of pancreatic proteases controls pancreatic secretion in most species and pancreatic growth in rodents. Its mechanism involves the inhibition of intraluminal proteases, resulting in sustained elevation of plasma cholecystokinin (CCK) concentrations, producing a chronic trophic stimulus to the pancreas that leads to the formation of pancreatic nodules and adenomas. Ximelagatran, whose active form, melagatran, inhibits both thrombin and the serine protease trypsin, is under clinical development as an oral anticoagulant. Recent data indicate species differences in the expression of CCK receptor subtypes in the pancreas. CCK1 receptors are abundant in rat pancreas but are either absent or present at very low levels in human pancreas. As part of the clinical studies, we examined whether long-term ximelagatran administration causes CCK release and exerts possible trophic effects on the pancreas in humans. METHODS: One hundred thirty patients requiring anticoagulation treatment for atrial fibrillation randomly received, in a double-blind fashion, either 36 mg oral ximelagatran twice daily or warfarin dose adjusted to an international normalized ratio of 2.0 to 3.0. Before enrollment and after 12 months of treatment, computed tomography scans of the pancreas were performed, and pancreas volumes were quantified using the summation-of-areas technique. Three months after the initiation of drug treatment, plasma CCK concentrations were measured by radioimmunoassay 120 minutes after the patients drank 240 mL of a mixed liquid meal (Ensure). RESULTS: After 3 months of treatment, plasma CCK concentrations did not differ between the ximelagatran and warfarin groups, 15 +/- 18 and 11 +/- 17 pmol/L (X +/- SD; P = 0.22), respectively. The initial average pancreas volumes were 82 +/- 31 and 88 +/- 28 mL in the ximelagatran and warfarin groups, respectively, and decreased to 70 +/- 25 and 75 +/- 28 mL, respectively, after 12 months of treatment. Although the decrease in pancreas volume with time was significant in each group (P = 0.0001), the magnitude of the volume reduction was similar in the 2 groups. CONCLUSION: In contrast to rats, in which long-term oral administration of ximelagatran stimulates pancreatic growth and adenoma formation, in humans, ximelagatran does not increase plasma CCK concentrations and has no demonstrable trophic effect on the human pancreas.

Authors
Liddle, RA; Toskes, PP; Horrow, J; Ghali, J; Dachman, A; Stong, D
MLA Citation
Liddle, RA, Toskes, PP, Horrow, J, Ghali, J, Dachman, A, and Stong, D. "Lack of trophic pancreatic effects in humans with long-term administration of ximelagatran." Pancreas 32.2 (March 2006): 205-210.
PMID
16552342
Source
pubmed
Published In
Pancreas
Volume
32
Issue
2
Publish Date
2006
Start Page
205
End Page
210
DOI
10.1097/01.mpa.0000202949.64870.87

Regulation of Pancreatic Secretion

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Regulation of Pancreatic Secretion." Physiology of the Gastrointestinal Tract 2 (2006): 1397-1435.
Source
scival
Published In
Physiology of the Gastrointestinal Tract
Volume
2
Publish Date
2006
Start Page
1397
End Page
1435
DOI
10.1016/B978-012088394-3/50058-1

Not for the faint of heart.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Not for the faint of heart." Gastroenterology 129.5 (November 2005): 1373-.
PMID
16285936
Source
pubmed
Published In
Gastroenterology
Volume
129
Issue
5
Publish Date
2005
Start Page
1373
DOI
10.1053/j.gastro.2005.09.030

Neurohormonal control of exocrine pancreatic secretion.

PURPOSE OF REVIEW: Investigations into the neural and hormonal control of pancreatic exocrine function have led to many exciting discoveries over the past year. This review seeks to identify those articles that further our understanding into the complex relation of the varying factors regulating pancreatic secretion. RECENT FINDINGS: Major findings include the new insights into the regulation of the pancreas through receptor-mediated mechanisms, investigations of pancreatic exocytosis, impairment of pancreatic exocrine function by insulin deficiency, the effects of surgical interventions for the treatment of chronic pancreatitis on pancreatic exocrine function, how exocrine function is altered by the cause of acute pancreatitis, and clinical observations relating to management of pancreatic disease and investigations of pancreatic function testing. SUMMARY: Over the past year, substantial new information has been published on the neurohormonal control of pancreatic exocrine function. These data provide insights into the physiology and pathophysiology of pancreatic secretion and diseases of exocrine insufficiency.

Authors
Noble, MD; Liddle, RA
MLA Citation
Noble, MD, and Liddle, RA. "Neurohormonal control of exocrine pancreatic secretion." Curr Opin Gastroenterol 21.5 (September 2005): 531-537. (Review)
PMID
16093766
Source
pubmed
Published In
Current Opinion in Gastroenterology
Volume
21
Issue
5
Publish Date
2005
Start Page
531
End Page
537

Transgenic expression of pancreatic secretory trypsin inhibitor-I ameliorates secretagogue-induced pancreatitis in mice.

BACKGROUND & AIMS: Endogenous trypsin inhibitors are believed to inhibit protease activity if trypsin becomes inadvertently activated within the acinar cell. However, this action remains unproven, and the role of endogenous pancreatic trypsin inhibitors in acute pancreatitis is unknown. In this study, we tested whether increased levels of pancreatic secretory trypsin inhibitor-I (PSTI-I) in mice could prevent secretagogue-induced pancreatitis. METHODS: Rat PSTI-I expression was targeted to pancreatic acinar cells in transgenic mice by creating a minigene driven by the rat elastase I enhancer/promoter. Secretagogue-induced pancreatitis was achieved by 12 hourly intraperitoneal injections of caerulein. The severity of pancreatitis was assessed by measurements of serum amylase, histologic grading, and pancreas wet weight-to-body weight ratio. Trypsinogen activation and trypsin activity were measured in pancreatic extracts. RESULTS: Targeted expression of PSTI-I to the pancreas increased endogenous trypsin inhibitor capacity by 190% (P <.01) in transgenic vs. nontransgenic mice. Caerulein administration to nontransgenic mice produced histologic evidence of acute pancreatitis, and significantly elevated serum amylase and pancreas weight ratio. In caerulein-treated transgenic mice, the histologic severity of pancreatitis was significantly reduced. There was no difference in trypsinogen activation peptide levels between caerulein-treated transgenic and nontransgenic mice. However, trypsin activity was significantly lower in transgenic mice receiving caerulein compared with nontransgenic mice. CONCLUSIONS: These data demonstrate that the severity of secretagogue-induced pancreatitis is significantly ameliorated in mice with higher pancreatic levels of trypsin inhibitor. We propose that PSTI-I prevents pancreatitis by inhibiting the activity of trypsin, rather than by reducing trypsinogen activation.

Authors
Nathan, JD; Romac, J; Peng, RY; Peyton, M; Macdonald, RJ; Liddle, RA
MLA Citation
Nathan, JD, Romac, J, Peng, RY, Peyton, M, Macdonald, RJ, and Liddle, RA. "Transgenic expression of pancreatic secretory trypsin inhibitor-I ameliorates secretagogue-induced pancreatitis in mice." Gastroenterology 128.3 (March 2005): 717-727.
PMID
15765407
Source
pubmed
Published In
Gastroenterology
Volume
128
Issue
3
Publish Date
2005
Start Page
717
End Page
727

Inhibition of Clostridium difficile toxin A-induced colitis in rats by APAZA.

A new compound, APAZA, consisting of a molecule of 5-aminosalicylic acid linked to one molecule of 4-aminophenylacetic acid by an azo bond, was testedfor its ability to inhibit acute colitis in rats caused by Clostridium difficile toxin A. When administered chronically for 5 days in drinking water, APAZA significantly inhibited toxin A-induced myeloperoxidase activity, luminal fluid accumulation, and structural damage to the colon at doses of from 1 to 100 mg/kg x day. For comparison, sulfasalazine was administered in identical doses and was found to significantly inhibit toxin A-induced colitis only at the dose of 100 mg/kg x day. When 4-aminophenylacetic acid alone was administered chronically in drinking water, it also inhibited toxin A-induced colonic inflammation at a dose of 100 mg/kg x day. In order to determine if 4-aminophenylacetic acid has a direct anti-inflammatory effect on the colon rather than a systemic effect, 4-aminophenylacetic acid was administered acutely to surgically prepared isolated colonic segments by intraluminal injection in anesthetized rats 30 min before toxin A was injected. 4-Aminophenylacetic acid strongly and significantly inhibited toxin A-induced colitis in this experiment at doses as low as 10 microg/segment. It is concluded that APAZA is a potent inhibitor of toxin A-induced colonic inflammation in rats and that its constituent, 4-aminophenylacetic acid, is responsible for this increased protection against colitis compared to the 5-aminosalicylic acid component of sulfasalazine.

Authors
McVey, DC; Liddle, RA; Riggs-Sauthier, J; Ekwuribe, N; Vigna, SR
MLA Citation
McVey, DC, Liddle, RA, Riggs-Sauthier, J, Ekwuribe, N, and Vigna, SR. "Inhibition of Clostridium difficile toxin A-induced colitis in rats by APAZA." Dig Dis Sci 50.3 (March 2005): 565-573.
PMID
15810644
Source
pubmed
Published In
Digestive Diseases and Sciences
Volume
50
Issue
3
Publish Date
2005
Start Page
565
End Page
573

Comment from the Editors

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Comment from the Editors." Gastroenterology 129.5 (2005): 1373--.
Source
scival
Published In
Gastroenterology
Volume
129
Issue
5
Publish Date
2005
Start Page
1373-
DOI
10.1053/j.gastro.2005.09.030

Susceptibility to pancreatitis related to PSTI/SPINK1 expression.

This article summarized several observations on the role of pancreatic secretory trypsin inhibitor in the pancreas. Although it long has been suspected that endogenous pancreatic trypsin inhibitors protect against inadvertent activation of trypsinogen, this hypothesis has gained strength from recent biochemical investigations and genetic studies of populations suffering from chronic pancreatitis. There is now considerable evidence from clinical disease associations and burgeoning experimental models that some forms of pancreatitis may be the result of an imbalance between active pancreatic proteases and their inhibitors within the pancreas. Future studies should clarify the precise molecular interactions between enzymes and inhibitors and how these may be manipulated to prevent or treat pancreatitis.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Susceptibility to pancreatitis related to PSTI/SPINK1 expression." Gastroenterol Clin North Am 33.4 (December 2004): 807-816. (Review)
PMID
15528019
Source
pubmed
Published In
Gastroenterology Clinics of North America
Volume
33
Issue
4
Publish Date
2004
Start Page
807
End Page
816
DOI
10.1016/j.gtc.2004.07.013

A unifying principle in training gastroenterologists.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "A unifying principle in training gastroenterologists." Gastroenterology 127.2 (August 2004): 377-.
PMID
15300566
Source
pubmed
Published In
Gastroenterology
Volume
127
Issue
2
Publish Date
2004
Start Page
377

Non-O1 Vibrio cholerae septicemia: case report, discussion of literature, and relevance to bioterrorism.

Non-O1 Vibrio cholerae (NOVC) is a rare cause of septicemia in the United States. We report a case of NOVC septicemia and discuss the literature pertaining to this organism. NOVC takes on new significance given that it can be confused with toxigenic V. cholerae, a Centers for Disease Control and Prevention category B bioterrorism agent.

Authors
Anderson, AML; Varkey, JB; Petti, CA; Liddle, RA; Frothingham, R; Woods, CW
MLA Citation
Anderson, AML, Varkey, JB, Petti, CA, Liddle, RA, Frothingham, R, and Woods, CW. "Non-O1 Vibrio cholerae septicemia: case report, discussion of literature, and relevance to bioterrorism." Diagn Microbiol Infect Dis 49.4 (August 2004): 295-297.
PMID
15313536
Source
pubmed
Published In
Diagnostic Microbiology and Infectious Disease
Volume
49
Issue
4
Publish Date
2004
Start Page
295
End Page
297
DOI
10.1016/j.diagmicrobio.2004.04.016

Identification of nonsulfated cholecystokinin-58 in canine intestinal extracts and its biological properties.

Nonsulfated CCK(58) [CCK(58)(ns)] has not been considered to be of biological importance because CCK(58)(ns) binds poorly to the CCK(A) receptor and has only been identified once in intestinal extracts. In this work, a radioimmunoassay specific for the COOH-terminal region of gastrin and CCK (antibody 5135) was used to monitor the purification of CCK molecular forms from canine intestinal extracts. A minor immunoreactive peak was associated with a major absorbance peak during an ion-exchange, HPLC step. Characterization of this minor immunoreactive peak demonstrated that it was CCK(58)(ns). CCK(58)(ns) is 14% as immunoreactive as sulfated CCK(8) [CCK(8)(s)]. Amino acid analysis demonstrated that CCK(58)(ns) was present at 50% the amount of CCK(58)(s). In addition, we found that CCK(58)(ns) does not potently displace an (125)I-labeled CCK(10) analog from the CCK(A) receptor in mouse pancreatic membranes and does not stimulate amylase release from isolated pancreatic acini, or stimulate pancreatic secretion in an anesthetized rat model. By contrast, CCK(58)(ns) does bind to CCK(B) receptors and stimulates gastric acid secretion via this receptor. The presence of CCK(58)(ns) and its ability to selectively stimulate the CCK(B) receptor without stimulation of the CCK(A) receptor suggest that CCK(58)(ns) may have unique physiological properties, especially tissues where the nonsulfated peptide can act as a paracrine or neurocrine agent.

Authors
Reeve, JR; Liddle, RA; McVey, DC; Vigna, SR; Solomon, TE; Keire, DA; Rosenquist, G; Shively, JE; Lee, TD; Chew, P; Green, GM; Coskun, T
MLA Citation
Reeve, JR, Liddle, RA, McVey, DC, Vigna, SR, Solomon, TE, Keire, DA, Rosenquist, G, Shively, JE, Lee, TD, Chew, P, Green, GM, and Coskun, T. "Identification of nonsulfated cholecystokinin-58 in canine intestinal extracts and its biological properties." Am J Physiol Gastrointest Liver Physiol 287.2 (August 2004): G326-G333.
PMID
15064233
Source
pubmed
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
287
Issue
2
Publish Date
2004
Start Page
G326
End Page
G333
DOI
10.1152/ajpgi.00520.2003

Calcineurin mediates pancreatic growth in protease inhibitor-treated mice.

CCK acts on pancreatic acinar cells to increase intracellular Ca(2+) leading to secretion of digestive enzymes and, in the long term, pancreatic growth. Calcineurin (CN) is a serine/threonine-specific protein phosphatase activated by Ca(2+) and calmodulin that recently has been shown to participate in the growth regulation of cardiac and skeletal myocytes. We therefore tested the effect of two different CN inhibitors, cyclosporine A (CsA) and FK506, on mouse pancreatic growth induced by oral administration of the synthetic protease inhibitor camostat, a known stimulator of endogenous CCK release. Mice were fed a powdered diet with or without 0.1% camostat. Pancreatic wet weight, protein, and DNA were increased in response to camostat in a time-dependent manner over 10 days in ICR mice but not in CCK-deficient mice. Both CsA (15 mg/kg) and FK506 (3 mg/kg) given twice daily blocked the increase in pancreatic wet weight and protein and DNA content induced by camostat. The increase in plasma CCK induced by camostat was not blocked by CsA or FK506. Camostat feeding also increased the relative amount of CN protein, whereas levels of MAPKs, ERKs, and p38 were not altered. In summary, 1) CCK released by chronic camostat feeding induces pancreatic growth in mice; 2) this growth is blocked by treatment with both CsA and FK506, indicating a role for CN; 3) CCK stimulation also increases CN protein. In conclusion, activation and possibly upregulation of CN may participate in regulation of pancreatic growth by CCK in mice.

Authors
Tashiro, M; Samuelson, LC; Liddle, RA; Williams, JA
MLA Citation
Tashiro, M, Samuelson, LC, Liddle, RA, and Williams, JA. "Calcineurin mediates pancreatic growth in protease inhibitor-treated mice." Am J Physiol Gastrointest Liver Physiol 286.5 (May 2004): G784-G790.
PMID
14684381
Source
pubmed
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
286
Issue
5
Publish Date
2004
Start Page
G784
End Page
G790
DOI
10.1152/ajpgi.00446.2003

Neurogenic inflammation and pancreatitis.

Stimulation of primary sensory neurons produces local vasodilation, plasma extravasation, and pain and is due largely to the release of the tachykinins substance P and calcitonin-gene-related peptide. Pathological activation of sensory neurons and the inflammatory sequelae are known as neurogenic inflammation and appear to be important in many organ systems, including the pancreas. Factors that stimulate primary sensory neurons include hydrogen ions, heat, leukotrienes, arachidonic acid metabolites, bradykinin, and proteases such as trypsin, all of which may participate in the generation of acute pancreatitis. The current review examines the cellular and molecular mechanisms involved in sensory nerve activation within the pancreas and the potential contribution of neurogenic inflammation to the pathogenesis of pancreatitis.

Authors
Liddle, RA; Nathan, JD
MLA Citation
Liddle, RA, and Nathan, JD. "Neurogenic inflammation and pancreatitis." Pancreatology 4.6 (2004): 551-559. (Review)
PMID
15550764
Source
pubmed
Published In
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]
Volume
4
Issue
6
Publish Date
2004
Start Page
551
End Page
559
DOI
10.1159/000082180

Malcolm P. Tyor, MD, (1923-2003) AGA president 1981-1982

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Malcolm P. Tyor, MD, (1923-2003) AGA president 1981-1982." GASTROENTEROLOGY 125.2 (August 2003): 288-288.
Source
wos-lite
Published In
Gastroenterology
Volume
125
Issue
2
Publish Date
2003
Start Page
288
End Page
288

Bringing new therapies to patients--what is the proper physician-industry relationship?

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Bringing new therapies to patients--what is the proper physician-industry relationship?." Gastroenterology 125.1 (July 2003): 7-.
PMID
12851864
Source
pubmed
Published In
Gastroenterology
Volume
125
Issue
1
Publish Date
2003
Start Page
7

Elevated plasma cholecystokinin and appetitive ratings after consumption of a liquid meal in humans.

OBJECTIVE: This study had two objectives. The first was to evaluate the possibility that, in a previous study, a soup preload augmented the reduction of food intake in a test meal induced by an exogenous infusion of cholecystokinin (CCK) because the soup also endogenously released CCK. The second was to compare CCK release by soup between men and women to determine whether the increased satiating effectiveness of soup in women as opposed to men could have been partly attributable to differences in CCK release. METHODS: By using a bioassay that measures all of its known isoforms, we determined plasma CCK levels at baseline and at several times postprandially in eight healthy, non-obese men and women (four of each sex). Each subject ingested 800 g of tomato soup, which was followed 30 min later by 300 g of a yogurt shake. Appetitive ratings were also collected and related to CCK levels. RESULTS: Ingestion of tomato soup significantly increased plasma CCK levels by 3.81 pmol/L (+/- 1.21 standard error, P = 0.016) over baseline within 30 min in all subjects combined. When CCK concentrations at 5 min after soup and 5 min after yogurt were averaged, the women's mean averaged concentration was 5.58 pmol/L (+/- 1.994, t = 2.80, P = 0.0073) higher than the men's. The elevated levels persisted but did not rise further upon consumption of the yogurt shake. Hunger ratings declined and fullness ratings increased after eating, although patterns of ratings did not match exactly patterns of CCK release. CONCLUSIONS: A large quantity of tomato soup stimulates significant CCK release; therefore, some of the satiating effects of soup preloads could have been mediated by an elevation in endogenous CCK.

Authors
Nolan, LJ; Guss, JL; Liddle, RA; Pi-Sunyer, FX; Kissileff, HR
MLA Citation
Nolan, LJ, Guss, JL, Liddle, RA, Pi-Sunyer, FX, and Kissileff, HR. "Elevated plasma cholecystokinin and appetitive ratings after consumption of a liquid meal in humans." Nutrition 19.6 (June 2003): 553-557.
PMID
12781859
Source
pubmed
Published In
Nutrition
Volume
19
Issue
6
Publish Date
2003
Start Page
553
End Page
557

Cholecystokinin: Its role in health and disease

Cholecystokinin is a classical gastrointestinal hormone secreted from endocrine cells of the small intestine on ingestion of a meal. It plays a major role in the coordination of many processes involved in the ingestion, digestion, and absorption of nutrients. In addition, cholecystokinin is produced by nerves of the peripheral nervous system and brain, where it functions as a neuroregulator. Since its discovery, important milestones in understanding the physiology and pathophysiology of cholecystokinin include (1) elucidation of its chemical composition and amino acid sequence, (2) development of assays for measuring blood levels of the hormone, (3) cloning of the cDNA and gene encoding cholecystokinin, (4) characterization of the cholecystokinin receptor, and (5) creation of novel cholecystokinin receptor agonists and antagonists. New molecular technologies continue to bring forward new insights into understanding of the biology of cholecystokinin. The current review places into context recent discoveries that impact understanding of the role of cholecystokinin in human health and disease. © 2003 Lippincott Williams & Wilkins, Inc.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Cholecystokinin: Its role in health and disease." Current Opinion in Endocrinology and Diabetes 10.1 (2003): 50-54.
Source
scival
Published In
Current opinion in endocrinology & diabetes
Volume
10
Issue
1
Publish Date
2003
Start Page
50
End Page
54
DOI
10.1097/00060793-200302000-00008

Primary sensory neurons: a common final pathway for inflammation in experimental pancreatitis in rats.

We hypothesized that neurogenic inflammation is a common final pathway for parenchymal inflammation in pancreatitis and evaluated the role of primary sensory neurons in secretagogue-induced and obstructive pancreatitis. Neonatal rats received either the primary sensory neuron-denervating agent capsaicin (50 mg/kg s.c.) or vehicle. At 8 wk of age, pancreatitis was produced by six hourly injections of caerulein (50 microg/kg i.p.) or by common pancreaticobiliary duct ligation (CPBDL). The severity of pancreatitis was assessed by serum amylase, pancreatic myeloperoxidase (MPO) activity, histological grading, pancreatic plasma extravasation, and wet-to-dry weight ratio. Caerulein significantly increased MPO activity and wet-to-dry weight ratio, produced histological evidence of edematous pancreatitis, induced plasma extravasation, and caused hyperamylasemia. CPBDL increased MPO activity and produced histological evidence of pancreatitis. Neonatal capsaicin administration significantly reduced tissue MPO levels, histological severity scores, and wet-to-dry weight ratio and abolished plasma extravasation. These results demonstrate that primary sensory neurons play a significant role in the inflammatory cascade in experimental pancreatitis and appear to constitute a common final pathway for pancreatic parenchymal inflammation.

Authors
Nathan, JD; Peng, RY; Wang, Y; McVey, DC; Vigna, SR; Liddle, RA
MLA Citation
Nathan, JD, Peng, RY, Wang, Y, McVey, DC, Vigna, SR, and Liddle, RA. "Primary sensory neurons: a common final pathway for inflammation in experimental pancreatitis in rats." Am J Physiol Gastrointest Liver Physiol 283.4 (October 2002): G938-G946.
PMID
12223354
Source
pubmed
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
283
Issue
4
Publish Date
2002
Start Page
G938
End Page
G946
DOI
10.1152/ajpgi.00105.2002

Neurohormonal control of pancreatic exocrine secretion.

The neurohormonal control of pancreatic exocrine secretion is a complex interaction of multiple pathways involving a large number of gut hormones, neurotransmitters, and neuropeptides. Recent studies have elucidated a role for cholecystokinin in the regulation of bicarbonate and fluid secretion from pancreatic duct cells and suggested that cholecystokinin stimulation of human pancreatic acinar cells is likely regulated by an indirect mechanism of stimulation of afferent neurons. Evidence supports the regulation of potassium channels in rat pancreatic acinar cells by the cyclic AMP-mediated agonist secretin. Mechanisms for the regulation of cholecystokinin and secretin release by releasing factors have also been elucidated. The area postrema has been implicated in the mediation of inhibition of pancreatic secretion by the gut hormones peptide YY and pancreatic polypeptide. The neurotransmitter serotonin has been demonstrated to play a role in acid-induced secretin release and in pancreatic secretion stimulated by luminal factors. The regulation of pancreatic exocrine secretion by purines, nitric oxide, and gamma-aminobutyric acid as well as by the neuropeptides pituitary adenylate cyclase-activating peptide, gastrin-releasing peptide, and substance P is reviewed. The role of the central nervous system in modulating pancreatic secretion is also described. This review highlights the recent advances in knowledge of the neurohormonal regulation of pancreatic exocrine secretion.

Authors
Nathan, JD; Liddle, RA
MLA Citation
Nathan, JD, and Liddle, RA. "Neurohormonal control of pancreatic exocrine secretion." Curr Opin Gastroenterol 18.5 (September 2002): 536-544.
PMID
17033330
Source
pubmed
Published In
Current Opinion in Gastroenterology
Volume
18
Issue
5
Publish Date
2002
Start Page
536
End Page
544

The best and the brightest.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "The best and the brightest." Gastroenterology 122.4 (April 2002): 851-852.
PMID
11910334
Source
pubmed
Published In
Gastroenterology
Volume
122
Issue
4
Publish Date
2002
Start Page
851
End Page
852

Luminal CCK-releasing factor stimulates CCK release from human intestinal endocrine and STC-1 cells.

CCK is secreted into the blood from intestinal endocrine cells following ingestion of a meal. Recently, it has been demonstrated that the ability of certain foods to stimulate CCK release is mediated by endogenously produced CCK-releasing factors. A newly discovered luminal CCK-releasing factor (LCRF) is secreted into the intestine, where it stimulates CCK secretion. However, the mechanism whereby LCRF affects intestinal epithelial cells is unknown. The current study was designed to determine whether LCRF has a direct effect on CCK cells to stimulate hormone secretion. In dispersed human intestinal mucosal cells, LCRF (5-200 nM) significantly stimulated CCK release in a concentration-dependent manner. This stimulatory effect was absent in calcium-free media and was inhibited by the L-type calcium-channel blockers diltiazem and nifedipine. To examine direct cellular effects of LCRF on CCK cells, further studies were conducted in the CCK-containing enteroendocrine cell line STC-1. As in native cells, LCRF significantly stimulated CCK release from STC-1 cells in a calcium-dependent manner. In cells loaded with a calcium-sensitive dye, LCRF stimulation produced a rapid increase in intracellular calcium. To examine the electrophysiological basis for this stimulation, whole cell recordings were made from STC-1 cells. Whole cell calcium currents were identified under basal conditions; moreover, calcium-channel activity was increased by LCRF. These studies demonstrate that 1) LCRF has a direct effect on human intestinal cells to stimulate CCK secretion, 2) stimulated hormone release is calcium dependent, and 3) LCRF activates calcium currents in CCK cells, which leads to CCK secretion.

Authors
Wang, Y; Prpic, V; Green, GM; Reeve, JR; Liddle, RA
MLA Citation
Wang, Y, Prpic, V, Green, GM, Reeve, JR, and Liddle, RA. "Luminal CCK-releasing factor stimulates CCK release from human intestinal endocrine and STC-1 cells." Am J Physiol Gastrointest Liver Physiol 282.1 (January 2002): G16-G22.
PMID
11751153
Source
pubmed
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
282
Issue
1
Publish Date
2002
Start Page
G16
End Page
G22

Primary sensory neurons: A common final pathway for inflammation in experimental pancreatitis in rats

We hypothesized that neurogenic inflammation is a common final pathway for parenchymal inflammation in pancreatitis and evaluated the role of primary sensory neurons in secretagogue-induced and obstructive pancreatitis. Neonatal rats received either the primary sensory neuron-denervating agent capsaicin (50 mg/kg sc) or vehicle. At 8 wk of age, pancreatitis was produced by six hourly injections of caerulein (50 μg/kg ip) or by common pancreaticobiliary duct ligation (CPBDL). The severity of pancreatitis was assessed by serum amylase, pancreatic myeloperoxidase (MPO) activity, histological grading, pancreatic plasma extravasation, and wet-to-dry weight ratio. Caerulein significantly increased MPO activity and wet-to-dry weight ratio, produced histological evidence of edematous pancreatitis, induced plasma extravasation, and caused hyperamylasemia. CPBDL increased MPO activity and produced histological evidence of pancreatitis. Neonatal capsaicin administration significantly reduced tissue MPO levels, histological severity scores, and wet-to-dry weight ratio and abolished plasma extravasation. These results demonstrate that primary sensory neurons play a significant role in the inflammatory cascade in experimental pancreatitis and appear to constitute a common final pathway for pancreatic parenchymal inflammation.

Authors
Nathan, JD; Peng, RY; Wang, Y; McVey, DC; Vigna, SR; Liddle, RA
MLA Citation
Nathan, JD, Peng, RY, Wang, Y, McVey, DC, Vigna, SR, and Liddle, RA. "Primary sensory neurons: A common final pathway for inflammation in experimental pancreatitis in rats." American Journal of Physiology - Gastrointestinal and Liver Physiology 283.4 46-4 (2002): G938-G946.
Source
scival
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
283
Issue
4 46-4
Publish Date
2002
Start Page
G938
End Page
G946

Luminal CCK-releasing factor stimulates CCK release from human intestinal endocrine and STC-1 cells

CCK is secreted into the blood from intestinal endocrine cells following ingestion of a meal. Recently, it has been demonstrated that the ability of certain foods to stimulate CCK release is mediated by endogenously produced CCK-releasing factors. A newly discovered luminal CCK-releasing factor (LCRF) is secreted into the intestine, where it stimulates CCK secretion. However, the mechanism whereby LCRF affects intestinal epithelial cells is unknown. The current study was designed to determine whether LCRF has a direct effect on CCK cells to stimulate hormone secretion. In dispersed human intestinal mucosal cells, LCRF (5-200 nM) significantly stimulated CCK release in a concentration-dependent manner. This stimulatory effect was absent in calcium-free media and was inhibited by the L-type calcium-channel blockers diltiazem and nifedipine. To examine direct cellular effects of LCRF on CCK cells, further studies were conducted in the CCK-containing enteroendocrine cell line STC-1. As in native cells, LCRF significantly stimulated CCK release from STC-1 cells in a calcium-dependent manner. In cells loaded with a calcium-sensitive dye, LCRF stimulation produced a rapid increase in intracellular calcium. To examine the electrophysiological basis for this stimulation, whole cell recordings were made from STC-1 cells. Whole cell calcium currents were identified under basal conditions; moreover, calcium-channel activity was increased by LCRF. These studies demonstrate that 1) LCRF has a direct effect on human intestinal cells to stimulate CCK secretion, 2) stimulated hormone release is calcium dependent, and 3) LCRF activates calcium currents in CCK cells, which leads to CCK secretion.

Authors
Wang, YU; Prpic, V; Green, GM; Jr, JRR; Liddle, RA
MLA Citation
Wang, YU, Prpic, V, Green, GM, Jr, JRR, and Liddle, RA. "Luminal CCK-releasing factor stimulates CCK release from human intestinal endocrine and STC-1 cells." American Journal of Physiology - Gastrointestinal and Liver Physiology 282.1 45-1 (2002): G16-G22.
Source
scival
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
282
Issue
1 45-1
Publish Date
2002
Start Page
G16
End Page
G22

Comment from the editors

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Comment from the editors." Gastroenterology 122.4 (2002): 851-852.
Source
scival
Published In
Gastroenterology
Volume
122
Issue
4
Publish Date
2002
Start Page
851
End Page
852

Capsaicin vanilloid receptor-1 mediates substance P release in experimental pancreatitis.

We examined whether the capsaicin vanilloid receptor-1 (VR1) mediates substance P (SP) release from primary sensory neurons in experimental pancreatitis. Pancreatitis was achieved by 12 hourly injections of caerulein (50 microg/kg ip) in mice. One group received capsazepine (100 micromol/kg sc), a competitive VR1 antagonist, at 4-h intervals. Neurokinin-1 receptor (NK1R) internalization in acinar cells, used as an index of endogenous SP release, was assessed by immunocytochemical quantification of NK1R endocytosis. The severity of pancreatitis was assessed by measurements of serum amylase, pancreatic myeloperoxidase (MPO) activity, and histological grading. Caerulein administration caused significant elevations in serum amylase and pancreatic MPO activity, produced histological evidence of pancreatitis, and caused a dramatic increase in NK1R endocytosis. Capsazepine treatment significantly reduced the level of NK1R endocytosis, and this was associated with similar reductions in pancreatic MPO activity and histological severity of pancreatitis. These results demonstrate that repeated caerulein stimulation causes experimental pancreatitis that is mediated in part by stimulation of VR1 on primary sensory neurons, resulting in endogenous SP release.

Authors
Nathan, JD; Patel, AA; McVey, DC; Thomas, JE; Prpic, V; Vigna, SR; Liddle, RA
MLA Citation
Nathan, JD, Patel, AA, McVey, DC, Thomas, JE, Prpic, V, Vigna, SR, and Liddle, RA. "Capsaicin vanilloid receptor-1 mediates substance P release in experimental pancreatitis." Am J Physiol Gastrointest Liver Physiol 281.5 (November 2001): G1322-G1328.
PMID
11668042
Source
pubmed
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
281
Issue
5
Publish Date
2001
Start Page
G1322
End Page
G1328

Vanilloid receptor-1-mediated substance P release in experimental pancreatitis in mice

Authors
Nathan, JD; McVey, DC; Patel, A; Thomas, J; Vigna, SR; Liddle, RA
MLA Citation
Nathan, JD, McVey, DC, Patel, A, Thomas, J, Vigna, SR, and Liddle, RA. "Vanilloid receptor-1-mediated substance P release in experimental pancreatitis in mice." GASTROENTEROLOGY 120.5 (April 2001): A539-A539.
Source
wos-lite
Published In
Gastroenterology
Volume
120
Issue
5
Publish Date
2001
Start Page
A539
End Page
A539
DOI
10.1016/S0016-5085(08)82676-5

Capsaicin vanilloid receptor-1 mediates substance P release in experimental pancreatitis

We examined whether the capsaicin vanilloid receptor-1 (VR1) mediates substance P (SP) release from primary sensory neurons in experimental pancreatitis. Pancreatitis was achieved by 12 hourly injections of caerulein (50 μg/kg ip) in mice. One group received capsazepine (100 μmol/kg sc), a competitive VR1 antagonist, at 4-h intervals. Neurokinin-1 receptor (NK1R) internalization in acinar cells, used as an index of endogenous SP release, was assessed by immunocytochemical quantification of NK1R endocytosis. The severity of pancreatitis was assessed by measurements of serum amylase, pancreatic myeloperoxidase (MPO) activity, and histological grading. Caerulein administration caused significant elevations in serum amylase and pancreatic MPO activity, produced histological evidence of pancreatitis, and caused a dramatic increase in NK1R endocytosis. Capsazepine treatment significantly reduced the level of NK1R endocytosis, and this was associated with similar reductions in pancreatic MPO activity and histological severity of pancreatitis. These results demonstrate that repeated caerulein stimulation causes experimental pancreatitis that is mediated in part by stimulation of VR1 on primary sensory neurons, resulting in endogenous SP release.

Authors
Nathan, JD; Patel, AA; McVey, DC; Thomas, JE; Prpic, V; Vigna, SR; Liddle, RA
MLA Citation
Nathan, JD, Patel, AA, McVey, DC, Thomas, JE, Prpic, V, Vigna, SR, and Liddle, RA. "Capsaicin vanilloid receptor-1 mediates substance P release in experimental pancreatitis." American Journal of Physiology - Gastrointestinal and Liver Physiology 281.5 44-5 (2001): G1322-G1328.
Source
scival
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
281
Issue
5 44-5
Publish Date
2001
Start Page
G1322
End Page
G1328

The capsaicin vanilloid receptor-1 (VR-1) mediates a portion of secretagogue-induced pancreatitis in mice.

Authors
Patel, AA; Thomas, JE; McVey, DC; Prpic, V; Vigna, SR; Liddle, RA
MLA Citation
Patel, AA, Thomas, JE, McVey, DC, Prpic, V, Vigna, SR, and Liddle, RA. "The capsaicin vanilloid receptor-1 (VR-1) mediates a portion of secretagogue-induced pancreatitis in mice." GASTROENTEROLOGY 118.4 (April 2000): A169-A169.
Source
wos-lite
Published In
Gastroenterology
Volume
118
Issue
4
Publish Date
2000
Start Page
A169
End Page
A169

Regulation of cholecystokinin secretion in humans.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Regulation of cholecystokinin secretion in humans." J Gastroenterol 35.3 (2000): 181-187. (Review)
PMID
10755686
Source
pubmed
Published In
Journal of Gastroenterology
Volume
35
Issue
3
Publish Date
2000
Start Page
181
End Page
187

Neurohumoral control of the exocrine pancreas.

Recent advances in the study of pancreatic exocrine secretion are reviewed, with an emphasis on neurohumoral mechanisms. In the past year, cDNA for the human pancreatic sodium-bicarbonate cotransporter was cloned, and the expressed protein was localized to pancreatic acini and ductal cells. Recent information suggests that the cholecystokinin B receptor has a role in pancreatic amylase release. Further evidence supports the concept of a protease-sensitive negative feedback mechanism regulating pancreatic exocrine secretion. Study of the expression of the receptors responsible for the regulation of pancreatic function has proven fruitful in the determination of the molecular mechanisms of hormone signal transduction and desensitization. Studies of peptide 1, pituitary adenylate cyclase-activating peptide, and gastrin-releasing peptide have shown how these peptides participate in the regulation of pancreatic secretion and have provided information on intracellular signaling pathways obtained using rat pancreatic tumor cells. Neural regulation via cholinergic receptors in isolated pancreatic acini and the mechanisms responsible for other neurotransmitters, such as calcitonin gene-related peptide, histamine, and dopamine, are reviewed. This review highlights recent discoveries in the neurohumoral regulation of pancreatic exocrine secretion.

Authors
Shetzline, MA; Liddle, RA
MLA Citation
Shetzline, MA, and Liddle, RA. "Neurohumoral control of the exocrine pancreas." Curr Opin Gastroenterol 15.5 (September 1999): 380-384.
PMID
17023977
Source
pubmed
Published In
Current Opinion in Gastroenterology
Volume
15
Issue
5
Publish Date
1999
Start Page
380
End Page
384

Guidelines for training in electronic ultrasound: guidelines for clinical application. From the ASGE. American Society for Gastrointestinal Endoscopy.

Authors
Van Dam, J; Brady, PG; Freeman, M; Gress, F; Gross, GW; Hassall, E; Hawes, R; Jacobsen, NA; Liddle, RA; Ligresti, RJ; Quirk, DM; Sahagun, J; Sugawa, C; Tenner, SM
MLA Citation
Van Dam, J, Brady, PG, Freeman, M, Gress, F, Gross, GW, Hassall, E, Hawes, R, Jacobsen, NA, Liddle, RA, Ligresti, RJ, Quirk, DM, Sahagun, J, Sugawa, C, and Tenner, SM. "Guidelines for training in electronic ultrasound: guidelines for clinical application. From the ASGE. American Society for Gastrointestinal Endoscopy." Gastrointest Endosc 49.6 (June 1999): 829-833. (Review)
PMID
10343245
Source
pubmed
Published In
Gastrointestinal Endoscopy
Volume
49
Issue
6
Publish Date
1999
Start Page
829
End Page
833

Luminal cholecystokinin releasing factor (LCRF) stimulates CCK release from intestinal, endocrine cells through a calcium influx pathway.

Authors
Liddle, RA; Prpic, V; Wang, Y; Romac, J; Green, GM; Reeve, JR
MLA Citation
Liddle, RA, Prpic, V, Wang, Y, Romac, J, Green, GM, and Reeve, JR. "Luminal cholecystokinin releasing factor (LCRF) stimulates CCK release from intestinal, endocrine cells through a calcium influx pathway." GASTROENTEROLOGY 116.4 (April 1999): A622-A622.
Source
wos-lite
Published In
Gastroenterology
Volume
116
Issue
4
Publish Date
1999
Start Page
A622
End Page
A622

Activation of calcium channels by cAMP in STC-1 cells is dependent upon Ca2+ calmodulin-dependent protein kinase II.

Activation of L-type calcium channels in the neuroendocrine, cholecytstokinin-secreting cell line, STC-1, is vital for secretion of CCK. In the present study, the regulation of L-type Ca2+ channels by cAMP and Ca2+ calmodulin dependent protein kinase II (CaM-KII) in STC-1 cells was investigated. Exposure to 3-isobutyl-1-methylxanthine (IBMX) increased intracellular cAMP levels, whole cell Ca2+ currents and activated Ca2+ channels in cell-attached membrane patches. Furthermore, in Fura-2AM loaded cells, cytosolic Ca2+ levels increased upon exposure to IBMX. By contrast, pretreatment of cells with the CaM-KII inhibitor KN-62, prevented IBMX activation of Ca2+ channels in cell-attached patches or increases in cytosolic Ca2+ levels. Inclusion of the synthetic peptide fragment 290-309 of CaM-KII, a CaM-KII antagonist, in the pipette solution, blocked the activation of whole cell Ca2+ currents upon addition of IBMX. These results indicate a unique mechanism of L-type Ca2+ channel activation involving two phosphorylation events.

Authors
Basavappa, S; Mangel, AW; Scott, L; Liddle, RA
MLA Citation
Basavappa, S, Mangel, AW, Scott, L, and Liddle, RA. "Activation of calcium channels by cAMP in STC-1 cells is dependent upon Ca2+ calmodulin-dependent protein kinase II." Biochem Biophys Res Commun 254.3 (January 27, 1999): 699-702.
PMID
9920804
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
254
Issue
3
Publish Date
1999
Start Page
699
End Page
702
DOI
10.1006/bbrc.1998.9997

Monitor peptide binding sites are expressed in the rat liver and small intestine.

125I-monitor peptide binding was performed using frozen sections of the rat liver and gut and visualized using autoradiography. Saturable binding was observed in unidentified single cells in the liver and in the mucosa of the small intestine. Epidermal growth factor (EGF) and GTPgammaS did not inhibit 125I-monitor peptide binding indicating that the binding sites are not EGF receptors or G protein-coupled receptors. The liver binding site exhibited an affinity 3.7-4.4-fold higher than those in the small intestine. It has been established that intraluminal monitor peptide releases cholecystokinin from the small intestine. The present results indicate that monitor peptide may also have liver associated functions.

Authors
McVey, DC; Romac, JM; Clay, WC; Kost, TA; Liddle, RA; Vigna, SR
MLA Citation
McVey, DC, Romac, JM, Clay, WC, Kost, TA, Liddle, RA, and Vigna, SR. "Monitor peptide binding sites are expressed in the rat liver and small intestine." Peptides 20.4 (1999): 457-464.
PMID
10458515
Source
pubmed
Published In
Peptides
Volume
20
Issue
4
Publish Date
1999
Start Page
457
End Page
464

Guidelines for training in endoscopic ultrasound

Authors
Dam, JV; Brady, PG; Freeman, M; Gress, F; Gross, GW; Hassall, E; Hawes, R; Jacobsen, NA; Liddle, RA; Ligresti, RJ; Quirk, DM; Sahagun, J; Sugawa, C; Tenner, SM
MLA Citation
Dam, JV, Brady, PG, Freeman, M, Gress, F, Gross, GW, Hassall, E, Hawes, R, Jacobsen, NA, Liddle, RA, Ligresti, RJ, Quirk, DM, Sahagun, J, Sugawa, C, and Tenner, SM. "Guidelines for training in endoscopic ultrasound." Gastrointestinal Endoscopy 49.6 (1999): 829-833.
Source
scival
Published In
Gastrointestinal Endoscopy
Volume
49
Issue
6
Publish Date
1999
Start Page
829
End Page
833
DOI
10.1016/S0016-5107(99)70312-3

Inhibition of Na+/H+ exchange stimulates CCK secretion in STC-1 cells.

It has been demonstrated that K+ channel regulation of membrane potential is critical for control of CCK secretion. Because certain K+ channels are pH sensitive, it was postulated that pH affects K+ channel activity in the CCK-secreting cell line STC-1 and may participate in regulating CCK secretion. The present study examines the role of electroneutral Na+/H+ exchange on extracellular acidification and hormone secretion. Treatment of STC-1 cells with the amiloride analog ethylisopropyl amiloride (EIPA) to inhibit Na+/H+ exchange inhibited Na+-dependent H+ efflux and increased basal CCK secretion. Substituting choline for NaCl in the extracellular medium elevated basal intracellular Ca2+ concentration and stimulated CCK release. Stimulatory effects on hormone secretion were blocked by the L-type Ca2+ channel blocker diltiazem, indicating that secretion was dependent on the influx of extracellular Ca2+. To determine whether the effects of EIPA and Na+ depletion were due to membrane depolarization, we tested graded KCl concentrations. The ability of EIPA to increase CCK secretion was inhibited by depolarization induced by 10-50 mM KCl in the bath. Maneuvers to lower intracellular pH (pHi), including reducing extracellular pH (pHo) to 7.0 or treatment with sodium butyrate, significantly increased CCK secretion. To examine whether pH directly affects membrane K+ permeability, we measured outward currents carried by K+, using whole cell patch techniques. K+ current was significantly inhibited by lowering pHo to 7.0. These effects appear to be mediated through changes in pHi, because intracellular dialysis with acidic solutions nearly eliminated current activity. These results suggest that Na+/H+ exchange and membrane potential may be functionally linked, where inhibition of Na+/H+ exchange lowers pHi and depolarizes the membrane, perhaps through inhibition of pH-sensitive K+ channels. In turn, K+ channel closure and membrane depolarization open voltage-dependent Ca2+ channels, leading to an increase in cytosolic Ca2+ and CCK release. The effects of pHi on K+ channels may serve as a potent stimulus for hormone secretion, linking cell metabolism and secretory functions.

Authors
Prpic, V; Fitz, JG; Wang, Y; Raymond, JR; Garnovskaya, MN; Liddle, RA
MLA Citation
Prpic, V, Fitz, JG, Wang, Y, Raymond, JR, Garnovskaya, MN, and Liddle, RA. "Inhibition of Na+/H+ exchange stimulates CCK secretion in STC-1 cells." Am J Physiol 275.4 Pt 1 (October 1998): G689-G695.
PMID
9756498
Source
pubmed
Published In
The American journal of physiology
Volume
275
Issue
4 Pt 1
Publish Date
1998
Start Page
G689
End Page
G695

Inhibition of Na+/H+ exchange stimulates CCK secretion in STC-1 cells

Authors
Prpic, V; Fitz, JG; Wang, Y; Raymond, JR; Garnovskaya, MN; Liddle, RA
MLA Citation
Prpic, V, Fitz, JG, Wang, Y, Raymond, JR, Garnovskaya, MN, and Liddle, RA. "Inhibition of Na+/H+ exchange stimulates CCK secretion in STC-1 cells." AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 275.4 (October 1998): G689-G695.
Source
wos-lite
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
275
Issue
4
Publish Date
1998
Start Page
G689
End Page
G695

Inhibition of gastric emptying in response to intestinal lipid is dependent on chylomicron formation.

Lipid in the intestine initiates feedback inhibition of proximal gastrointestinal function and food intake. In rats and humans, inhibition of gastric emptying is mediated, at least in part, by cholecystokinin (CCK)-A receptors, and in rats there is evidence for involvement of an intestinal vagal afferent pathway. The mechanism by which luminal lipid acts to release CCK or activate vagal afferent nerve terminals is unclear. The role of chylomicron formation in this sensory transduction pathway has been investigated using the hydrophobic surfactant Pluronic L-81 that inhibits chylomicron formation. Gastric emptying of liquids was measured in awake rats fitted with a Thomas gastric fistula and a duodenal cannula. Intestinal perfusion of lipid induced a dose-dependent inhibition of gastric emptying (6, 12, and 39% inhibition for 25, 50, and 100 mg lipid, respectively). Perfusion of lipid with Pluronic L-81 (2.8% wt/vol) reversed the lipid-induced inhibition of gastric emptying. Pluronic L-63, a chemically similar surfactant that has no effect on chylomicron formation, had no effect on lipid-induced inhibition of gastric emptying. Perfusion of the intestine with lipid (100 mg) increased plasma levels of CCK from 1.9 +/- 0.8 to 6. 5 +/- 1 pM. This increase was blocked by Pluronic L-81 but unaffected by L-63. These results provide evidence that chylomicron formation is important in the signaling of lipid in the intestinal lumen to CCK endocrine cells and to producing feedback inhibition of gastric emptying.

Authors
Raybould, HE; Meyer, JH; Tabrizi, Y; Liddle, RA; Tso, P
MLA Citation
Raybould, HE, Meyer, JH, Tabrizi, Y, Liddle, RA, and Tso, P. "Inhibition of gastric emptying in response to intestinal lipid is dependent on chylomicron formation." Am J Physiol 274.6 Pt 2 (June 1998): R1834-R1838.
PMID
9841489
Source
pubmed
Published In
The American journal of physiology
Volume
274
Issue
6 Pt 2
Publish Date
1998
Start Page
R1834
End Page
R1838

Inhibition of gastric emptying in response to intestinal lipid is dependent on chylomicron formation

Authors
Raybould, HE; Meyer, JH; Tabrizi, Y; Liddle, RA; Tso, P
MLA Citation
Raybould, HE, Meyer, JH, Tabrizi, Y, Liddle, RA, and Tso, P. "Inhibition of gastric emptying in response to intestinal lipid is dependent on chylomicron formation." AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY 274.6 (June 1998): R1834-R1838.
Source
wos-lite
Published In
American journal of physiology. Regulatory, integrative and comparative physiology
Volume
274
Issue
6
Publish Date
1998
Start Page
R1834
End Page
R1838

On the measurement of cholecystokinin.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "On the measurement of cholecystokinin." Clin Chem 44.5 (May 1998): 903-904.
PMID
9590358
Source
pubmed
Published In
Clinical chemistry
Volume
44
Issue
5
Publish Date
1998
Start Page
903
End Page
904

Regulation of cholecystokinin secretion in STC-1 cells through pH-sensitive potassium channels.

Authors
Wang, Y; Prpic, V; Fitz, JG; Liddle, RA
MLA Citation
Wang, Y, Prpic, V, Fitz, JG, and Liddle, RA. "Regulation of cholecystokinin secretion in STC-1 cells through pH-sensitive potassium channels." GASTROENTEROLOGY 114.4 (April 15, 1998): A1189-A1189.
Source
wos-lite
Published In
Gastroenterology
Volume
114
Issue
4
Publish Date
1998
Start Page
A1189
End Page
A1189

Monitor peptide binding sites are expressed in liver and small intestine.

Authors
McVey, DC; Romac, J; Clay, W; Kost, T; Liddle, RA; Vigna, SR
MLA Citation
McVey, DC, Romac, J, Clay, W, Kost, T, Liddle, RA, and Vigna, SR. "Monitor peptide binding sites are expressed in liver and small intestine." GASTROENTEROLOGY 114.4 (April 15, 1998): A1164-A1164.
Source
wos-lite
Published In
Gastroenterology
Volume
114
Issue
4
Publish Date
1998
Start Page
A1164
End Page
A1164
DOI
10.1016/S0016-5085(98)84732-X

Bioactivity of intraduodenally and intravenously infused fragments of luminal cholecystokinin releasing factor (LCRF).

A luminal cholecystokinin releasing factor (LCRF), has been purified from intestinal secretion and found to have a mass of 8136 daltons. The amino-terminal 41 residues have been sequenced. Previous studies showed that intraduodenal infusion of the synthetic amino-terminal 35 amino acid peptide, LCRF1-35 significantly stimulated pancreatic protein and fluid secretion in conscious rats, but the peptide did not stimulate amylase release from isolated, dispersed pancreatic acini. In the present study, several fragments of LCRF were synthesized and tested for CCK-releasing activity (pancreatic protein secretion) to determine whether shorter fragments of LCRF exhibit the characteristic biological activity of native LCRF and synthetic LCRF1-35. Compounds tested were LCRF1-41, LCRF1-35, LCRF1-65 and LCRF11-25. Of the fragments shorter than LCRF1-35, only LCRF11-25 but not LCRF1-6 had significant CCK releasing activity. LCRF1-41 was equivalent to LCRF1-35 in potency and efficacy. Intravenous and intraduodenal infusion of LCRF1-35 elicited nearly identical dose-response curves.

Authors
Spannagel, AW; Reeve, JR; Greeley, GH; Yanaihara, N; Liddle, RA; Green, GM
MLA Citation
Spannagel, AW, Reeve, JR, Greeley, GH, Yanaihara, N, Liddle, RA, and Green, GM. "Bioactivity of intraduodenally and intravenously infused fragments of luminal cholecystokinin releasing factor (LCRF)." Regul Pept 73.3 (February 27, 1998): 161-164.
PMID
9556078
Source
pubmed
Published In
Regulatory Peptides
Volume
73
Issue
3
Publish Date
1998
Start Page
161
End Page
164

Erratum: Purification and characterization of a luminal cholecystokinin- releasing factor from rat intestinal secretion (Proceedings of the National Academy of Sciences of the United States of America (April 30, 1996) 93:9 (4415-4420))

Authors
Spannagel, AW; Green, GM; Guan, D; Liddle, RA; Faull, K; Jr, RJR
MLA Citation
Spannagel, AW, Green, GM, Guan, D, Liddle, RA, Faull, K, and Jr, RJR. "Erratum: Purification and characterization of a luminal cholecystokinin- releasing factor from rat intestinal secretion (Proceedings of the National Academy of Sciences of the United States of America (April 30, 1996) 93:9 (4415-4420))." Proceedings of the National Academy of Sciences of the United States of America 95.16 (1998): 9710--.
Source
scival
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
95
Issue
16
Publish Date
1998
Start Page
9710-

Inhibition of gastric emptying in response to intestinal lipid is dependent on chylomicron formation

Lipid in the intestine initiates feedback inhibition of proximal gastrointestinal function and food intake. In rats and humans, inhibition of gastric emptying is mediated, at least in part, by cholecystokinin (CCK)-A receptors, and in rats there is evidence for involvement of an intestinal vagal afferent pathway. The mechanism by which luminal lipid acts to release CCK or activate vagal afferent nerve terminals is unclear. The role of chylomicron formation in this sensory transduction pathway has been investigated using the hydrophobic surfactant Pluronic L-81 that inhibits chylomicron formation. Gastric emptying of liquids was measured in awake rats fitted with a Thomas gastric fistula and a duodenal cannula. Intestinal perfusion of lipid induced a dose-dependent inhibition of gastric emptying (6, 12, and 39% inhibition for 25, 50, and 100 mg lipid, respectively). Perfusion of lipid with Pluronic L-81 (2.8% wt/vol) reversed the lipid- induced inhibition of gastric emptying. Pluronic L-63, a chemically similar surfactant that has no effect on chylomicron formation, had no effect on lipid-induced inhibition of gastric emptying. Perfusion of the intestine with lipid (100 mg) increased plasma levels of CCK from 1.9 ± 0.8 to 6.5 ± 1 pM. This increase was blocked by Pluronic L-81 but unaffected by L-63. These results provide evidence that chylomicron formation is important in the signaling of lipid in the intestinal lumen to CCK endocrine cells and to producing feedback inhibition of gastric emptying.

Authors
Raybould, HE; Meyer, JH; Tabrizi, Y; Liddle, RA; Tso, P
MLA Citation
Raybould, HE, Meyer, JH, Tabrizi, Y, Liddle, RA, and Tso, P. "Inhibition of gastric emptying in response to intestinal lipid is dependent on chylomicron formation." American Journal of Physiology - Regulatory Integrative and Comparative Physiology 274.6 43-6 (1998): R1834-R1838.
Source
scival
Published In
American journal of physiology. Regulatory, integrative and comparative physiology
Volume
274
Issue
6 43-6
Publish Date
1998
Start Page
R1834
End Page
R1838

Inhibition of Na+/H+ exchange stimulates CCK secretion in STC-1 cells

It has been demonstrated that K+ channel regulation of membrane potential is critical for control of CCK secretion. Because certain K+ channels are pH sensitive, it was postulated that pH affects K+ channel activity in the CCK-secreting cell line STC-1 and may participate in regulating CCK secretion. The present study examines the role of electroneutral Na+/H+ exchange on extracellular acidification and hormone secretion. Treatment of STC-1 cells with the amiloride analog ethylisopropyl amiloride (EIPA) to inhibit Na+/H+ exchange inhibited Na+-dependent H+ efflux and increased basal CCK secretion. Substituting choline for NaCl in the extracellular medium elevated basal intracellular Ca2+ concentration and stimulated CCK release. Stimulatory effects on hormone secretion were blocked by the L-type Ca2+ channel blocker diltiazem, indicating that secretion was dependent on the influx of extracellular Ca2+. To determine whether the effects of EIPA and Na+ depletion were due to membrane depolarization, we tested graded KCl concentrations. The ability of EIPA to increase CCK secretion was inhibited by depolarization induced by 10-50 mM KCl in the bath. Maneuvers to lower intracellular pH (pH(i)), including reducing extracellular pH (pH(o)) to 7.0 or treatment with sodium butyrate, significantly increased CCK secretion. To examine whether pH directly affects membrane K+ permeability, we measured outward currents carried by K+, using whole cell patch techniques. K+ current was significantly inhibited by lowering pH(o) to 7.0. These effects appear to be mediated through changes in pH(i), because intracellular dialysis with acidic solutions nearly eliminated current activity. These results suggest that Na+/H+ exchange and membrane potential may be functionally linked, where inhibition of Na+/H+ exchange lowers phi and depolarizes the membrane, perhaps through inhibition of pH- sensitive K+ channels. In turn, K+ channel closure and membrane depolarization open voltage-dependent Ca2+ channels, leading to an increase in cytosolic Ca2+ and CCK release. The effects of pH(i) on K+ channels may serve as a potent stimulus for hormone secretion, linking cell metabolism and secretor/functions.

Authors
Prpic, V; Fitz, JG; Wang, Y; Raymond, JR; Garnovskaya, MN; Liddle, RA
MLA Citation
Prpic, V, Fitz, JG, Wang, Y, Raymond, JR, Garnovskaya, MN, and Liddle, RA. "Inhibition of Na+/H+ exchange stimulates CCK secretion in STC-1 cells." American Journal of Physiology - Gastrointestinal and Liver Physiology 275.4 38-4 (1998): G689-G695.
Source
scival
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
275
Issue
4 38-4
Publish Date
1998
Start Page
G689
End Page
G695

Salmeterol powder compared with albuterol aerosol as maintenance therapy for asthma in adolescent and adult patients

Two multicenter, randomized, double-masked, placebo-controlled studies involving 451 adolescent and adult patients with mild-to-moderate asthma compared the efficacy and safety of salmeterol powder 50 μg twice daily with albuterol 180 μg four times daily or placebo (with albuterol as needed) for 12 weeks. Patients had forced expiratory volume in I second (FEV1) of 50% to 80%. Throughout the 12-week treatment period, the mean change from baseline in percentage of predicted FEV1 was significantly greater with salmeterol than with placebo; mean area under the curve for FEV1 was significantly greater with salmeterol than with albuterol or placebo. Significant improvements in morning and evening peak expiratory flow, percentage of nights without awakening, and asthma symptoms were observed with salmeterol. Salmeterol was well tolerated, and no clinically significant changes in electrocardiographic activity were observed.

Authors
Kemp, J; Wolfe, J; Grady, J; LaForce, C; Stahl, E; Arledge, T; Liddle, R
MLA Citation
Kemp, J, Wolfe, J, Grady, J, LaForce, C, Stahl, E, Arledge, T, and Liddle, R. "Salmeterol powder compared with albuterol aerosol as maintenance therapy for asthma in adolescent and adult patients." Clinical Therapeutics 20.2 (1998): 270-282.
PMID
9589818
Source
scival
Published In
Clinical Therapeutics
Volume
20
Issue
2
Publish Date
1998
Start Page
270
End Page
282
DOI
10.1016/S0149-2918(98)80090-8

Distribution and localization of a novel cholecystokinin-releasing factor in the rat gastrointestinal tract.

The purpose of this study was to examine the distribution and localization of an intestinal cholecystokinin (CCK)-releasing factor, called luminal CCK-releasing factor (LCRF), in the gastrointestinal tract and pancreas of the rat. RIA analysis indicates that LCRF immunoreactivity is found throughout the gut including the pancreas, stomach, duodenum, jejunum, ileum, and colon with the highest levels in the small intestine. Immunohistochemistry analysis shows LCRF immunoreactivity staining in intestinal villi, Brunner's glands of the duodenum, the duodenal myenteric plexus, gastric pits, pancreatic ductules, and pancreatic islets. These results indicate potential sources for secretagogue-stimulated release of luminal LCRF and support the hypothesis that LCRF is secreted into the intestinal lumen to stimulate CCK release from mucosal CCK cells.

Authors
Tarasova, N; Spannagel, AW; Green, GM; Gomez, G; Reed, JT; Thompson, JC; Hellmich, MR; Reeve, JR; Liddle, RA; Greeley, GH
MLA Citation
Tarasova, N, Spannagel, AW, Green, GM, Gomez, G, Reed, JT, Thompson, JC, Hellmich, MR, Reeve, JR, Liddle, RA, and Greeley, GH. "Distribution and localization of a novel cholecystokinin-releasing factor in the rat gastrointestinal tract." Endocrinology 138.12 (December 1997): 5550-5554.
PMID
9389543
Source
pubmed
Published In
Endocrinology
Volume
138
Issue
12
Publish Date
1997
Start Page
5550
End Page
5554
DOI
10.1210/endo.138.12.5554

Regulation of biliary secretion through apical purinergic receptors in cultured rat cholangiocytes.

To evaluate whether ATP in bile serves as a signaling factor regulating ductular secretion, voltage-clamp studies were performed using a novel normal rat cholangiocyte (NRC) model. In the presence of amiloride (100 microM) to block Na+ channels, exposure of the apical membrane to ATP significantly increased the short-circuit current (Isc) from 18.2 +/- 5.9 to 52.8 +/- 12.7 microA (n = 18). The response to ATP is mediated by basolateral-to-apical Cl- transport because it is inhibited by 1) the Cl- channel blockers 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (1 mM), diphenylanthranilic acid (1.5 mM), or 5-nitro-2-(3-phenylpropylamino)benzoic acid (50 or 100 microM) in the apical chamber, 2) the K+ channel blocker Ba2+ (5 mM), or 3) the Na(+)-K(+)-2Cl- cotransport inhibitor bumetanide (200 microM) in the basolateral chamber. Other nucleotides stimulated an increase in Isc with a rank order potency of UTP = ATP = adenosine 5'-O-(3)-thiotriphosphate, consistent with P2u purinergic receptors. ADP, AMP, 2-methylthioadenosine 5'-triphosphate, and adenosine had no effect. A cDNA encoding a rat P2u receptor (rP2uR) was isolated from a liver cDNA library, and functional expression of the corresponding mRNA in Xenopus laevis oocytes resulted in the appearance of ATP-stimulated currents with a similar pharmacological profile. Northern analysis identified hybridizing mRNA transcripts in NRC as well as other cell types in rat liver. These findings indicate that exposure of polarized cholangiocytes to ATP results in luminal Cl- secretion through activation of P2u receptors in the apical membrane. Release of ATP into bile may serve as an autocrine or paracrine signal regulating cholangiocyte secretory function.

Authors
Schlenker, T; Romac, JM; Sharara, AI; Roman, RM; Kim, SJ; LaRusso, N; Liddle, RA; Fitz, JG
MLA Citation
Schlenker, T, Romac, JM, Sharara, AI, Roman, RM, Kim, SJ, LaRusso, N, Liddle, RA, and Fitz, JG. "Regulation of biliary secretion through apical purinergic receptors in cultured rat cholangiocytes." Am J Physiol 273.5 Pt 1 (November 1997): G1108-G1117.
PMID
9374709
Source
pubmed
Published In
The American journal of physiology
Volume
273
Issue
5 Pt 1
Publish Date
1997
Start Page
G1108
End Page
G1117

An amino-terminal fragment of LCRF, LCRF-(1-35), has the same activity as the natural peptide.

A cholecystokinin (CCK)-releasing peptide, luminal CCK-releasing factor (LCRF), has been purified from rat jejunal secretion. Amino acid analysis and mass spectral analysis showed that the purified peptide is composed of 70-75 amino acid residues and has a mass of 8,136 Da. Microsequence analysis of LCRF yielded an amino acid sequence for the amino-terminal 41 residues. To determine the biologically active region of the molecule, a peptide was synthesized consisting of the amino-terminal 35 amino acids of LCRF. In this study, intraduodenal infusion of LCRF-(1-35) significantly stimulated pancreatic secretion in conscious rats. The dose-response curves to LCRF-(1-35) and to monitor peptide were similar and biphasic, with higher doses producing submaximal pancreatic secretory responses. The CCK-A receptor antagonist MK-329 abolished the pancreatic secretory response to intraduodenally infused LCRF-(1-35). These results demonstrate that LCRF biological activity is contained within the amino-terminal 35-amino acid portion of LCRF, and this fragment may be useful for investigating the role of LCRF in gastrointestinal function.

Authors
Spannagel, AW; Reeve, JR; Liddle, RA; Guan, D; Green, GM
MLA Citation
Spannagel, AW, Reeve, JR, Liddle, RA, Guan, D, and Green, GM. "An amino-terminal fragment of LCRF, LCRF-(1-35), has the same activity as the natural peptide." Am J Physiol 273.3 Pt 1 (September 1997): G754-G758.
PMID
9316481
Source
pubmed
Published In
The American journal of physiology
Volume
273
Issue
3 Pt 1
Publish Date
1997
Start Page
G754
End Page
G758

Postprandial cholecystokinin release and gastric emptying in patients with bulimia nervosa.

This study was designed to investigate the biological underpinnings of the observed deficit in satiety in patients with bulimia nervosa. Eight women with bulimia nervosa and 10 age- and weight-matched control subjects consumed three laboratory meals consisting of 200, 400, and 600 g of a radiolabeled liquid meal. For 1 h after each meal, blood samples were obtained at 10-min intervals for measurement of cholecystokinin concentration and gastric emptying was measured. Subjects also completed perceptual rating scales at 10-min intervals. Compared with control subjects, patients with bulimia nervosa showed a blunting of postprandial cholecystokinin release, particularly with larger meal sizes, as well as delayed gastric emptying. Increasing meal size was associated with increased desire to binge eat in patients but not in control subjects. These data lend support to a model in which increased gastric capacity, perhaps resulting from repeated binge eating, gives rise to delayed gastric emptying and blunted postprandial cholecystokinin release, leading to an impaired satiety response, which tends to perpetuate the illness.

Authors
Devlin, MJ; Walsh, BT; Guss, JL; Kissileff, HR; Liddle, RA; Petkova, E
MLA Citation
Devlin, MJ, Walsh, BT, Guss, JL, Kissileff, HR, Liddle, RA, and Petkova, E. "Postprandial cholecystokinin release and gastric emptying in patients with bulimia nervosa." Am J Clin Nutr 65.1 (January 1997): 114-120.
PMID
8988922
Source
pubmed
Published In
American Journal of Clinical Nutrition
Volume
65
Issue
1
Publish Date
1997
Start Page
114
End Page
120

Cholecystokinin cells.

Cholecystokinin (CCK) is an important hormonal regulator of the digestive process. CCK cells are concentrated in the proximal small intestine, and hormone is secreted into the blood upon the ingestion of food. The physiological actions of CCK include stimulation of pancreatic secretion and gallbladder contraction, regulation of gastric emptying, and induction of satiety. Therefore, in a highly coordinated manner, CCK regulates the ingestion, digestion, and absorption of nutrients. CCK is produced by two separate cell types: endocrine cells of the small intestine and various neurons in the gastrointestinal tract and central nervous system. Accordingly, CCK can function as either a hormone or a neuropeptide. This review focuses on the physiology of the CCK cell in the intestine and, in particular, on how the CCK cell is regulated to secrete its hormone product. The effects of ingested nutrients on the CCK cell and the intracellular messenger systems involved in controlling secretion are reviewed. A summary is provided of recent studies examining the electrophysiological properties of CCK cells and newly discovered proteins that act as releasing factors for CCK, which mediate feedback pathways critical for regulated secretion in the intact organism.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Cholecystokinin cells." Annu Rev Physiol 59 (1997): 221-242. (Review)
PMID
9074762
Source
pubmed
Published In
Annual Review of Physiology
Volume
59
Publish Date
1997
Start Page
221
End Page
242
DOI
10.1146/annurev.physiol.59.1.221

An amino-terminal fragment of LCRF, LCRF-(1-35), has the same activity as the natural peptide

A cholecystokinin (CCK)-releasing peptide, luminal CCK-releasing factor (LCRF), has been purified from rat jejunal secretion. Amino acid analysis and mass spectral analysis showed that the purified peptide is composed of 70-75 amino acid residues and has a mass of 8,136 Da. Microsequence analysis of LCRF yielded an amino acid sequence for the amino-terminal 41 residues. To determine the biologically active region of the molecule, a peptide was synthesized consisting of the amino-terminal 35 amine acids of LCRF. In this study, intraduodenal infusion of LCRF-(1- 35) significantly stimulated pancreatic secretion in conscious rats. The dose-response curves to LCRF-(1- 35) and to monitor peptide were similar and biphasic, with higher doses producing submaximal pancreatic secretory responses. The CCK-A receptor antagonist MK-329 abolished the pancreatic secretory response to intraduodenally infused LCRF-(1-35). These results demonstrate that LCRF biological activity is contained within the amino-terminal 35-amino acid portion of LCRF, and this fragment may be useful for investigating the role of LCRF in gastrointestinal function.

Authors
Spannagel, AW; Jr, JRR; Liddle, RA; Guan, D; Green, GM
MLA Citation
Spannagel, AW, Jr, JRR, Liddle, RA, Guan, D, and Green, GM. "An amino-terminal fragment of LCRF, LCRF-(1-35), has the same activity as the natural peptide." American Journal of Physiology - Gastrointestinal and Liver Physiology 273.3 36-3 (1997): G754-G758.
Source
scival
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
273
Issue
3 36-3
Publish Date
1997
Start Page
G754
End Page
G758

An amino-terminal fragment of LCRF, LCRF-(1-35), has the same activity as the natural peptide

A cholecystoki nin (CCK)-releasing peptide, luminal CCK-releasing factor (LCRF), has been purified from rat jejunal secretion. Amino acid analysis and mass spectral analysis showed that the purified peptide is composed of 70-75 amino acid residues and has a mass of 8, 136 Da. Microsequence analysis of LCRF yielded an amino acid sequence for the ammo-terminal 41 residues. To determine the biologically active region of the molecule, a peptide was synthesized consisting of the aminoterminal 35 amino acids of LCRF. In this study, intraduodenal infusion of LCRF-(1-35) significantly stimulated pancreatic secretion in conscious rats. The dose-response curves to LCRF-(1-35) and to monitor peptide were similar and biphasic, with higher doses producing submaximal pancreatic secretory responses. The CCK-A receptor antagonist MK-329 abolished the pancreatic secretory response to intraduodenally infused LCRF-(1-35). These results demonstrate that LCRF biological activity is contained within the amino-terminal 35-amino acid portion of LCRF, and this fragment may be useful for investigating the role of LCRF in gastrointestinal function. Copyright © 1997 the American Physiological Society.

Authors
Spannagel, AW; Jr, JRR; Liddle, RA; Guan, D; Green, GM
MLA Citation
Spannagel, AW, Jr, JRR, Liddle, RA, Guan, D, and Green, GM. "An amino-terminal fragment of LCRF, LCRF-(1-35), has the same activity as the natural peptide." American Journal of Physiology 273.3 PART 1 (1997): G706-G712.
Source
scival
Published In
The American journal of physiology
Volume
273
Issue
3 PART 1
Publish Date
1997
Start Page
G706
End Page
G712

Regulation of biliary secretion through apical purinergic receptors in cultured rat cholangiocytes

To evaluate whether ATP in bile serves as a signaling factor regulating ductular secretion, voltage-clamp studies were performed using a novel normal rat cholangiocyte (NRC) model. In the presence of amiloride (100 μM) to block Na+ channels, exposure of the apical membrane to ATP significantly increased the short-circuit current (I(SC)) from 18.2 ± 5.9 to 52.8 ± 12.7 μA (n = 18). The response to ATP is mediated by basolateral-to-apical Cl- transport because it is inhibited by 1) the Cl- channel blockers 4,4'- diisothiocyanostilbene-2,2'-disulfonic acid (1 mM), diphenylanthranilic acid (1.5 mM), or 5-nitro-2-(3-phenylpropylamino)benzoic acid (50 or 100 μM) in the apical chamber, 2) the K+ channel blocker Ba2+ (5 mM), or 3) the Na+- K+-2Cl cotransport inhibitor bumetanide (200 μM) in the basolateral chamber. Other nucleotides stimulated an increase in I(SC) with a rank order potency of UTP = ATP = adenosine 5'-O-(3)-thiotriphosphate, consistent with P(2U) purinergic receptors. ADP, AMP, 2-methylthioadenosine 5'-triphosphate, and adenosine had no effect. A cDNA encoding a rat P(2U) receptor (rP(2U)R) was isolated from a liver cDNA library, and functional expression of the corresponding mRNA in Xenopus laevis oocytes resulted in the appearance of ATP-stimulated currents with a similar pharmacological profile. Northern analysis identified hybridizing mRNA transcripts in NRC as well as other cell types in rat liver. These findings indicate that exposure of polarized cholangiocytes to ATP results in luminal Cl- secretion through activation of P(2U) receptors in the apical membrane. Release of ATP into bile may serve as an autocrine or paracrine signal regulating cholangiocyte secretory function.

Authors
Schlenker, T; Romac, JM-J; Sharara, AI; Roman, RM; Kim, SJ; Larusso, N; Liddle, RA; Fitz, JG
MLA Citation
Schlenker, T, Romac, JM-J, Sharara, AI, Roman, RM, Kim, SJ, Larusso, N, Liddle, RA, and Fitz, JG. "Regulation of biliary secretion through apical purinergic receptors in cultured rat cholangiocytes." American Journal of Physiology - Gastrointestinal and Liver Physiology 273.5 36-5 (1997): G1108-G1117.
Source
scival
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
273
Issue
5 36-5
Publish Date
1997
Start Page
G1108
End Page
G1117

Regulation of cholecystokinin secretion in STC-1 cells by nitric oxide.

In the present study we evaluated the effects of agents anticipated to change NO levels on the secretion of cholecystokinin (CCK) from STC-1 cells. After a 15-min treatment with the nitric oxide (NO) generating agent sodium nitroprusside (SNP; 10 microM), a 24% inhibition in basal CCK release and an increase in cellular guanosine 3',5'-cyclic monophosphate (cGMP) levels were noted. By contrast, SNP (10 microM) had no effect on CCK release stimulated by L-phenylalanine (20 mM). Inhibition of NO synthase (NOS) with NG-nitro-L-arginine methyl ester (L-NAME) produced dose-dependent stimulation in CCK release. L-NAME (100-400 microM) also inhibited ATP-sensitive potassium (KATP) channels in cell-attached patches. Pretreatment of cells with disopyramide (200 microM), a KATP channel blocker, blocked L-NAME stimulation of CCK release. After inhibition of potassium channel activity by L-NAME, addition of the nonhydrolyzable cGMP analogue 8-bromo-cGMP (1-2 mM) reactivated potassium channels. NO-generating agents had no effect on channel activity in inside-out membrane patches. It is concluded that NO may serve as an important regulator of basal CCK release.

Authors
Mangel, AW; Scott, L; Prpic, V; Liddle, RA
MLA Citation
Mangel, AW, Scott, L, Prpic, V, and Liddle, RA. "Regulation of cholecystokinin secretion in STC-1 cells by nitric oxide." Am J Physiol 271.4 Pt 1 (October 1996): G650-G654.
PMID
8897884
Source
pubmed
Published In
The American journal of physiology
Volume
271
Issue
4 Pt 1
Publish Date
1996
Start Page
G650
End Page
G654

Evidence that CCK-58 has structure that influences its biological activity.

Many biologically active peptides exist in multiple molecular forms, but the functional significance of regions outside the region of bioactivity is unknown. The biological and immunological data presented in this study indicate that cholecystokinin-58 (CCK-58), unlike other forms of cholecystokinin, has structure that influences its bioactivity. CCK-58 was purified from acid extracts of canine intestinal mucosa until a single absorbance peak was obtained during reverse-phase chromatography. Amino acid analysis precisely determined the peptide concentrations of purified CCK-58 and synthetic CCK-8. Our hypothesis was that if the amino terminus of CCK-58 influences its bioactivity then its activity would be modified when this region was removed from the peptide. To evaluate the importance of the amino terminus of CCK-58 to influence its biological activity, the abilities of CCK-58 and CCK-8 to release amylase from pancreatic acini were compared before and after tryptic digestion. Tryptic digestion of CCK-58 decreased the half-maximal stimulation (EC50) for amylase release from 96 to 28 pM. The EC50 for digested CCK-58 was similar to that for CCK-8 (17 pM). These results suggest that CCK-58 has a structure that shields its bioactive carboxyl terminus. This is further supported by the finding that carboxyl fragments generated from CCK-58 by trypsin or by partial acid hydrolysis were greater than twofold more immunoreactive than the intact CCK-58. The diminished activity of CCK-58 SK shields the carboxyl terminus, which is important to its biological and immunological activities.

Authors
Reeve, JR; Eysselein, VE; Rosenquist, G; Zeeh, J; Regner, U; Ho, FJ; Chew, P; Davis, MT; Lee, TD; Shively, JE; Brazer, SR; Liddle, RA
MLA Citation
Reeve, JR, Eysselein, VE, Rosenquist, G, Zeeh, J, Regner, U, Ho, FJ, Chew, P, Davis, MT, Lee, TD, Shively, JE, Brazer, SR, and Liddle, RA. "Evidence that CCK-58 has structure that influences its biological activity." Am J Physiol 270.5 Pt 1 (May 1996): G860-G868.
PMID
8967499
Source
pubmed
Published In
The American journal of physiology
Volume
270
Issue
5 Pt 1
Publish Date
1996
Start Page
G860
End Page
G868

Purification and characterization of a luminal cholecystokinin-releasing factor from rat intestinal secretion.

Cholecystokinin (CCK) secretion in rats and humans is inhibited by pancreatic proteases and bile acids in the intestine. It has been hypothesized that the inhibition of CCK release caused by pancreatic proteases is due to proteolytic inactivation of a CCK-releasing peptide present in intestinal secretion. To purify the putative luminal CCK-releasing factor (LCRF), intestinal secretions were collected by perfusing a modified Thiry-Vella fistula of jejunum in conscious rats. From these secretions, the peptide was concentrated by ultrafiltration followed by low-pressure reverse-phase chromatography and purified by reverse-phase high-pressure liquid chromatography. Purity was confirmed by high-performance capillary electrophoresis. Fractions were assayed for CCK-releasing activity by their ability to stimulate pancreatic protein secretion when infused into the proximal small intestine of conscious rats. Partially purified fractions strongly stimulated both pancreatic secretion and CCK release while CCK receptor blockade abolished the pancreatic response. Amino acid analysis and mass spectral analysis showed that the purified peptide is composed of 70-75 amino acid residues and has a mass of 8136 Da. Microsequence analysis of LCRF yielded an amino acid sequence for 41 residues as follows: STFWAYQPDGDNDPTDYQKYEHTSSPSQLLAPGDYPCVIEV. When infused intraduodenally, the purified peptide stimulated pancreatic protein and fluid secretion in a dose-related manner in conscious rats and significantly elevated plasma CCK levels. Immunoaffinity chromatography using antisera raised to synthetic LCRF-(1-6) abolished the CCK releasing activity of intestinal secretions. These studies demonstrate, to our knowledge, the first chemical characterization of a luminally secreted enteric peptide functioning as an intraluminal regulator of intestinal hormone release.

Authors
Spannagel, AW; Green, GM; Guan, D; Liddle, RA; Faull, K; Reeve, JR
MLA Citation
Spannagel, AW, Green, GM, Guan, D, Liddle, RA, Faull, K, and Reeve, JR. "Purification and characterization of a luminal cholecystokinin-releasing factor from rat intestinal secretion." Proc Natl Acad Sci U S A 93.9 (April 30, 1996): 4415-4420.
PMID
8633081
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
93
Issue
9
Publish Date
1996
Start Page
4415
End Page
4420

Beta-adrenergic regulation of cholecystokinin secretion in STC-1 cells.

Previously, it has been shown that an increase in adenosine 3',5'-cyclic monophosphate (cAMP) levels stimulates intestinal secretion of cholecystokinin (CCK); however, the mechanisms for increasing intracellular cAMP levels are not known. Using the CCK-secreting intestinal cell line, STC-1, we evaluated whether beta-adrenergic receptors (beta-ARs) might be present on STC-1 cells and whether they stimulated CCK release through increases in cAMP. Photoaffinity labeling of beta-ARs from solubilized STC-1 cell membranes revealed photoincorporation of the agonist [125I]iodocyanopindolol into an approximately 75-kDa band. Addition of the beta-AR agonist, isoproterenol, in the presence of 3-isobutyl-1-methylxanthine, produced a concentration-dependent increase in both cAMP levels and CCK release. Blockade of beta 1- and/or beta 2-ARs significantly inhibited isoproterenol-stimulated increases in cAMP production and CCK release. With the use of fura 2-loaded cells to measure changes in intracellular Ca2+ concentration ([Ca2+]i), isoproterenol stimulation was found to increase cytosolic Ca2+ levels. To evaluate whether this increase in [Ca2+]i was due to release of Ca2+ or influx of Ca2+, cells were treated with the L-type calcium channel blocker, diltiazem, which inhibited isoproterenol-stimulated CCK secretion. Furthermore, in patch-clamp studies with inside-out membrane patches, addition of the catalytic subunit of protein kinase A activated diltiazem-sensitive Ca2+ channels. It is concluded that beta-ARs are present on STC-1 cells and are coupled to the production of cAMP, which may increase CCK release through a calcium-dependent process.

Authors
Scott, L; Prpic, V; Capel, WD; Basavappa, S; Mangel, AW; Gettys, TW; Liddle, RA
MLA Citation
Scott, L, Prpic, V, Capel, WD, Basavappa, S, Mangel, AW, Gettys, TW, and Liddle, RA. "Beta-adrenergic regulation of cholecystokinin secretion in STC-1 cells." Am J Physiol 270.2 Pt 1 (February 1996): G291-G297.
PMID
8779971
Source
pubmed
Published In
The American journal of physiology
Volume
270
Issue
2 Pt 1
Publish Date
1996
Start Page
G291
End Page
G297

Depolarization-stimulated cholecystokinin secretion is mediated by L-type calcium channels in STC-1 cells.

To examine the role of calcium channels in depolarization-activated cholecystokinin (CCK) release, studies were performed in an intestinal CCK-secreting cell line, STC-1. Blockade of potassium channels with barium chloride (5 mM) increased the release of CCK by 374.6 +/- 46.6% of control levels. Barium-induced secretion was inhibited by the L-type calcium-channel blocker, nicardipine. Nicardipine (10(-9)-10(-5) M) produced a dose-dependent inhibition in barium-stimulated secretion with a half-maximal inhibition (IC50) value of 0.1 microM. A second L-type calcium-channel blocker, diltiazem (10(-9)-10(-4) M), also inhibited barium-induced CCK secretion with an IC50 value of 5.1 microM. By contrast, the T-type calcium-channel blocker, nickel chloride (10(-7)-10(-8) M), failed to significantly inhibit barium-induced CCK secretion. To further evaluate a role for L-type calcium channels in the secretion of CCK, the effects of the L-type calcium channel opener, BAY K 8644, were examined. BAY K 8644 (10(-8)-10(-4) M) produced a dose-dependent stimulation in CCK release with a mean effective concentration value of 0.2 microM. Recordings of single-channel currents from inside-out membrane patches showed activation of calcium channels by BAY K 8644 (1 microM), with a primary channel conductance of 26.0 +/- 1.2 pS. It is concluded that inhibition of potassium channel activity depolarizes the plasma membrane, thereby activating L-type, but not T-type, calcium channels. The corresponding influx of calcium serves to trigger secretion of CCK.

Authors
Mangel, AW; Scott, L; Liddle, RA
MLA Citation
Mangel, AW, Scott, L, and Liddle, RA. "Depolarization-stimulated cholecystokinin secretion is mediated by L-type calcium channels in STC-1 cells." Am J Physiol 270.2 Pt 1 (February 1996): G287-G290.
PMID
8779970
Source
pubmed
Published In
The American journal of physiology
Volume
270
Issue
2 Pt 1
Publish Date
1996
Start Page
G287
End Page
G290

beta-Adrenergic regulation of cholecystokinin secretion in STC-1 cells

Authors
Scott, L; Prpic, V; Capel, WD; Basavappa, S; Mangel, AW; Gettys, TW; Liddle, RA
MLA Citation
Scott, L, Prpic, V, Capel, WD, Basavappa, S, Mangel, AW, Gettys, TW, and Liddle, RA. "beta-Adrenergic regulation of cholecystokinin secretion in STC-1 cells." AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 270.2 (February 1996): G291-G297.
Source
wos-lite
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
270
Issue
2
Publish Date
1996
Start Page
G291
End Page
G297

Adaptation to fat markedly increases pancreatic secretory response to intraduodenal fat in rats.

Exposure to higher levels of fat in the diet increases the secretion of fat-digesting enzymes in pancreatic juice. This study examines the functional consequences of this phenomenon and demonstrates that adapting rats to high fat (triglyceride) loads increases the release of cholecystokinin (CCK) and the pancreatic secretory response to intraduodenal fat. Lipolytic activity in the small intestine was also higher in adapted rats. Exchanging pancreatic juice from unadapted rats with pancreatic juice from adapted rats decreased the response to fat in adapted rats and increased the response to fat in unadapted rats. Infusing oleic acid into unadapted rats stimulated CCK secretion and pancreatic exocrine secretion to levels observed with triglycerides in adapted rats. Pancreatic exocrine secretion in response to intraduodenal fat in rats adapted to a high-fat (20%) diet were significantly higher than the responses seen in rats fed a low-fat (5%) diet. Adaptation to fat increases the pancreatic secretory and plasma CCK responses to fat, apparently by increasing the efficiency of triglyceride digestion and thereby increasing CCK release.

Authors
Spannagel, AW; Nakano, I; Tawil, T; Chey, WY; Liddle, RA; Green, GM
MLA Citation
Spannagel, AW, Nakano, I, Tawil, T, Chey, WY, Liddle, RA, and Green, GM. "Adaptation to fat markedly increases pancreatic secretory response to intraduodenal fat in rats." Am J Physiol 270.1 Pt 1 (January 1996): G128-G135.
PMID
8772510
Source
pubmed
Published In
The American journal of physiology
Volume
270
Issue
1 Pt 1
Publish Date
1996
Start Page
G128
End Page
G135

Regulation of cholecystokinin secretion in STC-1 cells by nitric oxide

In the present study, we evaluated the effects of agents anticipated to change NO levels on the secretion of cholecystokinin (CCK) from STC-1 cells. After a 15-min treatment with the nitric oxide (NO)generating agent sodium nitroprusside (SNP; 10 μM), a 24% inhibition in basal CCK release and an increase in cellular guanosine 3',5'-cyclic monophosphate (cGMP) levels were noted. By contrast, SNP (10 μM) had no effect on CCK release stimulated by L-phenylalanine (20 mM). Inhibition of NO synthase (NOS) with N(G)-nitro-L- arginine methyl ester (L-NAME) produced dose-dependent stimulation in CCK release. L-NAME (100-400 μM) also inhibited ATP-sensitive potassium (K(ATP)) channels in cell-attached patches. Pretreatment of cells with disopyramide (200 μM), a K(ATP) channel blocker, blocked L-NAME stimulation of CCK release. After inhibition of potassium channel activity by L-NAME, addition of the nonhydrolyzable cGMP analogue 8-bromo-cGMP (1-2 mM) reactivated potassium channels. NO-generating agents had no effect on channel activity in inside-out membrane patches. It is concluded that NO may serve as an important regulator of basal CCK release.

Authors
Mangel, AW; Scott, L; Prpic, V; Liddle, RA
MLA Citation
Mangel, AW, Scott, L, Prpic, V, and Liddle, RA. "Regulation of cholecystokinin secretion in STC-1 cells by nitric oxide." American Journal of Physiology - Gastrointestinal and Liver Physiology 271.4 34-4 (1996): G650-G654.
Source
scival
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
271
Issue
4 34-4
Publish Date
1996
Start Page
G650
End Page
G654

Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene

Hereditary pancreatitis (HP) is a rare, early-onset genetic disorder characterized by epigastric pain and often more serious complications. We now report that an Arg-His substitution at residue 117 of the cationic trypsinogen gene is associated with the HP phenotype. This mutation was observed in all HP affected individuals and obligate carriers from five kindreds, but not in individuals who married into the families nor in 140 unrelated individuals. X-ray crystal structure analysis, molecular modelling, and protein digest data indicate that the Arg 117 residue is a trypsin- sensitive site. Cleavage at this site is probably part of a fail-safe mechanism by which trypsin, which is activated within the pancreas, may be inactivated; loss of this cleavage site would permit autodigestion resulting in pancreatitis.

Authors
Whitcomb, DC; Gorry, MC; Preston, RA; Furey, W; Sossenheimer, MJ; Ulrich, CD; Martin, SP; Jr, LKG; Amann, ST; Toskes, PP; Liddle, R; McGrath, K; Uomo, G; Post, JC; Ehrlich, GD
MLA Citation
Whitcomb, DC, Gorry, MC, Preston, RA, Furey, W, Sossenheimer, MJ, Ulrich, CD, Martin, SP, Jr, LKG, Amann, ST, Toskes, PP, Liddle, R, McGrath, K, Uomo, G, Post, JC, and Ehrlich, GD. "Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene." Nature Genetics 14.2 (1996): 141-145.
PMID
8841182
Source
scival
Published In
Nature Genetics
Volume
14
Issue
2
Publish Date
1996
Start Page
141
End Page
145
DOI
10.1038/ng1096-141

Adaptation to fat markedly increases pancreatic secretory response to intraduodenal fat in rats

Exposure to higher levels of fat in the diet increases the secretion of fat-digesting enzymes in pancreatic juice. This study examines the functional consequences of this phenomenon and demonstrates that adapting rats to high fat (triglyceride) loads increases the release of cholecystokinin (CCK) and the pancreatic secretory response to intraduodenal fat. Lipolytic activity in the small intestine was also higher in adapted rats. Exchanging pancreatic juice from unadapted rats with pancreatic juice from adapted rats decreased the response to fat in adapted rats and increased the response to fat in unadapted rats. Infusing oleic acid into unadapted rats stimulated CCK secretion and pancreatic exocrine secretion to levels observed with triglycerides in adapted rats. Pancreatic exocrine secretion in response to intraduodenal fat in rats adapted to a high-fat (20%) diet were significantly higher than the responses seen in rats fed a low-fat (5%) diet. Adaptation to fat increases the pancreatic secretory and plasma CCK responses to fat, apparently by increasing the efficiency of triglyceride digestion and thereby increasing CCK release.

Authors
Spannagel, AW; Nakano, I; Tawil, T; Chey, WY; Liddle, RA; Green, GM
MLA Citation
Spannagel, AW, Nakano, I, Tawil, T, Chey, WY, Liddle, RA, and Green, GM. "Adaptation to fat markedly increases pancreatic secretory response to intraduodenal fat in rats." American Journal of Physiology - Gastrointestinal and Liver Physiology 270.1 33-1 (1996): G128-G135.
Source
scival
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
270
Issue
1 33-1
Publish Date
1996
Start Page
G128
End Page
G135

Evidence that CCK-58 has structure that influences its biological activity

Many biologically active peptides exist in mul- tiple molecular forms, but the functional significance of regions outside the region of bioactivity is unknown. The biological and immunological data presented in this study indicate that cholecystokinin-58 (CCK-58), unlike other forms of cholecystokinin, has structure that influences its bioactivity. CCK-58 was purified from acid extracts of canine intestinal mucosa until a single absorbance peak was obtained during reverse-phase chromatography. Amino acid analysis precisely determined the peptide concentrations of purified CCK-58 and synthetic CCK-8. Our hypothesis was that if the amino terminus of CCK-58 influences its bioactivity then its activity would be modified when this region was removed from the peptide. To evaluate the importance of the amino terminus of CCK-58 to influence its biological activity, the abilities of CCK-58 and CCK-8 to release amylase from pancreatic acini were compared before and after tryptic digestion. Tryptic digestion of CCK-58 decreased the halfmaximal stimulation (EC50) for amylase release from 96 to 28 pM. The EC50 for digested CCK-58 was similar to that for CCK-8 (17 pM). These results suggest that CCK-58 has a structure that shields its bioactive carboxyl terminus. This is further supported by the finding that carboxyl fragments generated from CCK-58 by trypsin or by partial acid hydrolysis were greater than twofold more immunoreactive than the intact CCK-58. The diminished activity of CCK-58 indicates that the amino terminus of CCK-58 shields the carboxyl terminus, which is important to its biological and immunological activities.

Authors
Jr, JRR; Eysselein, VE; Rosenquist, G; Zeeh, J; Regner, U; Ho, FJ; Chew, P; Davis, MT; Terry, DL; Shively, JE; Brazer, SR; Liddle, RA
MLA Citation
Jr, JRR, Eysselein, VE, Rosenquist, G, Zeeh, J, Regner, U, Ho, FJ, Chew, P, Davis, MT, Terry, DL, Shively, JE, Brazer, SR, and Liddle, RA. "Evidence that CCK-58 has structure that influences its biological activity." American Journal of Physiology - Gastrointestinal and Liver Physiology 270.5 33-5 (1996): G860-G869.
Source
scival
Published In
American Journal of Physiology - Gastrointestinal and Liver Physiology
Volume
270
Issue
5 33-5
Publish Date
1996
Start Page
G860
End Page
G869

β-adrenergic regulation of cholecystokinin secretion in STC-1 cells

Previously, it has been shown that an increase in adenosine 3',5'-cyclic monophosphate (cAMP) levels stimulates intestinal secretion of cholecystokinin (CCK); however, the mechanisms for increasing intracellular cAMP levels are not known. Using the CCK-secreting intestinal cell line, STC- 1, we evaluated whether β-adrenergic receptors (β-ARs) might be present on STC-1 cells and whether they stimulated CCK release through increases in cAMP. Photoaffinity labeling of β-ARs from solubilized STC-1 cell membranes revealed photoincorporation of the agonist [125I]iodocyanopindolol into an ~75-kDa band. Addition of the β-AR agonist, isoproterenol, in the presence of 3-isobutyl-1-methylxanthine, produced a concentration-dependent increase in both cAMP levels and CCK release. Blockade of β1- and/or β2-ARs significantly inhibited isoproterenol-stimulated increases in cAMP production and CCK release. With the use of fura 2-loaded cells to measure changes in intracellular Ca2+ concentration ([Ca2+](i)), isoproterenol stimulation was found to increase cytosolic Ca2+ levels. To evaluate whether this increase in [Ca2+](i) was due to release of Ca2+ or influx of Ca2+, cells were treated with the L-type calcium channel blocker, diltiazem, which inhibited isoproterenol-stimulated CCK secretion. Furthermore, in patch- clamp studies with inside-out membrane patches, addition of the catalytic subunit of protein kinase A activated diltiazem-sensitive Ca2+ channels. It is concluded that β-ARs are present on STC-1 cells and are coupled to the production of cAMP, which may increase CCK release through a calcium- dependent process.

Authors
Scott, L; Prpic, V; Capel, WD; Basavappa, S; Mangel, AW; Gettys, TW; Liddle, RA
MLA Citation
Scott, L, Prpic, V, Capel, WD, Basavappa, S, Mangel, AW, Gettys, TW, and Liddle, RA. "β-adrenergic regulation of cholecystokinin secretion in STC-1 cells." American Journal of Physiology - Gastrointestinal and Liver Physiology 270.2 33-2 (1996): G291-G297.
Source
scival
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
270
Issue
2 33-2
Publish Date
1996
Start Page
G291
End Page
G297

Depolarization-stimulated cholecystokinin secretion is mediated by L-type calcium channels in STC-1 cells

To examine the role of calcium channels in depolarization-activated cholecystokinin (CCK) release, studies were performed in an intestinal CCK- secreting cell line, STC-1. Blockade of potassium channels with barium chloride (5 mM) increased the release of CCK by 374.6 ± 46.6% of control levels. Barium-induced secretion was inhibited by the L-type calcium-channel blocker, nicardipine. Nicardipine (10-9-10-5 M) produced a dose-dependent inhibition in barium-stimulated secretion with a half-maximal inhibition (IC50) value of 0.1 μM. A second L-type calcium-channel blocker, diltiazem (10-9-10-4 M), also inhibited barium-induced CCK secretion with an IC50 value of 5.1 μM. By contrast, the T-type calcium-channel blocker, nickel chloride (10-7-10-3 M), failed to significantly inhibit barium-induced CCK secretion. To further evaluate a role for L-type calcium channels in the secretion of CCK, the effects of the L-type calcium channel opener, BAY K 8644, were examined. BAY K 8644 (10-8-10-4 M) produced a dose-dependent stimulation in CCK release with a mean effective concentration value of 0.2 μM. Recordings of single-channel currents from inside-out membrane patches showed activation of calcium channels by BAY K 8644 (1 μM), with a primary channel conductance of 26.0 ± 1.2 pS. It is concluded that inhibition of potassium channel activity depolarizes the plasma membrane, thereby activating L-type, but not T-type, calcium channels. The corresponding influx of calcium serves to trigger secretion of CCK.

Authors
Mangel, AW; Scott, L; Liddle, RA
MLA Citation
Mangel, AW, Scott, L, and Liddle, RA. "Depolarization-stimulated cholecystokinin secretion is mediated by L-type calcium channels in STC-1 cells." American Journal of Physiology - Gastrointestinal and Liver Physiology 270.2 33-2 (1996): G287-G290.
Source
scival
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
270
Issue
2 33-2
Publish Date
1996
Start Page
G287
End Page
G290

Neurohumoral control of the exocrine pancreas

Recent advances in the study of pancreatic exocrine secretion are reviewed, with emphasis on neurohumoral mechanisms. Pancreatic exocrine and endocrine function are precisely regulated and involve both neural and hormonal mediators. The role of gut peptides continues to be an active area of investigation. The stimulatory role of the adrenergic component of the sympathetic nervous system and vagal control of hormone-stimulated pancreatic exocrine secretion are described. Studies of the peptidergic nervous system support the importance of both stimulatory (cholecystokinin) and inhibitory (pancreatic peptide) peptides in the coordination of exocrine pancreatic secretion. Molecular biology techniques have elucidated peptide signaling pathways for humoral mediators of pancreatic secretion. The role of nitric oxide on pancreatic blood flow and pancreatic secretion is explored. The properties of proteins that stimulate hormone release and pancreatic secretion are discussed. Finally, the role of growth factors on pancreatic duct growth and pancreatic cancer is reviewed. These findings over the past year elucidate some of the complex neurohormonal factors that regulate pancreatic function.

Authors
Shetzline, MA; Liddle, RA
MLA Citation
Shetzline, MA, and Liddle, RA. "Neurohumoral control of the exocrine pancreas." Current Opinion in Gastroenterology 12.5 (1996): 423-428.
Source
scival
Published In
Current Opinion in Gastroenterology
Volume
12
Issue
5
Publish Date
1996
Start Page
423
End Page
428
DOI
10.1097/00001574-199609000-00003

Chemical messengers of the gut.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Chemical messengers of the gut." West J Med 163.5 (November 1995): 485-486.
PMID
8533422
Source
pubmed
Published In
Western Journal of Medicine
Volume
163
Issue
5
Publish Date
1995
Start Page
485
End Page
486

CLONING, FUNCTIONAL-CHARACTERIZATION AND TISSUE EXPRESSION OF THE RAT-LIVER P-2U RECEPTOR

Authors
SHARARA, AI; ROMAC, JMJ; LIDDLE, RA; FITZ, JG
MLA Citation
SHARARA, AI, ROMAC, JMJ, LIDDLE, RA, and FITZ, JG. "CLONING, FUNCTIONAL-CHARACTERIZATION AND TISSUE EXPRESSION OF THE RAT-LIVER P-2U RECEPTOR." HEPATOLOGY 22.4 (October 1995): 790-790.
Source
wos-lite
Published In
Hepatology
Volume
22
Issue
4
Publish Date
1995
Start Page
790
End Page
790

Regulation of cholecystokinin secretion by intraluminal releasing factors.

Ingested nutrients stimulate secretion of gastrointestinal hormones that are necessary for the coordinated processes of digestion and absorption of food. One of the most important hormonal regulators of the digestive process is cholecystokinin (CCK). This hormone is concentrated in the proximal small intestine and is secreted into the blood on the ingestion of proteins and fats. The physiological actions of CCK include stimulation of pancreatic secretion and gallbladder contraction, regulation of gastric emptying, and induction of satiety. Therefore, in a highly coordinated manner CCK regulates the ingestion, digestion, and absorption of nutrients. The manner by which foods affect enteric hormone secretion is largely unknown. However, it has recently become apparent that two CCK-releasing factors are present in the lumen of the proximal small intestine. One of these factors, known as monitor peptide, has been chemically characterized. Monitor peptide is produced by pancreatic acinar cells and is secreted by way of the pancreatic duct into the duodenum. On reaching the small intestine, monitor peptide interacts with CCK cells to induce hormone secretion. A CCK-releasing factor of intestinal origin has been partially characterized and is responsible for stimulation of CCK secretion after 1) ingestion of protein or fats, 2) instillation of protease inhibitors into the duodenum, or 3) diversion of bile-pancreatic juice from the upper small intestine. Together, these releasing factors provide positive and negative feedback mechanisms for regulation of CCK secretion. This review discusses the physiological observations that have led to the chemical characterization of the CCK-releasing factors and the potential implications of this work to other hormones of the gastrointestinal tract.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Regulation of cholecystokinin secretion by intraluminal releasing factors." Am J Physiol 269.3 Pt 1 (September 1995): G319-G327. (Review)
PMID
7573441
Source
pubmed
Published In
The American journal of physiology
Volume
269
Issue
3 Pt 1
Publish Date
1995
Start Page
G319
End Page
G327

REGULATION OF CHOLECYSTOKININ SECRETION BY INTRALUMINAL RELEASING FACTORS

Authors
LIDDLE, RA
MLA Citation
LIDDLE, RA. "REGULATION OF CHOLECYSTOKININ SECRETION BY INTRALUMINAL RELEASING FACTORS." AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 269.3 (September 1995): G319-G327.
Source
wos-lite
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
269
Issue
3
Publish Date
1995
Start Page
G319
End Page
G327

CHOLECYSTOKININ IS A PHYSIOLOGICAL MEDIATOR OF FAT-INDUCED LOWER ESOPHAGEAL SPHINCTER RELAXATION

Authors
CIACCIA, D; BRAZER, SR; LAWSON, DC; MANTYH, CR; LIDDLE, RA; PAPPAS, TN
MLA Citation
CIACCIA, D, BRAZER, SR, LAWSON, DC, MANTYH, CR, LIDDLE, RA, and PAPPAS, TN. "CHOLECYSTOKININ IS A PHYSIOLOGICAL MEDIATOR OF FAT-INDUCED LOWER ESOPHAGEAL SPHINCTER RELAXATION." April 1995.
Source
wos-lite
Published In
Gastroenterology
Volume
108
Issue
4
Publish Date
1995
Start Page
A584
End Page
A584
DOI
10.1016/0016-5085(95)26648-8

REGULATION OF L-TYPE CALCIUM CHANNELS BY PROTEIN KINASE-A AND CALCIUM-CALMODULIN KINASE-II IN STC-1 CELLS

Authors
MANGEL, AW; LIDDLE, RA
MLA Citation
MANGEL, AW, and LIDDLE, RA. "REGULATION OF L-TYPE CALCIUM CHANNELS BY PROTEIN KINASE-A AND CALCIUM-CALMODULIN KINASE-II IN STC-1 CELLS." GASTROENTEROLOGY 108.4 (April 1995): A988-A988.
Source
wos-lite
Published In
Gastroenterology
Volume
108
Issue
4
Publish Date
1995
Start Page
A988
End Page
A988
DOI
10.1016/0016-5085(95)28255-6

PAIN RELIEF AFTER ENDOSCOPIC STENTING IN CHRONIC-PANCREATITIS IS ASSOCIATED WITH REDUCTION IN FASTING CHOLECYSTOKININ LEVELS

Authors
EISEN, GM; COLEMAN, SD; MANIATIS, A; COTTON, PB; LIDDLE, RA
MLA Citation
EISEN, GM, COLEMAN, SD, MANIATIS, A, COTTON, PB, and LIDDLE, RA. "PAIN RELIEF AFTER ENDOSCOPIC STENTING IN CHRONIC-PANCREATITIS IS ASSOCIATED WITH REDUCTION IN FASTING CHOLECYSTOKININ LEVELS." GASTROENTEROLOGY 108.4 (April 1995): A352-A352.
Source
wos-lite
Published In
Gastroenterology
Volume
108
Issue
4
Publish Date
1995
Start Page
A352
End Page
A352

Dietary regulation of glucose-dependent insulinotropic peptide (GIP) gene expression in rat small intestine.

The hormone, glucose-dependent insulinotropic peptide (GIP), is an important incretin regulator of the gastrointestinal tract. To investigate whether diet is important for the control of GIP gene expression in the small intestine, GIP messenger RNA (mRNA) levels were measured in rats during fasting and after glucose or fat administration. Ribonuclease protection analyses revealed that glucose and fat administration increased GIP mRNA levels by 4-fold and 2.5-fold, respectively, compared with the control, and that prolonged fasting decreased GIP mRNA levels to 44% of those of control animals. Glucose infusion increased plasma GIP levels and tended to stimulate an increase in the GIP hormone concentration in the mucosa of the small intestine. Administration of fat also stimulated an increase of plasma GIP levels but did not modify tissue GIP concentrations. Prolonged fasting tended to decrease plasma GIP levels, although GIP tissue concentrations did not change. These data suggest that dietary glucose or fat stimulates GIP synthesis and secretion, and that food deprivation causes a decrease in GIP synthesis and secretion. This regulation involves changes at the pretranslational level and is reflected by modifications of GIP mRNA expression.

Authors
Higashimoto, Y; Opara, EC; Liddle, RA
MLA Citation
Higashimoto, Y, Opara, EC, and Liddle, RA. "Dietary regulation of glucose-dependent insulinotropic peptide (GIP) gene expression in rat small intestine." Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 110.2 (February 1995): 207-214.
PMID
7599968
Source
pubmed
Published In
Comparative Biochemistry and Physiology. Part C, Pharmacology, Toxicology & Endocrinology
Volume
110
Issue
2
Publish Date
1995
Start Page
207
End Page
214

PHENYLALANINE-STIMULATED SECRETION OF CHOLECYSTOKININ IS CALCIUM-DEPENDENT

Authors
MANGEL, AW; PRPIC, V; WONG, H; BASAVAPPA, S; HURST, LJ; SCOTT, L; GARMAN, RL; HAYES, JS; SHARARA, AI; SNOW, ND; WALSH, JH; LIDDLE, RA
MLA Citation
MANGEL, AW, PRPIC, V, WONG, H, BASAVAPPA, S, HURST, LJ, SCOTT, L, GARMAN, RL, HAYES, JS, SHARARA, AI, SNOW, ND, WALSH, JH, and LIDDLE, RA. "PHENYLALANINE-STIMULATED SECRETION OF CHOLECYSTOKININ IS CALCIUM-DEPENDENT." AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 268.1 (January 1995): G90-G94.
Source
wos-lite
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
268
Issue
1
Publish Date
1995
Start Page
G90
End Page
G94

Regulation of cholecystokinin secretion by intraluminal releasing factors

Ingested nutrients stimulate secretion of gastrointestinal hormones that are necessary for the coordinated processes of digestion and absorption of food. One of the most important hormonal regulators of the digestive process is cholecystokinin (CCK). This hormone is concentrated in the proximal small intestine and is secreted into the blood on the ingestion of proteins and fats. The physiological actions of CCK include stimulation of pancreatic secretion and gallbladder contraction, regulation of gastric emptying, and induction of satiety. Therefore, in a highly coordinated manner CCK regulates the ingestion, digestion, and absorption of nutrients. The manner by which foods affect enteric hormone secretion is largely unknown. However, it has recently become apparent that two CCK-releasing factors are present in the lumen of the proximal small intestine. One of these factors, known as monitor peptide, has been chemically characterized. Monitor peptide is produced by pancreatic acinar cells and is secreted by way of the pancreatic duct into the duodenum. On reaching the small intestine, monitor peptide interacts with CCK cells to induce hormone secretion. A CCK-releasing factor of intestinal origin has been partially characterized and is responsible for stimulation of CCK secretion after 1) ingestion of protein or fats, 2) instillation of protease inhibitors into the duodenum, or 3) diversion of bile-pancreatic juice from the upper small intestine. Together, these releasing factors provide positive and negative feedback mechanisms for regulation of CCK secretion. This review discusses the physiological observations that have led to the chemical characterization of the CCK-releasing factors and the potential implications of this work to other hormones of the gastrointestinal tract.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Regulation of cholecystokinin secretion by intraluminal releasing factors." American Journal of Physiology - Gastrointestinal and Liver Physiology 269.3 32-3 (1995): G319-G327.
Source
scival
Published In
American Journal of Physiology - Gastrointestinal and Liver Physiology
Volume
269
Issue
3 32-3
Publish Date
1995
Start Page
G319
End Page
G327

Phenylalanine-stimulated secretion of cholecystokinin is calcium dependent

The secretion of cholecystokinin was examined in STC-1 cells, an intestinal cholecystokinin (CCK)secreting cell line. Exposure to the amino acid L-phenylalanine increased release of CCK by 135%, 180%, and 251% of control levels after 15-min treatments with 5, 20, and 50 mM phenylalanine, respectively. L-Phenylalanine-induced secretion of CCK was inhibited by the calcium channel blocker diltiazem (10 μM). L-Phenylalanine (20 mM) also significantly increased cytosolic calcium levels in fura 2-acetoxymethyl ester (fura 2-AM)-loaded cells, and this increase was diltiazem sensitive. D- Phenylalanine, over the dose range of 5-50 mM, produced nonsignificant increases in CCK release. Treatment of STC-1 cells with 300 ng/ml of pertussis toxin for either 4 or 24 h did not significantly affect either basal release of CCK or L-phenylalanine-stimulated secretion. Patch-clamp recordings from cell-attached membrane patches showed a stimulation in calcium channel activity after L-phenylalanine. These results indicate that, in STC-1 cells, L-phenylalanine stimulates release of cholecystokinin via a calcium-dependent process.

Authors
Mangel, AW; Prpic, V; Wong, H; Basavappa, S; Hurst, LJ; Scott, L; Garman, RL; Hayes, JS; Sharara, AI; Snow, ND; Walsh, JH; Liddle, RA
MLA Citation
Mangel, AW, Prpic, V, Wong, H, Basavappa, S, Hurst, LJ, Scott, L, Garman, RL, Hayes, JS, Sharara, AI, Snow, ND, Walsh, JH, and Liddle, RA. "Phenylalanine-stimulated secretion of cholecystokinin is calcium dependent." American Journal of Physiology - Gastrointestinal and Liver Physiology 268.1 31-1 (1995): G90-G94.
Source
scival
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
268
Issue
1 31-1
Publish Date
1995
Start Page
G90
End Page
G94

Regulation of cholecystokinin secretion by bombesin in STC-1 cells.

Bombesin stimulates cholecystokinin (CCK) secretion, presumably by a direct effect on the intestinal CCK cell. The present objectives were to characterize bombesin-stimulated CCK release and to investigate the role of calcium in CCK secretion in an intestinal CCK-producing cell line (STC-1). Bombesin caused a dose-dependent release of CCK, which was reduced either in the absence of extracellular calcium or by calcium channel blockade, suggesting that influx of calcium is necessary for CCK secretion. Bombesin caused an increase in intracellular calcium concentration ([Ca2+]i) and increased efflux of 45Ca2+ from 45Ca(2+)-loaded cells. Radioligand binding studies and Northern analysis were consistent with the expression of a bombesin receptor. Thus bombesin stimulation of CCK release occurs via binding to a receptor and is dependent on increased [Ca2+]i. We propose that the STC-1 cell line may provide a useful model for studying the regulation of intestinal CCK secretion.

Authors
Snow, ND; Prpic, V; Mangel, AW; Sharara, AI; McVey, DC; Hurst, LJ; Vigna, SR; Liddle, RA
MLA Citation
Snow, ND, Prpic, V, Mangel, AW, Sharara, AI, McVey, DC, Hurst, LJ, Vigna, SR, and Liddle, RA. "Regulation of cholecystokinin secretion by bombesin in STC-1 cells." Am J Physiol 267.5 Pt 1 (November 1994): G859-G865.
PMID
7977748
Source
pubmed
Published In
The American journal of physiology
Volume
267
Issue
5 Pt 1
Publish Date
1994
Start Page
G859
End Page
G865

REGULATION OF CHOLECYSTOKININ SECRETION BY BOMBESIN IN STC-1 CELLS

Authors
SNOW, ND; PRPIC, V; MANGEL, AW; SHARARA, AI; MCVEY, DC; HURST, LJ; VIGNA, SR; LIDDLE, RA
MLA Citation
SNOW, ND, PRPIC, V, MANGEL, AW, SHARARA, AI, MCVEY, DC, HURST, LJ, VIGNA, SR, and LIDDLE, RA. "REGULATION OF CHOLECYSTOKININ SECRETION BY BOMBESIN IN STC-1 CELLS." AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 267.5 (November 1994): G859-G865.
Source
wos-lite
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
267
Issue
5
Publish Date
1994
Start Page
G859
End Page
G865

Characterization of ATP-sensitive potassium channels in intestinal, cholecystokinin-secreting cells.

In the present study, the electrophysiologic properties of ATP-sensitive potassium channels were evaluated in an intestinal, cholecystokinin-secreting cell line (STC-1). Channels were operative under basal conditions and, in cell-attached membrane patches, channel activity was decreased by glucose or disopyramide, agents which classically inhibit ATP-sensitive potassium channels. Channel activity was increased by the KATP channel opener, diazoxide. Intestinal ATP-sensitive potassium channels appear to behave in a similar manner to those found in cardiac and pancreatic beta cells.

Authors
Basavappa, S; Liddle, RA; Mangel, AW
MLA Citation
Basavappa, S, Liddle, RA, and Mangel, AW. "Characterization of ATP-sensitive potassium channels in intestinal, cholecystokinin-secreting cells." Biochem Biophys Res Commun 204.2 (October 28, 1994): 855-860.
PMID
7980553
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
204
Issue
2
Publish Date
1994
Start Page
855
End Page
860
DOI
10.1006/bbrc.1994.2538

Regulation of cholecystokinin secretion by ATP-sensitive potassium channels.

The relationship of potassium channel activity to the secretion of cholecystokinin (CCK) was evaluated in STC-1 cells, an intestinal CCK-secreting cell line. Patch-clamp and 86Rb efflux studies showed that an ATP-sensitive potassium channel was endogenously expressed in STC-1 cells. Furthermore, channels are present in sufficient number to significantly modulate whole cell potassium permeability after either channel activation or closure with diazoxide (100 microM) or disopyramide (200 microM), respectively. Inhibition of channel activity with glucose (5-20 mM) was found to depolarize the plasma membrane, increase cytosolic calcium levels, and stimulate CCK release. Glucose-mediated release of CCK, as well as the increase in cytosolic calcium, was inhibited by the calcium channel blocker diltiazem (10 microM). It is concluded that intestinal secretion of CCK may be tonically controlled by activity of basally active ATP-sensitive potassium channels, and after inhibition of channel activity, calcium-dependent CCK secretion is stimulated.

Authors
Mangel, AW; Prpic, V; Snow, ND; Basavappa, S; Hurst, LJ; Sharara, AI; Liddle, RA
MLA Citation
Mangel, AW, Prpic, V, Snow, ND, Basavappa, S, Hurst, LJ, Sharara, AI, and Liddle, RA. "Regulation of cholecystokinin secretion by ATP-sensitive potassium channels." Am J Physiol 267.4 Pt 1 (October 1994): G595-G600.
PMID
7943324
Source
pubmed
Published In
The American journal of physiology
Volume
267
Issue
4 Pt 1
Publish Date
1994
Start Page
G595
End Page
G600

REGULATION OF CHOLECYSTOKININ SECRETION BY ATP-SENSITIVE POTASSIUM CHANNELS

Authors
MANGEL, AW; PRPIC, V; SNOW, ND; BASAVAPPA, S; HURST, LJ; SHARARA, AI; LIDDLE, RA
MLA Citation
MANGEL, AW, PRPIC, V, SNOW, ND, BASAVAPPA, S, HURST, LJ, SHARARA, AI, and LIDDLE, RA. "REGULATION OF CHOLECYSTOKININ SECRETION BY ATP-SENSITIVE POTASSIUM CHANNELS." AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 267.4 (October 1994): G595-G600.
Source
wos-lite
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
267
Issue
4
Publish Date
1994
Start Page
G595
End Page
G600

Regulation of cholecystokinin synthesis and secretion in rat intestine.

Cholecystokinin is a classical gastrointestinal hormone that is produced by discrete endocrine cells of the upper small intestine. Cholecystokinin is produced in various molecular forms that result from differences in posttranslation processing of a single gene product. Cholecystokinin is secreted from the intestine in response to the ingestion of food. We observed that specific dietary substances increase the rate of transcription of the cholecystokinin gene and stimulate cholecystokinin release in rats. In contrast the paracrine transmitter, somatostatin, inhibits dietary-stimulated cholecystokinin secretion and lowers intestinal mRNA levels. Evidence that cholecystokinin gene expression is not necessarily linked to hormone secretion is supported by the observation that the neuropeptide, bombesin, stimulates cholecystokinin release but does not modify intestinal cholecystokinin mRNA levels. To examine the intracellular messengers that might regulate the cholecystokinin cell directly, we developed an in vitro method for studying cholecystokinin release from isolated intestinal mucosal cells. In this perifusion system, cholecystokinin release was stimulated by membrane depolarizing concentrations of KCl (50 mmol/L), the calcium ionophore A23187 (1 mumol/L), and the cAMP analogue dibutyryl cAMP (1 mumol/L). Biologically active cholecystokinin was also released in a dose-dependent manner by the peptide transmitters, bombesin and monitor peptide. These findings indicate that neurotransmitters and hormones may directly regulate the cholecystokinin cell and suggest that the phosphoinositide and adenylate cyclase cascades mediate stimulated-cholecystokinin secretion.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Regulation of cholecystokinin synthesis and secretion in rat intestine." J Nutr 124.8 Suppl (August 1994): 1308S-1314S. (Review)
PMID
8064378
Source
pubmed
Published In
The Journal of nutrition
Volume
124
Issue
8 Suppl
Publish Date
1994
Start Page
1308S
End Page
1314S

REGULATION OF CHOLECYSTOKININ SYNTHESIS AND SECRETION IN RAT INTESTINE

Authors
LIDDLE, RA
MLA Citation
LIDDLE, RA. "REGULATION OF CHOLECYSTOKININ SYNTHESIS AND SECRETION IN RAT INTESTINE." August 1994.
Source
wos-lite
Published In
The Journal of nutrition
Volume
124
Issue
8
Publish Date
1994
Start Page
S1308
End Page
S1314

Regulation of cholecystokinin secretion by calcium-dependent calmodulin kinase II: differential effects of phenylalanine and cAMP.

The release of cholecystokinin was investigated in STC-1 cells, an intestinal cholecystokinin-secreting cell line. Fifteen minute incubation of cells with the amino acid, L-phenylalanine (20 mM), or the phosphodiesterase inhibitor, IBMX (100 microM), stimulated cholecystokinin secretion. Stimulation of secretion by both agents was associated with an increase in cytosolic calcium and was inhibited by the calcium channel blocker, diltiazem (10 microM). The calcium-calmodulin kinase II inhibitor, KN-65 (1.4 microM), markedly reduced IBMX-stimulated secretion, but had no effect on phenylalanine-mediated activity. KN-62 also inhibited IBMX-induced increases in cytosolic calcium, suggesting that cAMP may activate diltiazem-sensitive calcium channels by a calmodulin-dependent process.

Authors
Prpic, V; Basavappa, S; Liddle, RA; Mangel, AW
MLA Citation
Prpic, V, Basavappa, S, Liddle, RA, and Mangel, AW. "Regulation of cholecystokinin secretion by calcium-dependent calmodulin kinase II: differential effects of phenylalanine and cAMP." Biochem Biophys Res Commun 201.3 (June 30, 1994): 1483-1489.
PMID
7517671
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
201
Issue
3
Publish Date
1994
Start Page
1483
End Page
1489
DOI
10.1006/bbrc.1994.1871

Developmental expression of the glucose-dependent insulinotropic polypeptide gene in rat intestine.

The developmental expression of the glucose-dependent insulinotropic polypeptide (GIP) gene was investigated in rat intestine. Steady state levels of GIP mRNA were determined in the intestine during fetal and postnatal development by double ribonuclease protection assays. GIP mRNA could be detected as early as day 20 of embryonic development and very low levels remained until postnatal day 3. The GIP mRNA levels increased markedly in the period between days 3 and 5 of postnatal life and then gradually increased toward adult levels. Since intron 1 of the GIP gene contains putative TATA and CCAAT boxes, and some potential cis-acting promoter elements, we examined whether or not another transcript starting from exon 2 of the GIP gene is expressed during development of rat intestine. Ribonuclease protection assays suggested that although an abbreviated transcript might exist starting from exon 2, it appears to be minor and its relative abundance is unchanged during development or following intraduodenal glucose stimulation. These observations suggest that GIP may play an important role in early postnatal development probably associated with suckling.

Authors
Higashimoto, Y; Liddle, RA
MLA Citation
Higashimoto, Y, and Liddle, RA. "Developmental expression of the glucose-dependent insulinotropic polypeptide gene in rat intestine." Biochem Biophys Res Commun 201.2 (June 15, 1994): 964-972.
PMID
8003038
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
201
Issue
2
Publish Date
1994
Start Page
964
End Page
972
DOI
10.1006/bbrc.1994.1796

Regulation of cholecystokinin gene expression in rat intestine.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Regulation of cholecystokinin gene expression in rat intestine." Ann N Y Acad Sci 713 (March 23, 1994): 22-31. (Review)
PMID
7910441
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
713
Publish Date
1994
Start Page
22
End Page
31

Natural and synthetic CCK-58. Novel reagents for studying cholecystokinin physiology.

CCK-58 is a unique reagent for testing how segments of a peptide far removed from its active site can influence the expression of its biological activity. Indications of tertiary structure have come from studies with natural peptide purified from canine small intestine. These studies gave clear indications that tertiary structure affects CCK-58 bioactivity, but the small quantities of CCK-58 available made it impossible to characterize completely how tertiary structure influenced bioactivity. Canine CCK-58 was synthesized manually using a solid support and was purified by reverse phase high pressure liquid chromatography (HPLC). Synthetic CCK-58 was characterized by isocratic reverse phase and gradient HPLC, amino acid analysis, mass spectral analysis, sequence analysis, and three bioassays. Synthetic and natural canine CCK-58 had the same elution profiles, amino acid composition, sequence, and mass. The two peptides were equipotent for the stimulation of pancreatic secretion. Natural canine CCK-58 was equipotent to CCK-8 for CCK "B" receptor binding, a further indication of the purity of the natural peptide. However, natural CCK-58 was more potent than CCK-8 for CCK "A" receptor binding and less potent than CCK-8 for stimulation of pancreatic secretion. These data support the concept that CCK-58 has a stable tertiary structure. This structure does not affect its binding to CCK "B" receptors, enhances its binding to low affinity CCK "A" receptors, and decreases its activity expressed through binding to high affinity CCK "A" receptors. The concept of a stable tertiary structure is also supported by the fact that many antibodies directed towards the carboxyl terminus of cholecystokinin react better with CCK-8 than CCK-58. The availability of synthetic CCK-58 will allow analysis of its tertiary structure by physical and chemical methods as well as studies on how peptide tertiary structure can affect receptor binding, receptor activation, metabolism in blood, degradation in interstitial fluid, and inactivation at the receptor. Evaluating all of these systems will help investigators understand the regulation of cholecystokinin activity by its major endocrine form, CCK-58.

Authors
Reeve, JR; Eysselein, VE; Ho, FJ; Chew, P; Vigna, SR; Liddle, RA; Evans, C
MLA Citation
Reeve, JR, Eysselein, VE, Ho, FJ, Chew, P, Vigna, SR, Liddle, RA, and Evans, C. "Natural and synthetic CCK-58. Novel reagents for studying cholecystokinin physiology." Ann N Y Acad Sci 713 (March 23, 1994): 11-21. (Review)
PMID
7514372
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
713
Publish Date
1994
Start Page
11
End Page
21

Inhibitors of ATP-sensitive potassium channels stimulate intestinal cholecystokinin secretion.

Recently, a role for adenosine 5'-triphosphate(ATP)-sensitive potassium channels in the regulation of cholecystokinin (CCK) secretion has been described in STC-1 cells, an intestinal CCK-secreting cell line. To examine whether a similar mechanism might participate in the regulation of hormone secretion from native CCK cells, the effects of two established inhibitors of ATP-sensitive potassium channels (e.g. glucose, disopyramide) were examined on CCK release from dispersed murine intestinal cells. Both glucose and disopyramide were found to stimulate CCK secretion. Furthermore, CCK release induced by glucose was inhibited by the calcium channel blocker diltiazem. It is concluded that, ATP-sensitive potassium channels may play a role in the regulation of intestinal CCK secretion.

Authors
Mangel, AW; Prpic, V; Scott, L; Liddle, RA
MLA Citation
Mangel, AW, Prpic, V, Scott, L, and Liddle, RA. "Inhibitors of ATP-sensitive potassium channels stimulate intestinal cholecystokinin secretion." Peptides 15.8 (1994): 1565-1566.
PMID
7700857
Source
pubmed
Published In
Peptides
Volume
15
Issue
8
Publish Date
1994
Start Page
1565
End Page
1566

Regulation of cholecystokinin secretion by bombesin in STC-1 cells

Bombesin stimulates cholecystokinin (CCK) secretion, presumably by a direct effect on the intestinal CCK cell. The present objectives were to characterize bombesin-stimulated CCK release and to investigate the role of calcium in CCK secretion in an intestinal CCK-producing cell line (STC-1). Bombesin caused a dose-dependent release of CCK, which was reduced either in the absence of extracellular calcium or by calcium channel blockade, suggesting that influx of calcium is necessary for CCK secretion. Bombesin caused an increase in intracellular calcium concentration ([Ca2+](i)) and increased efflux of 45Ca2+ from 45Ca2+-loaded cells. Radioligand binding studies and Northern analysis were consistent with the expression of a bombesin receptor. Thus bombesin stimulation of CCK release occurs via binding to a receptor and is dependent on increased [Ca2+](i). We propose that the STC-1 cell line may provide a useful model for studying the regulation of intestinal CCK secretion.

Authors
Snow, ND; Prpic, V; Mangel, AW; Sharara, AI; McVey, DC; Hurst, LJ; Vigna, SR; Liddle, RA
MLA Citation
Snow, ND, Prpic, V, Mangel, AW, Sharara, AI, McVey, DC, Hurst, LJ, Vigna, SR, and Liddle, RA. "Regulation of cholecystokinin secretion by bombesin in STC-1 cells." American Journal of Physiology - Gastrointestinal and Liver Physiology 267.5 30-5 (1994): G859-G865.
Source
scival
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
267
Issue
5 30-5
Publish Date
1994
Start Page
G859
End Page
G865

Regulation of cholecystokinin secretion by ATP-sensitive potassium channels

Authors
Mangel, AW; Prpic, V; Snow, ND; Basavappa, S; Hurst, LJ; Sharara, AI; Liddle, RA
MLA Citation
Mangel, AW, Prpic, V, Snow, ND, Basavappa, S, Hurst, LJ, Sharara, AI, and Liddle, RA. "Regulation of cholecystokinin secretion by ATP-sensitive potassium channels." AM.J.PHYSIOL. 267.4 part 1 (1994): G595-G600.
Source
scival
Published In
AM.J.PHYSIOL.
Volume
267
Issue
4 part 1
Publish Date
1994
Start Page
G595
End Page
G600

Regulation of cholecystokinin secretion by ATP-sensitive potassium channels

The relationship of potassium channel activity to the secretion of cholecystokinin (CCK) was evaluated in STC-I cells, an intestinal CCK- secreting cell line. Patch-clamp and 86Rb efflux studies showed that an ATP-sensitive potassium channel was endogenously expressed in STC-1 cells. Furthermore, channels are present in sufficient number to significantly modulate whole cell potassium permeability after either channel activation or closure with diazoxide (100 μM) or disopyramide (200 μM), respectively. Inhibition of channel activity with glucose (5-20 mM) was found to depolarize the plasma membrane, increase cytosolic calcium levels, and stimulate CCK release. Glucose-mediated release of CCK, as well as the increase in cytosolic calcium, was inhibited by the calcium channel blocker diltiazem (10 μM). It is concluded that intestinal secretion of CCK may be tonically controlled by activity of basally active ATP-sensitive potassium channels, and after inhibition of channel activity, calcium-dependent CCK secretion is stimulated.

Authors
Mangel, AW; Prpic, V; Snow, ND; Basavappa, S; Hurst, LJ; Sharara, AI; Liddle, RA
MLA Citation
Mangel, AW, Prpic, V, Snow, ND, Basavappa, S, Hurst, LJ, Sharara, AI, and Liddle, RA. "Regulation of cholecystokinin secretion by ATP-sensitive potassium channels." American Journal of Physiology - Gastrointestinal and Liver Physiology 267.4 30-4 (1994): G595-G600.
Source
scival
Published In
American journal of physiology. Gastrointestinal and liver physiology
Volume
267
Issue
4 30-4
Publish Date
1994
Start Page
G595
End Page
G600

Regulation of cholecystokinin synthesis and secretion in rat intestine

Cholecystokinin is a classical gastrointestinal hormone that is produced by discrete endocrine cells of the upper small intestine. Cholecystokinin is produced in various molecular forms that result from differences in posttranslation processing of a single gene product. Cholecystokinin is secreted from the intestine in response to the ingestion of food. We observed that specific dietary substances increase the rate of transcription of the cholecystokinin gene and stimulate cholecystokinin release in rats. In contrast the paracrine transmitter, somatostatin, inhibits dietary-stimulated cholecystokinin secretion and lowers intestinal mRNA levels. Evidence that cholecystokinin gene expression is not necessarily linked to hormone secretion is supported by the observation that the neuropeptide, bombesin, stimulates cholecystokinin release but does not modify intestinal cholecystokinin mRNA levels. To examine the intracellular messengers that might regulate the cholecystokinin cell directly, we developed an in vitro method for studying cholecystokinin release from isolated intestinal mucosal cells. In this perifusion system, cholecystokinin release was stimulated by membrane depolarizing concentrations of KCI (50 mmol/L), the calcium ionophore A23187 (1 μmol/L), and the cAMP analogue dibutyryl cAMP (1 μmol/L). Biologically active cholecystokinin was also released in a dose- dependent manner by the peptide transmitters, bombesin and monitor peptide. These findings indicate that neurotransmitters and hormones may directly regulate the cholecystokinin cell and suggest that the phosphoinositide and adenylate cyclase cascades mediate stimulated-cholecystokinin secretion.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Regulation of cholecystokinin synthesis and secretion in rat intestine." Journal of Nutrition 124.8 SUPPL. (1994): 1308S-1314S.
Source
scival
Published In
Journal of Nutrition
Volume
124
Issue
8 SUPPL.
Publish Date
1994
Start Page
1308S
End Page
1314S

Regulation of cholecystokinin secretion by bombesin in STC-1 cells

Authors
Snow, ND; Prpic, V; Mangel, AW; Sharara, AI; McVey, DC; Hurst, LJ; Vigna, SR; Liddle, RA
MLA Citation
Snow, ND, Prpic, V, Mangel, AW, Sharara, AI, McVey, DC, Hurst, LJ, Vigna, SR, and Liddle, RA. "Regulation of cholecystokinin secretion by bombesin in STC-1 cells." AM.J.PHYSIOL. 267.5 part 1 (1994): G859-G865.
Source
scival
Published In
AM.J.PHYSIOL.
Volume
267
Issue
5 part 1
Publish Date
1994
Start Page
G859
End Page
G865

Total synthesis, purification, and characterization of human [Phe(p-CH2SO 3Na)52, Nle32,53,56, Nal55]-CCK20-58, [Tyr52, Nle32,53,56, Nal55]-CCK-58, and [Phe(p-CH2SO3Na)52, Nle32,53,56, Nal55]-CCK-58.

The synthesis of [Phe(p-CH2SO3Na)52, Nle32,53,56 Nal55]-CCK20-58, [Tyr52, Nle32,53,56, Nal55]-CCK-58 and of [Phe(p-CH2SO3Na)52, Nle32,53,56, Nal55]-CCK-58 using the (9-fluorenylmethyloxy)-carbonyl (Fmoc) strategy on a 2,4-DMBHA resin is described. The crude peptide preparations were extremely complex when analyzed by RP-HPLC, capillary zone electrophoresis (CZE), and ion-exchange chromatography (IE-FPLC). We found that the most effective strategy for purification included cation-exchange chromatography followed by a RP-HPLC desalting step. The highly purified peptides (purity greater than 90%) were characterized by RP-HPLC, size exclusion HPLC (SEC), IE-FPLC, CZE, mass spectrometry, amino acid analysis, and Edman sequence analysis (for [Tyr52, Nle32,53,56, Nal55]-CCK-58). The results demonstrate the applicability of the 2,4-DMBHA resin for Fmoc solid-phase synthesis of long peptides amides (58 residues in length in this case) as well as the efficacy of an FPLC/RP-HPLC approach for the purification of very long, heterogeneous crude peptides, allowing a true assessment of the biological properties of these analogs to be carried out. [Phe(p-CH2SO3Na)52, Nle32,53,56, Nal55]-CCK20-58 was less than 1% as potent as CCK-8 while [Tyr52, Nle32,53,56, Nal55]-CCK-58 and [Phe(p-CH2SO3Na)52, Nle32,53,56, Nal55]-CCK-58 were inactive at the doses tested (< 0.01%).

Authors
Miranda, MT; Craig, AG; Miller, C; Liddle, RA; Rivier, JE
MLA Citation
Miranda, MT, Craig, AG, Miller, C, Liddle, RA, and Rivier, JE. "Total synthesis, purification, and characterization of human [Phe(p-CH2SO 3Na)52, Nle32,53,56, Nal55]-CCK20-58, [Tyr52, Nle32,53,56, Nal55]-CCK-58, and [Phe(p-CH2SO3Na)52, Nle32,53,56, Nal55]-CCK-58." J Protein Chem 12.5 (October 1993): 533-544.
PMID
7511387
Source
pubmed
Published In
Journal of protein chemistry
Volume
12
Issue
5
Publish Date
1993
Start Page
533
End Page
544

Potassium channels regulate cholecystokinin secretion in STC-1 cells.

Following blockade of plasma membrane potassium channels with barium or tetraethylammonium chloride, release of cholecystokinin was increased in an intestinal cell line (STC-1). Treatment with calcium channel blockers inhibited barium- or TEA-induced secretion. Barium chloride also stimulated 45Ca efflux from STC-1 cells. Whole cell patch clamp recordings revealed a voltage-activated, L-type calcium current. We conclude that, inhibition of basally active potassium channels may depolarize STC-1 cells, producing activation of voltage-gated calcium influx pathways. Influx of calcium may lead to a release of intracellular calcium which stimulates cholecystokinin secretion.

Authors
Snow, ND; Mangel, AW; Sharara, AI; Liddle, RA
MLA Citation
Snow, ND, Mangel, AW, Sharara, AI, and Liddle, RA. "Potassium channels regulate cholecystokinin secretion in STC-1 cells." Biochem Biophys Res Commun 195.3 (September 30, 1993): 1379-1385.
PMID
8216272
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
195
Issue
3
Publish Date
1993
Start Page
1379
End Page
1385
DOI
10.1006/bbrc.1993.2196

Evidence for indirect dietary regulation of cholecystokinin release in rats.

Food ingestion stimulates cholecystokinin (CCK) release from the proximal intestine, but the mechanisms involved are not well understood. To investigate this effect in vivo in intact rats, plasma CCK was measured after orogastric feeding of proteins, protein hydrolysates, amino acids, glucose, and starch. Intact proteins were the only nutrients to stimulate CCK release. The possibility of direct interaction between different dietary constituents and intestinal CCK-secreting endocrine cells was then examined using a perfusion system containing isolated mucosal cells from the rat duodenojejunum. The functional validity of this system was established by demonstrating that monitor peptide and bombesin both stimulated CCK release in a dose-dependent manner. The stimulatory effect of bombesin required extracellular calcium and was not inhibited by addition of tetrodotoxin. Perifusion of proteins, protein digests, and carbohydrates did not stimulate CCK release. These results indicate that proteins stimulate CCK release postprandially via an indirect mechanism, most likely related to inhibition of intraluminal trypsin. Perifusion of dispersed mucosal cells constitutes a reproducible model to investigate hormonal and peptidergic regulation of CCK release in vitro.

Authors
Sharara, AI; Bouras, EP; Misukonis, MA; Liddle, RA
MLA Citation
Sharara, AI, Bouras, EP, Misukonis, MA, and Liddle, RA. "Evidence for indirect dietary regulation of cholecystokinin release in rats." Am J Physiol 265.1 Pt 1 (July 1993): G107-G112.
PMID
8338159
Source
pubmed
Published In
The American journal of physiology
Volume
265
Issue
1 Pt 1
Publish Date
1993
Start Page
G107
End Page
G112

Synthesis of human CCK26-33 and CCK-33 related analogues on 2,4-DMBHA and TMBHA.

New analogues of human cholecystokinin in which the Tyr(SO3H) has been replaced by Phe(p-CH2SO3Na), methionines by norleucines, and tryptophan by 2-naphthylalanine([Phe(p-CH2- SO3Na)27,Nle28,31,Nal30]-CCK26-33 and [Phe(p-CH2SO3Na)27,Nle7,28,31,Nal30]-CCK-33) were synthesized by Fmoc solid phase methodology on two different resins (2,4- dimethoxybenzhydrylamine- and 4-(benzyloxy)-2',4'-dimethoxybenzhydrylamine resins, 2,4-DMBHA and TMBHA resins, respectively). While the syntheses on the TMBHA appeared to be more sluggish than those carried out on the 2,4-DMBHA, both final crude products were of equivalent relative purity and after purification gave approximately the same final yields of analogues estimated to have a purity greater than 93% using RPHPLC and CZE. The peptides were further characterized by amino acid analysis and LSIMS. Phe(p-CH2SO3Na)27,Nle7,28,31,Nal30]-CCK-33 was submitted to 33 Edman cycles and shown to be the desired product with less than 3% preview. Both analogues were tested for their ability to stimulate amylase release from isolated rat pancreatic acini. In this assay, [Phe(p-CH2SO3Na)27,Nle28,31,Nal30]-CCK26-33 and Phe(p-CH2SO3Na)27,Nle7,28,31,Nal30]-CCK-33 were 10 and 30 times less potent than CCK-8, respectively.

Authors
Miranda, MT; Liddle, RA; Rivier, JE
MLA Citation
Miranda, MT, Liddle, RA, and Rivier, JE. "Synthesis of human CCK26-33 and CCK-33 related analogues on 2,4-DMBHA and TMBHA." J Med Chem 36.12 (June 11, 1993): 1681-1688.
PMID
7685390
Source
pubmed
Published In
Journal of Medicinal Chemistry
Volume
36
Issue
12
Publish Date
1993
Start Page
1681
End Page
1688

Calcium-dependent regulation of cholecystokinin secretion and potassium currents in STC-1 cells.

Secretory and electrophysiological properties of STC-1 cells, a cholecystokinin-secreting cell line, were examined with a radioimmunoassay and patch-clamp recording techniques. Stimulation of cholecystokinin secretion was seen after exposure to agents anticipated to increase the level of intracellular calcium, including thapsigargin (8 microM), bombesin (50 nM), potassium-induced depolarization (50 mM), or after blockade of potassium channels with barium chloride (2 mM). The secretory effects of these agents were blocked by pretreatment with the calcium channel blocker diltiazem (1 microM). Whole cell patch-clamp recordings showed a hyperpolarizing shift in reversal potential after exposure to either thapsigargin (8 microM) or bombesin (50 nM) from a control value of -27 +/- 3 to -57 +/- 7 or -48 +/- 6 mV, respectively. This shift was in the direction of the reversal potential for potassium and was blocked by barium chloride (5 mM). Single-channel recordings from cell-attached membrane patches showed an inwardly rectifying potassium channel with channel open probability modulated by bombesin. These results indicate that in STC-1 cells a potassium current is increased by agents that stimulate CCK secretion, presumably by increasing the level of cytosolic calcium. STC-1 cells may serve as a model system to study the electrophysiological and secretory mechanisms involved in the release of cholecystokinin.

Authors
Mangel, AW; Snow, ND; Misukonis, MA; Basavappa, S; Middleton, JP; Fitz, JG; Liddle, RA
MLA Citation
Mangel, AW, Snow, ND, Misukonis, MA, Basavappa, S, Middleton, JP, Fitz, JG, and Liddle, RA. "Calcium-dependent regulation of cholecystokinin secretion and potassium currents in STC-1 cells." Am J Physiol 264.6 Pt 1 (June 1993): G1031-G1036.
PMID
8333529
Source
pubmed
Published In
The American journal of physiology
Volume
264
Issue
6 Pt 1
Publish Date
1993
Start Page
G1031
End Page
G1036

Isolation and characterization of the gene encoding rat glucose-dependent insulinotropic peptide.

The rat glucose-dependent insulinotropic peptide (GIP) gene has been isolated and characterized. The gene spans approximately 8.2 kilobase pairs (kb) and the GIP mRNA (0.8 kb) is encoded by six exons. The 42 amino acid hormone is encoded by exons 3 and 4. The exon-intron organization of the rat GIP gene revealed that the splice acceptor site for intron 2 is 24 nucleotides downstream compared to the comparable splice acceptor site in the human gene. This intron sliding results in an 8 amino acid deletion in the amino terminal extension of the prepropeptide. Primer extension analysis and RNase protection assay demonstrated the existence of multiple closely spaced sites for transcriptional initiation. Both the 5'-flanking region and intron 1 contain TATA and CCAAT boxes consistent with initiation of gene transcription, although a TATA box in intron 1 is functionally inactive in adult rats in spite of its reasonable location.

Authors
Higashimoto, Y; Liddle, RA
MLA Citation
Higashimoto, Y, and Liddle, RA. "Isolation and characterization of the gene encoding rat glucose-dependent insulinotropic peptide." Biochem Biophys Res Commun 193.1 (May 28, 1993): 182-190.
PMID
8503905
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
193
Issue
1
Publish Date
1993
Start Page
182
End Page
190
DOI
10.1006/bbrc.1993.1607

Reduced postprandial cholecystokinin (CCK) secretion in patients with noninsulin-dependent diabetes mellitus: evidence for a role for CCK in regulating postprandial hyperglycemia.

The plasma cholecystokinin (CCK) response to a test meal was studied in 16 control subjects and 15 patients with noninsulin-dependent diabetes mellitus (NIDDM). Basal CCK levels were approximately 1 pmol in both groups. However, after the test meal, plasma CCK levels were 2-fold greater in the controls when compared to the diabetics. In controls, CCK levels maximally increased by 5.6 +/- 0.8 pmol (mean +/- SEM) 10 min after feeding, whereas in the NIDDM patients this value was 1.9 +/- 0.6 pmol (P < 0.001). After the test meal, the normal subjects showed no postprandial rise in blood glucose, whereas the diabetic patient showed a rise of 2.6 +/- 0.7 mmol. To determine whether the decreased CCK levels may have been related to the postprandial hyperglycemia, 7 diabetic subjects were infused with CCK. With this CCK infusion, postprandial glucose levels did not rise. These data suggest, therefore: 1) a role for cholecystokinin in regulating postprandial hyperglycemia in man, 2) abnormalities in CCK secretion occur in NIDDM and may contribute to the hyperglycemia seen in this disease.

Authors
Rushakoff, RA; Goldfine, ID; Beccaria, LJ; Mathur, A; Brand, RJ; Liddle, RA
MLA Citation
Rushakoff, RA, Goldfine, ID, Beccaria, LJ, Mathur, A, Brand, RJ, and Liddle, RA. "Reduced postprandial cholecystokinin (CCK) secretion in patients with noninsulin-dependent diabetes mellitus: evidence for a role for CCK in regulating postprandial hyperglycemia." J Clin Endocrinol Metab 76.2 (February 1993): 489-493.
PMID
8432795
Source
pubmed
Published In
Journal of Clinical Endocrinology and Metabolism
Volume
76
Issue
2
Publish Date
1993
Start Page
489
End Page
493
DOI
10.1210/jcem.76.2.8432795

Calcium-dependent regulation of cholecystokinin secretion and potassium currents in STC-1 cells

Secretory and electrophysiological properties of STC-1 cells, a cholecystokinin-secreting cell line, were examined with a radioimmunoassay and patch-clamp recording techniques. Stimulation of cholecystokinin secretion was seen after exposure to agents anticipated to increase the level of intracellular calcium, including thapsigargin (8 μM), bombesin (50 nM), potassium-induced depolarization (50 mM), or after blockade of potassium channels with barium chloride (2 mM). The secretory effects of these agents were blocked by pretreatment with the calcium channel blocker diltiazem (1 μM). Whole cell patch-clamp recordings showed a hyperpolarizing shift in reversal potential after exposure to either thapsigargin (8 μM) or bombesin (50 nM) from a control value of -27 ± 3 to -57 ± 7 or -48 ± 6 mV, respectively. This shift was in the direction of the reversal potential for potassium and was blocked by barium chloride (5 mM). Single-channel recordings from cell-attached membrane patches showed an inwardly rectifying potassium channel with channel open probability modulated by bombesin. These results indicate that in STC-1 cells a potassium current is increased by agents that stimulate CCK secretion, presumably by increasing the level of cytosolic calcium. STC-1 cells may serve as a model system to study the electrophysiological and secretory mechanisms involved in the release of cholecystokinin.

Authors
Mangel, AW; Snow, ND; Misukonis, MA; Basavappa, S; Middleton, JP; Fitz, JG; Liddle, RA
MLA Citation
Mangel, AW, Snow, ND, Misukonis, MA, Basavappa, S, Middleton, JP, Fitz, JG, and Liddle, RA. "Calcium-dependent regulation of cholecystokinin secretion and potassium currents in STC-1 cells." American Journal of Physiology - Gastrointestinal and Liver Physiology 264.6 27-6 (1993): G1031-G1036.
Source
scival
Published In
The American journal of physiology
Volume
264
Issue
6 27-6
Publish Date
1993
Start Page
G1031
End Page
G1036

Evidence for indirect dietary regulation of cholecystokinin release in rats

Food ingestion stimulates cholecystokinin (CCK) release from the proximal intestine, but the mechanisms involved are not well understood. To investigate this effect in vivo in intact rats, plasma CCK was measured after orogastric feeding of proteins, protein hydrolysates, amino acids, glucose, and starch. Intact proteins were the only nutrients to stimulate CCK release. The possibility of direct interaction between different dietary constituents and intestinal CCK-secreting endocrine cells was then examined using a perifusion system containing isolated mucosal cells from the rat duodenojejunum. The functional validity of this system was established by demonstrating that monitor peptide and bombesin both stimulated CCK release in a dose-dependent manner. The stimulatory effect of bombesin required extracellular calcium and was not inhibited by addition of tetrodotoxin. Perifusion of proteins, protein digests, and carbohydrates did not stimulate CCK release. These results indicate that proteins stimulate CCK release postprandially via an indirect mechanism, most likely related to inhibition of intraluminal trypsin. Perifusion of dispersed mucosal cells constitutes a reproducible model to investigate hormonal and peptidergic regulation of CCK release in vitro.

Authors
Sharara, AI; Bouras, EP; Misukonis, MA; Liddle, RA
MLA Citation
Sharara, AI, Bouras, EP, Misukonis, MA, and Liddle, RA. "Evidence for indirect dietary regulation of cholecystokinin release in rats." American Journal of Physiology - Gastrointestinal and Liver Physiology 265.1 28-1 (1993): G107-G112.
Source
scival
Published In
American Journal of Physiology - Gastrointestinal and Liver Physiology
Volume
265
Issue
1 28-1
Publish Date
1993
Start Page
G107
End Page
G112

Total synthesis, purification, and characterization of human [Phe(p- CH2SO 3Na)52, Nle32,53,56, Nal55]-CCK20-58, [Tyr52, Nle32,5

Authors
Miranda, MTM; Craig, AG; Miller, C; Liddle, RA; Rivier, JE
MLA Citation
Miranda, MTM, Craig, AG, Miller, C, Liddle, RA, and Rivier, JE. "Total synthesis, purification, and characterization of human [Phe(p- CH2SO 3Na)52, Nle32,53,56, Nal55]-CCK20-58, [Tyr52, Nle32,5." Journal of Protein Chemistry 12.5 (1993): 533-544.
Source
scival
Published In
Journal of protein chemistry
Volume
12
Issue
5
Publish Date
1993
Start Page
533
End Page
544
DOI
10.1007/BF01025118

Intraventricular CCK-8 reduces single meal size in the baboon by interaction with type-A CCK receptors.

Intraventricular cholecystokinin COOH-terminal octapeptide (CCK-8) decreases meal size in the meal-trained baboon. In the present study, we tested whether this action is mediated by CCK-A receptors, CCK-B receptors, or both. Intraventricular administration of the selective CCK-A receptor agonist A71623 at 1 and 10 nmol/kg suppressed 30-min meal size 69 +/- 22% and 75 +/- 7%, respectively. Additionally, intraventricular A71623 was equipotent to CCK-8 at 1 nmol/kg (% suppression of meal by CCK = 59 +/- 17). However, intraventricular administration of the CCK-B receptor agonist A63387 at 10 nmol/kg had no effect on 30-min meal size (% suppression = 18 +/- 29). Intravenous administration of 10 nmol/kg A71623 did not result in an alteration of meal size, but prandial plasma insulin and glucose responses were delayed and blunted. Basal plasma insulin levels doubled after intravenous administration of A71623. Both behavioral and metabolic responses to A71623 in the baboon are virtually identical to those we have previously observed after CCK-8 treatment. Thus we conclude that the predominant receptor population with which intraventricular CCK-8 interacts are type-A CCK receptors that are accessible to the ventricular system of the baboon.

Authors
Figlewicz, DP; Nadzan, AM; Sipols, AJ; Green, PK; Liddle, RA; Porte, D; Woods, SC
MLA Citation
Figlewicz, DP, Nadzan, AM, Sipols, AJ, Green, PK, Liddle, RA, Porte, D, and Woods, SC. "Intraventricular CCK-8 reduces single meal size in the baboon by interaction with type-A CCK receptors." Am J Physiol 263.4 Pt 2 (October 1992): R863-R867.
PMID
1415799
Source
pubmed
Published In
The American journal of physiology
Volume
263
Issue
4 Pt 2
Publish Date
1992
Start Page
R863
End Page
R867

Molecular cloning of rat glucose-dependent insulinotropic peptide (GIP).

A cDNA clone encoding glucose-dependent insulinotropic peptide (GIP) was identified that consisted of 34 bp of 5' untranslated sequence, an open reading frame of 432 bp and 115 bp in the 3' untranslated region. The deduced amino acid sequence revealed a 144 amino acid preprohormone consisting of a 43 amino acid N-terminal extension including a signal peptide, a 42 amino acid hormone, and a 59 amino acid C-terminal extension. Rat GIP differs from the human hormone by two amino acid substitutions: arginine for histidine at position 18 and leucine for isoleucine at position 40. A single mRNA from small intestine of approximately 800 bases was identified on Northern blot analysis in equivalent amounts in proximal and distal small intestine.

Authors
Higashimoto, Y; Simchock, J; Liddle, RA
MLA Citation
Higashimoto, Y, Simchock, J, and Liddle, RA. "Molecular cloning of rat glucose-dependent insulinotropic peptide (GIP)." Biochim Biophys Acta 1132.1 (August 17, 1992): 72-74.
PMID
1380834
Source
pubmed
Published In
Biochimica et Biophysica Acta: international journal of biochemistry and biophysics
Volume
1132
Issue
1
Publish Date
1992
Start Page
72
End Page
74

Regulation of appetite and cholecystokinin secretion in anorexia nervosa.

Six patients with anorexia nervosa, the same patients after weight normalization, and six healthy control subjects had similar fasting and postprandial plasma cholecystokinin concentrations. These data do not support the hypothesis that low levels of hunger and food intake in anorexic patients reflect hypersecretion of this endogenous hormone, which is thought to inhibit hunger, promote satiety, and reduce feeding.

Authors
Geracioti, TD; Liddle, RA; Altemus, M; Demitrack, MA; Gold, PW
MLA Citation
Geracioti, TD, Liddle, RA, Altemus, M, Demitrack, MA, and Gold, PW. "Regulation of appetite and cholecystokinin secretion in anorexia nervosa." Am J Psychiatry 149.7 (July 1992): 958-961.
PMID
1609878
Source
pubmed
Published In
American Journal of Psychiatry
Volume
149
Issue
7
Publish Date
1992
Start Page
958
End Page
961
DOI
10.1176/ajp.149.7.958

Cholecystokinin cells purified by fluorescence-activated cell sorting respond to monitor peptide with an increase in intracellular calcium.

Cholecystokinin (CCK) is secreted from specific enteroendocrine cells of the upper small intestine upon ingestion of a meal. In addition to nutrients, endogenously produced factors appear to act within the gut lumen to stimulate CCK release. One such factor is a trypsin-sensitive CCK-releasing peptide found in pancreatic juice, known as monitor peptide. This peptide is active within the intestinal lumen and is hypothesized to stimulate CCK secretion by interacting directly with the CCK cell. We have found that monitor peptide releases CCK from isolated rat intestinal mucosal cells and that this effect is dependent upon extracellular calcium. In the present study, we used monitor peptide as a tool for isolating CCK cells from a population of small intestinal mucosal cells. Dispersed rat intestinal mucosal cells were loaded with the calcium-sensitive fluorochrome Indo-1, and CCK secretory cells were identified spectrofluorometrically by their change in fluorescence when stimulated with monitor peptide. Cells demonstrating a change in their emission fluorescence ratio were sorted using a fluorescence-activated cell sorter. More than 90% of the sorted cells stained positively for CCK with immunohistochemical staining. Furthermore, sorted cells secreted CCK when stimulated with membrane-depolarizing concentrations of potassium chloride, dibutyryl cAMP, calcium ionophore, and monitor peptide. These findings indicate that functional intestinal CCK cells can be highly enriched using fluorescence-activated cell sorting. Furthermore, monitor peptide appears to interact directly with CCK cells to signal CCK release through an increase in intracellular calcium.

Authors
Liddle, RA; Misukonis, MA; Pacy, L; Balber, AE
MLA Citation
Liddle, RA, Misukonis, MA, Pacy, L, and Balber, AE. "Cholecystokinin cells purified by fluorescence-activated cell sorting respond to monitor peptide with an increase in intracellular calcium." Proc Natl Acad Sci U S A 89.11 (June 1, 1992): 5147-5151.
PMID
1594624
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
89
Issue
11
Publish Date
1992
Start Page
5147
End Page
5151

Role of calcium in monitor peptide-stimulated cholecystokinin release from perifused intestinal cells.

Monitor peptide stimulates cholecystokinin (CCK) release from the intestine, but the cellular mechanisms responsible for this effect are uncertain. In the present study, the roles of membrane potential difference and calcium influx in monitor peptide-mediated CCK release were examined in a perifusion system containing isolated mucosal cells from the rat duodenum. This method represents an in vitro system in which CCK-releasing cells can be challenged with secretagogues or other maneuvers to study the dynamics of hormone secretion. High concentrations of KCl (50 mM), which reduce electrical potential difference across the cell membrane, caused the release of CCK. This effect was inhibited by the calcium channel blocker MnCl2. Monitor peptide stimulated CCK release in a dose-dependent manner at concentrations from 3 x 10(-12) to 3 x 10(-8) M. The requirement for extracellular calcium in secretagogue-stimulated release of CCK was investigated using ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), a calcium chelator, and MnCl2. A calcium-free environment supplemented with 2 mM EGTA completely inhibited CCK secretion in response to stimulatory doses of monitor peptide. CCK secretion was restored when calcium was reintroduced into the system. Similarly, MnCl2 completely blocked monitor peptide-stimulated CCK release. These data indicate that membrane depolarization and monitor peptide stimulate the release of CCK through calcium-dependent mechanisms, suggesting that increases in intracellular calcium within CCK cells are likely to be important in CCK release.

Authors
Bouras, EP; Misukonis, MA; Liddle, RA
MLA Citation
Bouras, EP, Misukonis, MA, and Liddle, RA. "Role of calcium in monitor peptide-stimulated cholecystokinin release from perifused intestinal cells." Am J Physiol 262.5 Pt 1 (May 1992): G791-G796.
PMID
1590389
Source
pubmed
Published In
The American journal of physiology
Volume
262
Issue
5 Pt 1
Publish Date
1992
Start Page
G791
End Page
G796

Role of calcium in monitor peptide-stimulated cholecystokinin release from perifused intestinal cells

Monitor peptide stimulates cholecystokinin (CCK) release from the intestine, but the cellular mechanisms responsible for this effect are uncertain. In the present study, the roles of membrane potential difference and calcium influx in monitor peptide-mediated CCK release were examined in a perifusion system containing isolated mucosal cells from the rat duodenum. This method represents an in vitro system in which CCK-releasing cells can be challenged with secretagogues or other maneuvers to study the dynamics of hormone secretion. High concentrations of KCl (50 mM), which reduce electrical potential difference across the cell membrane, caused the release of CCK. This effect was inhibited by the calcium channel blocker MnCl2. Monitor peptide stimulated CCK release in a dose-dependent manner at concentrations from 3 x 10-12 to 3 x 10-8 M. The requirement for extracellular calcium in secretagogue-stimulated release of CCK was investigated using ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'- tetraacetic acid (EGTA), a calcium chelator, and MnCl2. A calcium-free environment supplemented with 2 mM EGTA completely inhibited CCK secretion in response to stimulatory doses of monitor peptide. CCK secretion was restored when calcium was reintroduced into the system. Similarly, MnCl2 completely blocked monitor peptide-stimulated CCK release. These data indicate that membrane depolarization and monitor peptide stimulate the release of CCK through calcium-dependent mechanisms, suggesting that increases in intracellular calcium within CCK cells are likely to be important in CCK release.

Authors
Bouras, EP; Misukonis, MA; Liddle, RA
MLA Citation
Bouras, EP, Misukonis, MA, and Liddle, RA. "Role of calcium in monitor peptide-stimulated cholecystokinin release from perifused intestinal cells." American Journal of Physiology - Gastrointestinal and Liver Physiology 262.5 25-5 (1992): G791-G796.
Source
scival
Published In
American Journal of Physiology - Gastrointestinal and Liver Physiology
Volume
262
Issue
5 25-5
Publish Date
1992
Start Page
G791
End Page
G796

Intraventricular CCK-8 reduces single meal size in the baboon by interaction with type-A CCK receptors

Intraventricular cholecystokinin COOH-terminal octapeptide (CCK-8) decreases meal size in the meal-trained baboon. In the present study, we tested whether this action is mediated by CCK-A receptors, CCK-B receptors, or both. Intraventricular administration of the selective CCK-A receptor agonist A71623 at 1 and 10 nmol/kg suppressed 30-min meal size 69 ± 22% and 75 ± 7%, respectively. Additionally, intraventricular A71623 was equipotent to CCK-8 at 1 nmol/kg (% suppression of meal by CCK = 59 ± 17). However, intraventricular administration of the CCK-B receptor agonist A63387 at 10 nmol/kg had no effect on 30-min meal size (% suppression = 18 ± 29). Intravenous administration of 10 nmol/kg A71623 did not result in an alteration of meal size, but prandial plasma insulin and glucose responses were delayed and blunted. Basal plasma insulin levels doubled after intravenous administration of A71623. Both behavioral and metabolic responses to A71623 in the baboon are virtually identical to those we have previously observed after CCK-8 treatment. Thus we conclude that the predominant receptor population with which intraventricular CCK-8 interacts are type-A- CCK receptors that are accessible to the ventricular system of the baboon.

Authors
Figlewicz, DP; Nadzan, AM; Sipols, AJ; Green, PK; Liddle, RA; Jr, DP; Woods, SC
MLA Citation
Figlewicz, DP, Nadzan, AM, Sipols, AJ, Green, PK, Liddle, RA, Jr, DP, and Woods, SC. "Intraventricular CCK-8 reduces single meal size in the baboon by interaction with type-A CCK receptors." American Journal of Physiology - Regulatory Integrative and Comparative Physiology 263.4 32-4 (1992): R863-R867.
Source
scival
Published In
American Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume
263
Issue
4 32-4
Publish Date
1992
Start Page
R863
End Page
R867

Characterization of canine intestinal cholecystokinin-58 lacking its carboxyl-terminal nonapeptide. Evidence for similar post-translational processing in brain and gut.

An antibody raised against a synthetic cholecystokinin (CCK) analog, (1-27)-(CCK)-33, corresponding to the midregion of CCK-58, detected immunoreactivity in intestinal extracts which eluted between the positions of CCK-33/39 and CCK-58 on high performance liquid chromatography. This peak, lacking carboxyl-terminal cholecystokinin immunoreactivity, was purified by reverse phase and cation-exchange chromatographies. Amino acid, mass spectral, and microsequence analysis established that it was the amino-terminal desnonapeptide fragment of cholecystokinin-58, (1-49)-CCK-58. It was demonstrated further that CCK-58 has less biological activity than CCK-8, suggesting that the amino terminus either sterically hindered the ability of CCK-58 to exert its biological activity or that its amino terminus acted at another site to inhibit release of amylase from rat pancreatic acini. The desnonapeptide of CCK-58 by itself had no biological activity, nor did it affect CCK-8-stimulated amylase release from isolated rat pancreatic acini, suggesting that the amino terminus shields the carboxyl terminus from expressing its biological activity. Its presence in intestine suggests that it is released into the circulation where it could be detected by midregion antibodies. The presence of high proportions of (1-49)-CCK-58 indicates that most CCK-8 is directly derived from CCK-58. Its occurrence in brain and intestine indicates similar processing for procholecystokinin in both tissues.

Authors
Reeve, JR; Eysselein, V; Eberlein, GA; Chew, P; Ho, FJ; Huebner, VD; Shively, JE; Lee, TD; Liddle, RA
MLA Citation
Reeve, JR, Eysselein, V, Eberlein, GA, Chew, P, Ho, FJ, Huebner, VD, Shively, JE, Lee, TD, and Liddle, RA. "Characterization of canine intestinal cholecystokinin-58 lacking its carboxyl-terminal nonapeptide. Evidence for similar post-translational processing in brain and gut." J Biol Chem 266.21 (July 25, 1991): 13770-13776.
PMID
1713209
Source
pubmed
Published In
The Journal of biological chemistry
Volume
266
Issue
21
Publish Date
1991
Start Page
13770
End Page
13776

Regulation of intestinal cholecystokinin and somatostatin mRNA by bombesin in rats.

The neuropeptide bombesin has been shown to stimulate secretion of several gastrointestinal hormones, including cholecystokinin (CCK). We have previously demonstrated that stimulation of CCK release by feeding is associated with an increase in steady-state intestinal CCK mRNA levels. The purpose of the present study was to determine whether bombesin stimulates CCK release in rats and, if so, to determine whether bombesin regulates CCK mRNA levels in a manner similar to that of feeding. To establish a proper dose of bombesin for stimulating CCK release, rats received 1-h intravenous infusions of 0.25, 1, 4, or 16 micrograms.kg-1.h-1 bombesin. Basal plasma CCK levels averaged 1.8 +/- 0.4 pM and increased to peak levels of 2.9 +/- 0.6 pM within 15 min of infusion with 4 micrograms.kg-1.h-1 bombesin (the maximally effective dose). With the use of this dose, rats then received infusions of bombesin or saline lasting up to 24 h. At 1, 2, 4, and 24 h, animals were killed for collection of plasma for CCK measurements and of intestine for measurements of intestinal CCK and somatostatin mRNA levels. Bombesin treatment stimulated an increase in plasma CCK levels at 1 h, but levels declined to basal by 4 h, where they remained at 24 h. Despite increasing plasma CCK levels, bombesin infusion, unlike dietary stimulation, had no effect on duodenal CCK mRNA levels. Finally, to determine whether the decrease in plasma CCK levels after prolonged bombesin treatment was due to tachyphylaxis, rats treated with bombesin for 4 h were also fed soybean trypsin inhibitor (a known stimulus of CCK secretion).(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Kanayama, S; Liddle, RA
MLA Citation
Kanayama, S, and Liddle, RA. "Regulation of intestinal cholecystokinin and somatostatin mRNA by bombesin in rats." Am J Physiol 261.1 Pt 1 (July 1991): G71-G77.
PMID
1677536
Source
pubmed
Published In
The American journal of physiology
Volume
261
Issue
1 Pt 1
Publish Date
1991
Start Page
G71
End Page
G77

Influence of food deprivation on intestinal cholecystokinin and somatostatin.

Dietary stimulation has trophic effects on the gastrointestinal tract, whereas prolonged fasting causes mucosal atrophy. Whether gastrointestinal endocrine cells within the mucosa are similarly affected is unknown. The present study was designed to determine the effects of food deprivation and refeeding on cholecystokinin (CCK) and somatostatin in the rat small intestine. RNA was prepared from the duodenum, and peptide and messenger RNA (mRNA) levels of CCK, somatostatin, and beta-actin were analyzed by hybridization with complementary DNA probes. During food deprivation for up to 5 days, plasma CCK levels decreased rapidly, followed by a decline in duodenal CCK mRNA levels and a more gradual decrease in mucosal CCK peptide concentrations. After 3 days of fasting, one group of rats was refed. After only 1 day of refeeding, all parameters (levels of plasma CCK, duodenal CCK mRNA, and duodenal CCK peptide) were restored to control levels. The reduction in CCK mRNA levels seen with fasting was specific, because food deprivation and refeeding produced no changes in either duodenal somatostatin concentrations or mRNA levels of somatostatin and beta-actin. These findings provide initial evidence that food deprivation inhibits duodenal CCK mRNA levels but does not affect duodenal somatostatin.

Authors
Kanayama, S; Liddle, RA
MLA Citation
Kanayama, S, and Liddle, RA. "Influence of food deprivation on intestinal cholecystokinin and somatostatin." Gastroenterology 100.4 (April 1991): 909-915.
PMID
1672115
Source
pubmed
Published In
Gastroenterology
Volume
100
Issue
4
Publish Date
1991
Start Page
909
End Page
915

Regulation of intestinal cholecystokinin and somatostatin mRNA by bombesin in rats

The neuropeptide bombesin has been shown to stimulate secretion of several gastrointestinal hormones, including cholecystokinin (CCK). We have previously demonstrated that stimulation of CCK release by feeding is associated with an increase in steady-state intestinal CCK mRNA levels. The purpose of the present study was to determine whether bombesin stimulates CCK release in rats and, if so, to determine whether bombesin regulates CCK mRNA levels in a manner similar to that of feeding. To establish a proper dose of bombesin for stimulating CCK release, rats received 1-h intravenous infusions of 0.25, 1, 4, or 16 μg·kg-1·h-1 bombesin. Basal plasma CCK levels averaged 1.8 ± 0.4 pM and increased to peak levels of 2.9 ± 0.6 pM within 15 min of infusion with 4 μg·kg-1·h-1 bombesin (the maximally effective dose). With the use of this dose, rats then received infusions of bombesin or saline lasting up to 24 h. At 1, 2, 4, and 24 h, animals were killed for collection of plasma for CCK measurements and of intestine for measurements of intestinal CCK and somatostatin mRNA levels. Bombesin treatment stimulated an increase in plasma CCK levels at 1 h, but levels declined to basal by 4 h, where they remained at 24 h. Despite increasing plasma CCK levels, bombesin infusion, unlike dietary stimulation, had no effect on duodenal CCK mRNA levels. Finally, to determine whether the decrease in plasma CCK levels after prolonged bombesin treatment was due to tachyphylaxis, rats treated with bombesin for 4 h were also fed soybean trypsin inhibitor (a known stimulus of CCK secretion). Trypsin inhibitor treatment caused a significant elevation in plasma CCK levels and increased intestinal CCK mRNA levels despite continuous bombesin infusion. These results indicate that bombesin stimulates CCK release in rats but that its effects are transient and likely reflect tachyphylaxis. In addition, although stimulating CCK secretion, bombesin does not modify CCK mRNA levels; thus its effects on CCK stimulation differ from those of dietary stimulation. We conclude that stimulation of CCK secretion is not obligatorily linked to hormone gene expression.

Authors
Kanayama, S; Liddle, RA
MLA Citation
Kanayama, S, and Liddle, RA. "Regulation of intestinal cholecystokinin and somatostatin mRNA by bombesin in rats." American Journal of Physiology - Gastrointestinal and Liver Physiology 261.1 24-1 (1991): G71-G77.
Source
scival
Published In
American Journal of Physiology - Gastrointestinal and Liver Physiology
Volume
261
Issue
1 24-1
Publish Date
1991
Start Page
G71
End Page
G77

Erratum: CCK-releasing activity of rat intestinal secretion: Effect of atropine and comparison with monitor peptide (Pancreas (1990) 6 (677-684))

Authors
Guan, D; Ohta, H; Tawil, T; Liddle, RA; Green, GM
MLA Citation
Guan, D, Ohta, H, Tawil, T, Liddle, RA, and Green, GM. "Erratum: CCK-releasing activity of rat intestinal secretion: Effect of atropine and comparison with monitor peptide (Pancreas (1990) 6 (677-684))." Pancreas 6.3 (1991): 373--.
Source
scival
Published In
Pancreas
Volume
6
Issue
3
Publish Date
1991
Start Page
373-

CCK-releasing activity of rat intestinal secretion: effect of atropine and comparison with monitor peptide.

A bioassay for studying the cholecystokinin (CCK)-releasing activity of intraluminal protease-sensitive bioactive peptides was developed. In conscious rats, bile and pancreatic juice were chronically diverted from the proximal intestine to the ileum to cause chronic stimulation of CCK release and pancreatic protein secretion. CCK-releasing activity of test substances was assayed during transient inhibition of CCK release by intraduodenal sodium taurocholate (78 mumols/h). Intestinal secretion as a source of the putative trypsin-sensitive intestinal CCK-releasing peptide was obtained by rapid intestinal perfusion of isolated Thiry-Vella fistulae of jejunum in conscious rats, collected with or without atropine pretreatment. Partially purified rat pancreatic secretory trypsin inhibitor (PSTI, or "monitor peptide") was compared with ovomucoid trypsin inhibitor (OMTI) and with concentrated jejunal secretions for CCK-releasing activity and trypsin inhibitor activity. Concentrated, heat-treated jejunal secretions were the strongest stimulants of CCK release and pancreatic protein secretion in this model. OMTI had no CCK-releasing activity in this model, whereas a larger amount (approximately 5x, based on trypsin inhibitor activity) of PSTI weakly but significantly stimulated CCK release. CCK-releasing activity manifested by pancreatic protein secretion was equivalent in intestinal washes from atropine-treated and control Thiry-Vella fistula donor rats. Concentrated jejunal secretions had no trypsin inhibitory activity, indicating that the putative intestinal CCK-releasing peptide and "monitor peptide" are different substances.

Authors
Guan, D; Ohta, H; Tawil, T; Liddle, RA; Green, GM
MLA Citation
Guan, D, Ohta, H, Tawil, T, Liddle, RA, and Green, GM. "CCK-releasing activity of rat intestinal secretion: effect of atropine and comparison with monitor peptide." Pancreas 5.6 (November 1990): 677-684.
PMID
2281081
Source
pubmed
Published In
Pancreas
Volume
5
Issue
6
Publish Date
1990
Start Page
677
End Page
684

Regulation of plasma cholecystokinin levels by bile and bile acids in the rat.

To determine whether intraduodenal bile acids inhibit pancreatic secretion and cholecystokinin (CCK) release independent of pancreatic proteases, experiments were conducted in rats with bile and pancreatic juice chronically diverted to the ileum. Diversion of bile and pancreatic juice increased plasma CCK concentration to 19.1 +/- 4.0 pmol/L. Intraduodenal sodium taurocholate (78 mumol/h) reduced plasma CCK concentration to 6.6 +/- 1.5 pmol/L after 1 hour, but values increased to 17.3 +/- 2.3 pmol/L after 13.5 hours despite continued taurocholate infusion. Pancreatic protein secretion was also significantly but transiently inhibited by taurocholate. However, neither acute nor chronic intraduodenal bile infusion significantly reduced plasma CCK concentration compared with sodium bicarbonate infusion (13.4 +/- 1.9 pmol/L vs. 15.0 +/- 1.7 pmol/L, respectively). Chronic (13.5 hours) intraduodenal infusion of taurocholate plus pancreatic juice caused a sustained reduction of plasma CCK level to 3.1 +/- 0.5 pmol/L, which significantly increased to 9.4 +/- 1.1 pmol/L after cessation of taurocholate but with continued infusion of pancreatic juice. The results indicate that bile does not inhibit CCK release and that bile acids do not physiologically inhibit pancreatic secretion or CCK release independent of the presence of pancreatic proteases.

Authors
Ohta, H; Guan, D; Tawil, T; Liddle, RA; Green, GM
MLA Citation
Ohta, H, Guan, D, Tawil, T, Liddle, RA, and Green, GM. "Regulation of plasma cholecystokinin levels by bile and bile acids in the rat." Gastroenterology 99.3 (September 1990): 819-825.
PMID
2379784
Source
pubmed
Published In
Gastroenterology
Volume
99
Issue
3
Publish Date
1990
Start Page
819
End Page
825

Atropine enhances food-stimulated CCK secretion in the rat.

The effect of atropine on plasma cholecystokinin (CCK) and pancreatic secretion during intraintestinal infusion of a conventional defined formula liquid diet (Ensure HN, Ross Laboratories, 1.06 kcal/ml) was studied in conscious rats. Rats were prepared with cannulae draining bile and pancreatic juice, which were returned to the duodenum at all times. Pancreatic secretion was monitored during intraduodenal infusion of 0.15 M NaCl for 2 h followed by Ensure HN, both infused at 4.62 ml/h. Rats were infused i.p. with atropine (500 micrograms/kg/h) or vehicle throughout the experiment, beginning 1 h before monitoring of basal pancreatic secretion. Basal and 15 min postprandial plasma CCK concentrations were determined by bioassay. Atropine inhibited basal pancreatic protein secretion by approximately 60%. However, protein secretion during infusion of the diet was not decreased by atropine, due to a larger incremental pancreatic protein secretory response in atropine-treated rats. Plasma CCK 15 min after beginning the diet infusion was significantly increased by atropine (8.09 +/- 1.77 pM in atropine-treated rats versus 3.14 +/- 0.64 pM in controls). The results indicate that rats compensate for loss of cholinergic input to the pancreas by increasing CCK release in response to a meal. This is hypothesized to occur by virtue of reduced feedback inhibition of CCK release due to anticholinergic reduction of basal levels of intestinal protease activity.

Authors
Nakano, I; Tawil, T; Spannagel, AW; Liddle, RA; Green, GM
MLA Citation
Nakano, I, Tawil, T, Spannagel, AW, Liddle, RA, and Green, GM. "Atropine enhances food-stimulated CCK secretion in the rat." Pancreas 5.5 (September 1990): 621-625.
PMID
2235972
Source
pubmed
Published In
Pancreas
Volume
5
Issue
5
Publish Date
1990
Start Page
621
End Page
625

Cholecystokinin is not a major hormonal regulator of lower esophageal sphincter pressure.

Although injection of cholecystokinin can reduce resting lower esophageal sphincter pressure, the physiological significance of this finding has not been established. The purpose of this double-blind crossover study was to determine the effect of physiological plasma levels of cholecystokinin on resting lower esophageal sphincter pressure. Eighteen normal male volunteers were studied on two separate days. Following a 20-minute baseline period, subjects received infusions of saline or synthetic cholecystokinin-8 at increasing rates. Basal plasma cholecystokinin levels averaged 1.3 +/- 0.2 pmol/L (mean +/- SE) and increased to levels of 7.4 +/- 0.9 pmol/L, 12.1 +/- 2.4 pmol/L, and 23.1 +/- 3.8 pmol/L during cholecystokinin infusion rates of 21, 42, and 84 pmol/min, respectively. Lower esophageal sphincter pressure was recorded continuously with a sleeved catheter. Basal lower esophageal sphincter pressure averaged 19.9 mm Hg and did not change with the first infusion, which produced physiological peak postprandial plasma levels of cholecystokinin. Lower esophageal sphincter pressure declined only during the infusions that produced plasma cholecystokinin levels two to four times greater than normal peak postprandial levels. Since infusion of cholecystokinin to levels that reproduce physiological blood levels does not significantly decrease lower esophageal sphincter pressure, it was concluded that cholecystokinin is not a major hormonal regulator of lower esophageal sphincter relaxation.

Authors
Brazer, SR; Borislow, DS; Liddle, RA
MLA Citation
Brazer, SR, Borislow, DS, and Liddle, RA. "Cholecystokinin is not a major hormonal regulator of lower esophageal sphincter pressure." Gastroenterology 99.3 (September 1990): 641-645.
PMID
2379771
Source
pubmed
Published In
Gastroenterology
Volume
99
Issue
3
Publish Date
1990
Start Page
641
End Page
645

Hunger in humans induced by MK-329, a specific peripheral-type cholecystokinin receptor antagonist.

Authors
Wolkowitz, OM; Gertz, B; Weingartner, H; Beccaria, L; Thompson, K; Liddle, RA
MLA Citation
Wolkowitz, OM, Gertz, B, Weingartner, H, Beccaria, L, Thompson, K, and Liddle, RA. "Hunger in humans induced by MK-329, a specific peripheral-type cholecystokinin receptor antagonist." Biol Psychiatry 28.2 (July 15, 1990): 169-173.
PMID
2378921
Source
pubmed
Published In
Biological Psychiatry
Volume
28
Issue
2
Publish Date
1990
Start Page
169
End Page
173

Regulation of pancreatic endocrine function by cholecystokinin: studies with MK-329, a nonpeptide cholecystokinin receptor antagonist.

A cholecystokinin (CCK) receptor antagonist, MK-329, was used to explore the physiological role of CCK in regulating pancreatic endocrine function in humans. The ability of CCK to increase plasma pancreatic polypeptide (PP) concentrations and blockade of this effect with MK-329 were evaluated in a double blind, balanced, four-period cross-over study. Eight subjects received single oral doses of 0.5, 2, or 10 mg MK-329 or placebo, followed by an iv infusion of CCK-8 (34 ng/kg.h). In placebo-treated subjects, PP increased from basal levels of 70 +/- 15 (+/- SE) to peak values of 291 +/- 58 pg/mL after CCK infusion (P less than 0.05 compared to basal). This increase in plasma PP concentration was inhibited in a dose-dependent fashion by MK-329, with 10 mg antagonizing the stimulatory effect of CCK infusion by nearly 80%. Second, the effect of MK-329 on meal-stimulated pancreatic endocrine responses was evaluated by giving placebo or 10 mg MK-329 2 h before ingestion of a mixed meal. Eight subjects were treated in a randomized two-period cross-over fashion. With placebo treatment, peak postprandial plasma insulin, glucagon, and glucose concentrations were 101 +/- 8 microU/mL, 195 +/- 15 pg/mL, and 150 +/- 10 mg/dL, respectively (all P less than 0.05). The integrated PP response following the meal was 56.3 +/- 11.1 ng/mL.minute. With MK-329 treatment, the integrated PP concentration was reduced to 33.9 +/- 2.2 ng/mL.min (P less than 0.05 compared to placebo treatment). Mean postprandial insulin, glucagon, and glucose concentrations did not differ between placebo and MK-329 treatments. We conclude that CCK receptor blockade with 10 mg MK-329 does not alter plasma insulin, glucagon, or glucose responses to a mixed meal. However, the observation that physiological concentrations of CCK increase plasma levels of PP, and the finding that CCK receptor blockade selectively attenuates the postprandial increase in plasma PP concentrations support a physiological role for CCK in regulating PP secretion.

Authors
Liddle, RA; Gertz, BJ; Kanayama, S; Beccaria, L; Gettys, TW; Taylor, IL; Rushakoff, RJ; Williams, VC; Coker, LD
MLA Citation
Liddle, RA, Gertz, BJ, Kanayama, S, Beccaria, L, Gettys, TW, Taylor, IL, Rushakoff, RJ, Williams, VC, and Coker, LD. "Regulation of pancreatic endocrine function by cholecystokinin: studies with MK-329, a nonpeptide cholecystokinin receptor antagonist." J Clin Endocrinol Metab 70.5 (May 1990): 1312-1318.
PMID
2186058
Source
pubmed
Published In
Journal of Clinical Endocrinology and Metabolism
Volume
70
Issue
5
Publish Date
1990
Start Page
1312
End Page
1318
DOI
10.1210/jcem-70-5-1312

Cholecystokinin does not stimulate prosomatostatin-derived peptides in man.

In man, plasma cholecystokinin (CCK) and somatostatin-28 (S-28) levels increase after ingestion of a mixed meal. Both peptides originate from the gastrointestinal tract. In supra- and periphysiological doses, CCK stimulates the release of somatostatin-14 from in vitro pancreatic islets and gastric cells and increases circulating somatostatin-like immunoreactivity in dogs, leading to the conjecture that CCK regulates somatostatin-like immunoreactivity secretion. Nonetheless, whether CCK is responsible in part for the meal-induced rise in S-28 in man has not been established. Therefore, the present study was designed to determine if CCK, at both physiological and supraphysiological concentrations, increases the circulating levels of prosomatostatin (proS)-derived peptides in humans. On 3 separate days, five healthy men ate a mixed liquid meal or received iv infusions of CCK at rates of 18 or 38 pmol/kg.h. Plasma levels of pro-S-derived peptides, including pro-S, S-14, S-13, S-28, and CCK, were measured. Basal CCK levels averaged 0.9 +/- 0.1 pmol/L and increased after the meal to a peak level of 5.4 +/- 1.5 pmol/L and averaged 3.1 +/- 1.2 pmol/L over 90 min. The mean basal levels of pro-S, S-14, and S-13, measured collectively, was 6.1 +/- 0.4 pmol/L eq S14 and was unaltered by food intake. The S-28 level was 6.7 +/- 0.6 pmol/L and rose to a zenith of 13.1 +/- 3.3 pmol/L by 90 min. Infusion of CCK at 18 and 38 pmol/kg.h produced steady state plasma CCK levels of 4.1 +/- 1.1 and 9.9 +/- 1.5 pmol/L, respectively. Basal levels of pro-S-derived peptides were unaltered during the infusion of either the low or high dose of CCK. We conclude that CCK by itself is not a physiological signal to the release of pro-S-derived peptides in man.

Authors
Liddle, RA; Ensinck, JW
MLA Citation
Liddle, RA, and Ensinck, JW. "Cholecystokinin does not stimulate prosomatostatin-derived peptides in man." J Clin Endocrinol Metab 70.5 (May 1990): 1403-1407.
PMID
1970830
Source
pubmed
Published In
Journal of Clinical Endocrinology and Metabolism
Volume
70
Issue
5
Publish Date
1990
Start Page
1403
End Page
1407
DOI
10.1210/jcem-70-5-1403

DIETARY-REGULATION OF PANCREATIC HORMONE GENE-EXPRESSION

Authors
YUDELMAN, PL; KANAYAMA, S; LIDDLE, RA
MLA Citation
YUDELMAN, PL, KANAYAMA, S, and LIDDLE, RA. "DIETARY-REGULATION OF PANCREATIC HORMONE GENE-EXPRESSION." CLINICAL RESEARCH 38.2 (April 1990): A423-A423.
Source
wos-lite
Published In
Clinical Research
Volume
38
Issue
2
Publish Date
1990
Start Page
A423
End Page
A423

REGULATION OF CHOLECYSTOKININ SECRETION INVITRO - A MODEL FOR STUDYING HORMONE-RELEASE FROM PERIFUSED DISPERSED INTESTINAL-MUCOSA

Authors
LIDDLE, RA; MISUKONIS, MA
MLA Citation
LIDDLE, RA, and MISUKONIS, MA. "REGULATION OF CHOLECYSTOKININ SECRETION INVITRO - A MODEL FOR STUDYING HORMONE-RELEASE FROM PERIFUSED DISPERSED INTESTINAL-MUCOSA." CLINICAL RESEARCH 38.2 (April 1990): A345-A345.
Source
wos-lite
Published In
Clinical Research
Volume
38
Issue
2
Publish Date
1990
Start Page
A345
End Page
A345

Somatostatin regulates duodenal cholecystokinin and somatostatin messenger RNA.

The gastrointestinal peptides, cholecystokinin (CCK) and somatostatin, are produced by discrete endocrine cells in the mucosa of the small intestine. Although somatostatin may inhibit CCK secretion, the mechanism by which this occurs is unknown. The present study was designed to determine the effect of somatostatin on intestinal CCK and somatostatin mRNA levels. Rats, prepared with indwelling intraduodenal and jugular cannulas, were first fed an elemental diet that did not stimulate CCK release. Next, as a means of stimulating CCK secretion, soybean trypsin inhibitor was added to the diet and perfused intraduodenally at 50 mg/h for 24 h. Trypsin inhibitor caused an 11-fold increase in plasma CCK levels and a 2.4-fold increase in duodenal CCK mRNA levels. Simultaneous intravenous infusion of somatostatin-14 (1-100 micrograms.kg-1.h-1) reduced trypsin inhibitor-stimulated CCK levels by 50% and lowered trypsin inhibitor-stimulated CCK mRNA levels by 58%. Somatostatin infusion also reduced intestinal somatostatin mRNA levels stimulated by trypsin inhibitor but did not affect basal somatostatin mRNA levels. Duodenal CCK and somatostatin peptide concentrations did not change under any of the experimental conditions. These studies demonstrate that somatostatin reduces duodenal CCK mRNA levels stimulated by diet and suggest that somatostatin itself inhibits duodenal somatostatin gene expression.

Authors
Kanayama, S; Liddle, RA
MLA Citation
Kanayama, S, and Liddle, RA. "Somatostatin regulates duodenal cholecystokinin and somatostatin messenger RNA." Am J Physiol 258.3 Pt 1 (March 1990): G358-G364.
PMID
1969232
Source
pubmed
Published In
The American journal of physiology
Volume
258
Issue
3 Pt 1
Publish Date
1990
Start Page
G358
End Page
G364

SOMATOSTATIN REGULATES DUODENAL CHOLECYSTOKININ AND SOMATOSTATIN MESSENGER-RNA

Authors
KANAYAMA, S; LIDDLE, RA
MLA Citation
KANAYAMA, S, and LIDDLE, RA. "SOMATOSTATIN REGULATES DUODENAL CHOLECYSTOKININ AND SOMATOSTATIN MESSENGER-RNA." AMERICAN JOURNAL OF PHYSIOLOGY 258.3 (March 1990): G358-G364.
Source
wos-lite
Published In
The American journal of physiology
Volume
258
Issue
3
Publish Date
1990
Start Page
G358
End Page
G364

Lack of cholinergic control in feedback regulation of pancreatic secretion in the rat.

The effect of atropine (100 micrograms/kg/h, i.v.) on plasma cholecystokinin and pancreatic secretion during diversion of bile and pancreatic juice from the intestine was studied in 8 conscious rats equipped with jugular vein, pancreatic, biliary, and duodenal cannulas, and with pyloric ligation and gastric drainage. Diversion of bile and pancreatic juice to the exterior for 4 h significantly increased pancreatic protein and fluid secretion. Atropine delayed the pancreatic response to diversion, but during 4 h of diversion, neither total nor incremental pancreatic protein or fluid secretion was inhibited by atropine. Plasma cholecystokinin levels were elevated after diverting bile and pancreatic juice and were not significantly reduced by atropine (23.0 +/- 6.6 pM vs. 16.0 +/- 3.9 pM at 1.5 h and 17.3 +/- 5.4 pM vs. 13.1 +/- 2.9 pM at 4 h after bile and pancreatic juice diversion; atropine-treated vs. controls, respectively). These results indicate that cholinergic nerves play no important role in feedback regulation of cholecystokinin release and that the previously reported suppressive effect of atropine on the pancreatic response to diversion of bile and pancreatic juice from the intestine was secondary to inhibition of gastric secretion.

Authors
Guan, D; Ohta, H; Tawil, T; Spannagel, AW; Liddle, RA; Green, GM
MLA Citation
Guan, D, Ohta, H, Tawil, T, Spannagel, AW, Liddle, RA, and Green, GM. "Lack of cholinergic control in feedback regulation of pancreatic secretion in the rat." Gastroenterology 98.2 (February 1990): 437-443.
PMID
2295400
Source
pubmed
Published In
Gastroenterology
Volume
98
Issue
2
Publish Date
1990
Start Page
437
End Page
443

Somatostatin regulates duodenal cholecystokinin and somatostatin messenger RNA

The gastrointestinal peptides, cholecystokinin (CCK) and somatostatin, are produced by discrete endocrine cells in the mucosa of the small intestine. Although somatostatin may inhibit CCK secretion, the mechanism by which this occurs is unknown. The present study was designed to determine the effect of somatostatin on intestinal CCK and somatostatin mRNA levels. Rats, prepared with indwelling intraduodenal and jugular cannulas, were first fed an elemental diet that did not stimulate CCK release. Next, as a means of stimulating CCK secretion, soybean trypsin inhibitor was added to the diet and perfused intraduodenally at 50 mg/h for 24 h. Trypsin inhibitor caused an 11-fold increase in plasma CCK levels and a 2.4-fold increase in duodenal CCK mRNA levels. Simultaneous intravenous infusion of somatostatin-14 (1-100 μg·kg-1·h-1) reduced trypsin inhibitor-stimulated CCK levels by 50% and lowered trypsin inhibitor-stimulated CCK mRNA levels by 58%. Somatostatin infusion also reduced intestinal somatostatin mRNA levels stimulated by trypsin inhibitor but did not affect basal somatostatin mRNA levels. Duodenal CCK and somatostatin peptide concentrations did not change under any of the experimental conditions. These studies demonstrate that somatostatin reduces duodenal CCK mRNA levels stimulated by diet and suggest that somatostatin itself inhibits duodenal somatostatin gene expression.

Authors
Kanayama, S; Liddle, RA
MLA Citation
Kanayama, S, and Liddle, RA. "Somatostatin regulates duodenal cholecystokinin and somatostatin messenger RNA." American Journal of Physiology - Gastrointestinal and Liver Physiology 258.3 21-3 (1990): C358-C364.
Source
scival
Published In
American Journal of Physiology - Gastrointestinal and Liver Physiology
Volume
258
Issue
3 21-3
Publish Date
1990
Start Page
C358
End Page
C364

Integrated actions of cholecystokinin on the gastrointestinal tract: use of the cholecystokinin bioassay.

This article has centered on the hormonal actions of CCK on a variety of different target tissues. Until the development of specific assays for measuring plasma levels of the hormone, it was not possible to distinguish physiologic from pharmacologic effects. However, by the methods described earlier it now has become clear that CCK, in physiologic concentrations, stimulates gallbladder contraction, delays gastric emptying, potentiates insulin secretion, and may affect satiety. Actions of CCK that have been studied by radioimmunoassay methods and determined also to be physiologic include stimulation of pancreatic exocrine secretion. Other actions of CCK that may be physiologic but have not been thoroughly investigated include effects on bowel motility, relaxation of lower esophageal sphincter pressure, regulation of sphincter of Oddi pressure, effects on analgesia, and modification of behavior. Some of these actions may be attributable to endogenous, but neurally released CCK and, therefore, would not be hormonal actions. However, continued investigations with specific CCK receptor antagonists together with accurate measurements of circulating levels of CCK should make it possible to define the physiologic importance of CCK on these other potential sites of action. The variety of CCK's physiologic effects emphasizes its integrative function on both digestive and metabolic processes. After a meal, in a highly coordinated fashion, CCK (1) regulates the movement of nutrients through the gastrointestinal tract, (2) contracts the gallbladder and stimulates pancreatic exocrine secretion to facilitate digestion, and (3) potentiates amino acid-induced insulin secretion and delays gastric emptying to maintain euglycemia. An effect to reduce food intake following food ingestion would be a logical extension of these integrated actions. Thus, CCK appears to have an essential role in regulating the intake, processing, and distribution of essential nutrients.

Authors
Liddle, RA
MLA Citation
Liddle, RA. "Integrated actions of cholecystokinin on the gastrointestinal tract: use of the cholecystokinin bioassay." Gastroenterol Clin North Am 18.4 (December 1989): 735-756. (Review)
PMID
2482253
Source
pubmed
Published In
Gastroenterology Clinics of North America
Volume
18
Issue
4
Publish Date
1989
Start Page
735
End Page
756

Endogenous cholecystokinin does not decrease food intake or gastric emptying in fasted rats.

To investigate the hypothesized inhibitory effect of cholecystokinin (CCK) released from the small intestine on food intake and gastric emptying, we infused soybean trypsin inhibitor (STI) into the stomach or duodenum of male rats deprived of food for 17 h. Intraduodenal infusions of STI (100-200 mg) before real or sham feeding, or during sham feeding, had no effect on food intake. Intragastric infusions of STI (100-200 mg) also had no effect on gastric emptying. Identical infusions of STI, however, increased bioassayable plasma CCK six to ninefold. The failure of endogenous, small intestinal CCK released by STI to decrease food intake or to decrease gastric emptying is evidence against the hypothesis that the inhibitions of food intake and of gastric emptying are physiological functions of small intestinal CCK in food-deprived rats. In contrast to the negative results with STI, administration of exogenous CCK-8 (2-4 micrograms/kg ip) significantly inhibited food intake and gastric emptying despite producing smaller increases of plasma CCK than STI produced. The reason for the differential effects of exogenous and endogenous CCK is not clear and requires further investigation.

Authors
Smith, GP; Greenberg, D; Falasco, JD; Avilion, AA; Gibbs, J; Liddle, RA; Williams, JA
MLA Citation
Smith, GP, Greenberg, D, Falasco, JD, Avilion, AA, Gibbs, J, Liddle, RA, and Williams, JA. "Endogenous cholecystokinin does not decrease food intake or gastric emptying in fasted rats." Am J Physiol 257.6 Pt 2 (December 1989): R1462-R1466.
PMID
2604005
Source
pubmed
Published In
The American journal of physiology
Volume
257
Issue
6 Pt 2
Publish Date
1989
Start Page
R1462
End Page
R1466

Effects of a novel cholecystokinin (CCK) receptor antagonist, MK-329, on gallbladder contraction and gastric emptying in humans. Implications for the physiology of CCK.

To explore the physiology of cholecystokinin (CCK) in humans, we investigated the effect on gallbladder contraction and gastric emptying of a recently developed CCK receptor antagonist, MK-329. In a double-blind, four-period crossover study eight subjects received single doses of 0.5, 2, or 10 mg MK-329, or placebo, followed by an intravenous infusion of CCK-8 (30 pmol/kg.h). In placebo-treated subjects gallbladder volumes decreased on average to 43% of initial volumes after 2 h of CCK infusion. MK-329 caused a dose-dependent inhibition of CCK-stimulated gallbladder contraction with 10 mg producing complete blockade (P less than 0.01, cf. placebo). Gallbladder contraction and gastric emptying rates after a mixed meal were then measured in a two-period crossover study. Subjects received placebo or 10 mg of MK-329 2 h before eating. Gastric emptying of both solids and liquids was measured simultaneously by gamma scintigraphy. In placebo-treated subjects plasma CCK levels increased postprandially to 2.3 pM, gallbladder volumes decreased 68.4 +/- 3.8% (SE), and the times for 50% emptying of liquids and solids from the stomach were 58 +/- 10 and 128 +/- 8 min, respectively. In MK-329-treated subjects there was a marked elevation in peak CCK levels to 13.8 pM (P less than 0.01, cf. placebo), and gallbladder contraction was completely inhibited. Solid and liquid emptying rates were unaffected. These findings demonstrate that (a) MK-329 is a potent, orally active antagonist of CCK in humans, and (b) CCK is the major regulator of postprandial gallbladder contraction. These data also support the concept of negative feedback regulation of CCK secretion and suggest that mechanisms other than CCK play a dominant role in the regulation of postprandial gastric emptying rates.

Authors
Liddle, RA; Gertz, BJ; Kanayama, S; Beccaria, L; Coker, LD; Turnbull, TA; Morita, ET
MLA Citation
Liddle, RA, Gertz, BJ, Kanayama, S, Beccaria, L, Coker, LD, Turnbull, TA, and Morita, ET. "Effects of a novel cholecystokinin (CCK) receptor antagonist, MK-329, on gallbladder contraction and gastric emptying in humans. Implications for the physiology of CCK." J Clin Invest 84.4 (October 1989): 1220-1225.
PMID
2794058
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
84
Issue
4
Publish Date
1989
Start Page
1220
End Page
1225
DOI
10.1172/JCI114288

Gallstone formation during weight-reduction dieting.

We investigated the development of gallstones over an 8-week period from the onset of dieting in 51 obese men and women and 26 nondieting control subjects. Gallbladder examinations were performed by abdominal real-time ultrasonography for the detection of gallstones. Initial sonography was performed prior to dieting and only those subjects in whom initial sonograms showed no gallstones or sludge were included in the study. Repeated sonography was performed at 4-week intervals for 8 weeks while they remained on a 2100-kJ/d diet. Initial weight of subjects prior to dieting averaged 105.9 +/- 3.8 kg (162% of ideal body weight) and decreased to 89.4 +/- 3.2 kg (137.3% of ideal body weight) after 8 weeks of dieting. Sonography performed after 4 weeks of dieting revealed new-onset gallbladder sludge in 1 subject and gallstones in 4 subjects. After 8 weeks of dieting sludge was detected in 3 subjects and gallstones in 13 (25.5%). In contrast, none of the nondieting subjects developed any detectable gallbladder abnormalities. During the dieting period, 1 of 51 subjects developed symptoms of biliary colic, necessitating cholecystectomy. On cessation of dieting with reinstitution of normal feeding, 2 additional subjects with stones developed symptoms severe enough to require cholecystectomy. In all 3 cases, cholesterol gallstones were recovered at the time of surgery. Eleven of the 13 patients with gallstones were followed up for 6 months after discontinuation of the diet. Besides the 3 undergoing cholecystectomy, 4 subjects had gallstones on follow-up ultrasound examination, while sonographically detectable gallstones had disappeared in 4 subjects. We conclude that this form of weight-reduction dieting predisposes to the development of gallstones and that gallstone formation is a risk of this type of prolonged calorie restriction. Dissolution or evacuation of gallstones may occur with resumption of a normal diet.

Authors
Liddle, RA; Goldstein, RB; Saxton, J
MLA Citation
Liddle, RA, Goldstein, RB, and Saxton, J. "Gallstone formation during weight-reduction dieting." Arch Intern Med 149.8 (August 1989): 1750-1753.
PMID
2669662
Source
pubmed
Published In
Archives of internal medicine
Volume
149
Issue
8
Publish Date
1989
Start Page
1750
End Page
1753

Feedback regulation by trypsin: evidence for intraluminal CCK-releasing peptide.

The mechanism by which intraluminal proteases inhibit pancreatic secretion and CCK release was investigated in conscious rats. We hypothesized that the stimulation of pancreatic secretion and CCK release that occurs in the absence of luminal trypsin is caused by a trypsin-sensitive, cholecystokinin (CCK)-releasing peptide that is tonically secreted intraluminally by the small intestine. We tested whether rapid saline perfusion of the lumen of the proximal intestine in rats with jejunostomies would wash out the putative peptide, thereby inhibiting the spontaneous pancreatic secretion caused by diverting bile and pancreatic juice from the intestine. Rats were prepared with cannulas draining bile and pancreatic juice, a duodenal cannula and a jejunostomy 10-12 cm from the ligament of Treitz. During diversion of bile and pancreatic juice to the exterior, the proximal intestine was perfused with phosphate-buffered saline at 3 ml/min via the duodenal cannula and the intestinal washes collected from the jejunostomy outlet. Rapid intestinal perfusion significantly inhibited pancreatic protein and fluid secretion stimulated by diversion of bile and pancreatic juice to the exterior. Reinfusion of the concentrated intestinal washes prevented the "washout" inhibition. The active factor in the intestinal washes was heat stable and trypsin sensitive. Rapid washout perfusion of isolated jejunal loops in Thiry-Vella fistula rats reduced plasma CCK from 20.4 +/- 3.6 to 10.4 +/- 1.8 pM, and reinfusion of the washes into the loop returned plasma CCK to 17.1 +/- 3.8 pM. The results support the hypothesis that a trypsin-sensitive, CCK-releasing peptide in intestinal secretions mediates feedback regulation of pancreatic secretion in rats.

Authors
Miyasaka, K; Guan, DF; Liddle, RA; Green, GM
MLA Citation
Miyasaka, K, Guan, DF, Liddle, RA, and Green, GM. "Feedback regulation by trypsin: evidence for intraluminal CCK-releasing peptide." Am J Physiol 257.2 Pt 1 (August 1989): G175-G181.
PMID
2764106
Source
pubmed
Published In
The American journal of physiology
Volume
257
Issue
2 Pt 1
Publish Date
1989
Start Page
G175
End Page
G181

Plasma secretin, CCK, and pancreatic secretion in response to dietary fat in the rat.

The role of fat in regulation of pancreatic secretion was studied in conscious rats by measuring pancreatic secretion and plasma cholecystokinin (CCK) and secretin responses to intraluminal infusion of fat, protein, or trypsin inhibitor via the duodenum. In rats with pancreatic juice continuously returned to the intestine, intraduodenal infusion of 20% emulsified fat (Liposyn), 10% casein, and 0.4% ovomucoid trypsin inhibitor (OMTI) stimulated equivalent increases of approximately threefold in pancreatic protein output. Proglumide reduced fat-stimulated pancreatic protein secretion by greater than 90% but did not inhibit the response to OMTI. Fat significantly increased plasma CCK from basal levels of 0.5 pM to 2-3 pM, but it was a weaker stimulant of CCK secretion than casein (peak CCK levels greater than 10 pM) or OMTI (peak CCK levels 5-6 pM). Fat significantly stimulated secretin release (21.7 pM) compared with casein (6.8 pM), OMTI (4.4 pM), and NaCl (3.5 pM). The inhibition of fat-stimulated pancreatic secretion by proglumide indicates that the small amounts of CCK released by fat are necessary for a normal pancreatic response, suggesting that this response may be the result of potentiation between secretin and small amounts of CCK.

Authors
Green, GM; Taguchi, S; Friestman, J; Chey, WY; Liddle, RA
MLA Citation
Green, GM, Taguchi, S, Friestman, J, Chey, WY, and Liddle, RA. "Plasma secretin, CCK, and pancreatic secretion in response to dietary fat in the rat." Am J Physiol 256.6 Pt 1 (June 1989): G1016-G1021.
PMID
2735407
Source
pubmed
Published In
The American journal of physiology
Volume
256
Issue
6 Pt 1
Publish Date
1989
Start Page
G1016
End Page
G1021

Intraventricular CCK inhibits food intake and gastric emptying in baboons.

To evaluate the role of cholecystokinin (CCK) as a physiological regulator of meal size and gastric emptying in the baboon, we measured plasma CCK bioactivity during 30-min meals alone and after intravenous or intraventricular infusions of CCK COOH-terminal octapeptide (CCK-8). Both intravenous (2 micrograms/kg) and intraventricular (1 microgram/kg) CCK-8 administration resulted in plasma CCK elevations comparable with normal prandial CCK levels: peak plasma levels were 4.1 +/- 0.9, 7.1 +/- 1.1, and 4.9 +/- 2.2 pM for pooled intravenous and intraventricular control, intravenous, and intraventricular conditions. Also, both treatments appeared to reduce gastric emptying as indicated by a significant suppression of postprandial plasma insulin and glucose levels. However, only intraventricular CCK reliably reduced meal size (percent of control meal size was 91 +/- 5% or 43 +/- 19% with intravenous or intraventricular CCK). We conclude that circulating endogenous CCK is a potent postprandial endocrine regulator of gastric emptying. However, the ability of CCK to decrease meal size may require direct interaction with the central nervous system.

Authors
Figlewicz, DP; Sipols, AJ; Porte, D; Woods, SC; Liddle, RA
MLA Citation
Figlewicz, DP, Sipols, AJ, Porte, D, Woods, SC, and Liddle, RA. "Intraventricular CCK inhibits food intake and gastric emptying in baboons." Am J Physiol 256.6 Pt 2 (June 1989): R1313-R1317.
PMID
2735457
Source
pubmed
Published In
The American journal of physiology
Volume
256
Issue
6 Pt 2
Publish Date
1989
Start Page
R1313
End Page
R1317

Inhibitory regulation of rat exocrine pancreas by peptide YY and pancreatic polypeptide.

Peptide YY (PYY) and pancreatic polypeptide (PP) have been shown to inhibit exocrine pancreatic secretion in vivo in a variety of species. This study evaluates the type of stimulation inhibited by PYY and PP by examining, in urethan-anesthetized rats, the inhibition of pancreatic secretion when stimulated to a comparable extent by cholecystokinin (CCK), 2-deoxy-D-glucose (2DG), bethanecol, and electrical vagal nerve stimulation. PYY at maximal infusion rates inhibited stimulation by CCK by 83%, bethanecol by 55%, and electrical nerve stimulation by 40%. The inhibition of CCK stimulation was half maximal at 250 pmol.kg-1.h-1. By contrast, PYY totally inhibited 2DG-stimulated secretion with half-maximal inhibition at 10 pmol. kg-1.h-1. PP acted similarly to PYY in inhibiting CCK and 2DG-stimulated pancreatic protein secretion but was fivefold weaker in each case. These findings indicate that PYY and PP have multiple actions but preferentially inhibit neurally mediated pancreatic secretion at a preacinar cell locus, possibly at a central site of action.

Authors
Putnam, WS; Liddle, RA; Williams, JA
MLA Citation
Putnam, WS, Liddle, RA, and Williams, JA. "Inhibitory regulation of rat exocrine pancreas by peptide YY and pancreatic polypeptide." Am J Physiol 256.4 Pt 1 (April 1989): G698-G703.
PMID
2565088
Source
pubmed
Published In
The American journal of physiology
Volume
256
Issue
4 Pt 1
Publish Date
1989
Start Page
G698
End Page
G703

Pancreatic digestive enzyme gene expression: effects of CCK and soybean trypsin inhibitor.

Regulation of pancreatic gene expression by cholecystokinin (CCK) was examined in the rat using cloned cDNA probes to quantify changes in specific mRNAs (amylase, trypsinogen I, chymotrypsinogen B, and ribonuclease). Rats were administered intraduodenally an elemental liquid diet. Plasma CCK levels were raised to levels comparable to physiological postprandial levels either by intraduodenal perfusion with soybean trypsin inhibitor (SBTI) (6.9 +/- 1.0 pM, n = 8) or by continuous intravenous infusion with cholecystokinin octapeptide (CCK-8, 6.0 +/- 0.9 pM, n = 6). SBTI infusion resulted in fivefold increases in trypsinogen I and chymotrypsinogen B mRNA levels after 48 h. In contrast SBTI infusion had no effect on amylase mRNA levels and led to a decrease in ribonuclease mRNA levels to approximately 50% of control after 48 h. Intravenous infusion with CCK-8 for 24 h resulted in plasma levels of CCK comparable to those obtained with SBTI and had similar effects on digestive enzyme mRNA levels. These data suggested that SBTI acted via its ability to raise plasma CCK levels. To further test the specificity of these effects, animals were infused intraduodenally with the specific CCK receptor antagonist L364,718. Although the antagonist itself had no effect on digestive enzyme mRNA levels, antagonist treatment totally abolished the effects of both CCK infusion and SBTI treatment. These data therefore indicate that CCK regulates digestive enzyme gene expression at plasma concentrations comparable to physiological postprandial levels. Furthermore, the ability of SBTI infusion to increase plasma CCK accounts for its effects on pancreatic digestive enzyme mRNA levels.

Authors
Rosewicz, S; Lewis, LD; Wang, XY; Liddle, RA; Logsdon, CD
MLA Citation
Rosewicz, S, Lewis, LD, Wang, XY, Liddle, RA, and Logsdon, CD. "Pancreatic digestive enzyme gene expression: effects of CCK and soybean trypsin inhibitor." Am J Physiol 256.4 Pt 1 (April 1989): G733-G738.
PMID
2468294
Source
pubmed
Published In
The American journal of physiology
Volume
256
Issue
4 Pt 1
Publish Date
1989
Start Page
G733
End Page
G738

EFFECT OF A NOVEL CHOLECYSTOKININ RECEPTOR ANTAGONIST, MK-329, ON PANCREATIC ENDOCRINE FUNCTION - IMPLICATIONS FOR THE PHYSIOLOGIC ROLE OF CCK

Authors
LIDDLE, RA; GERTZ, BJ; KANAYAMA, S; BECCARIA, L; GETTYS, TW; TAYLOR, IL; RUSHAKOFF, RJ; WILLIAMS, VC; COKER, LD
MLA Citation
LIDDLE, RA, GERTZ, BJ, KANAYAMA, S, BECCARIA, L, GETTYS, TW, TAYLOR, IL, RUSHAKOFF, RJ, WILLIAMS, VC, and COKER, LD. "EFFECT OF A NOVEL CHOLECYSTOKININ RECEPTOR ANTAGONIST, MK-329, ON PANCREATIC ENDOCRINE FUNCTION - IMPLICATIONS FOR THE PHYSIOLOGIC ROLE OF CCK." CLINICAL RESEARCH 37.2 (April 1989): A369-A369.
Source
wos-lite
Published In
Clinical Research
Volume
37
Issue
2
Publish Date
1989
Start Page
A369
End Page
A369

BULIMIA NERVOSA - REPLY

Authors
GERACIOTI, TD; LIDDLE, RA
MLA Citation
GERACIOTI, TD, and LIDDLE, RA. "BULIMIA NERVOSA - REPLY." NEW ENGLAND JOURNAL OF MEDICINE 320.11 (March 16, 1989): 735-736.
Source
wos-lite
Published In
The New England journal of medicine
Volume
320
Issue
11
Publish Date
1989
Start Page
735
End Page
736

Meal-related cholecystokinin secretion in eating and affective disorders.

The satiety-inducing effects of centrally and peripherally administered cholecystokinin (CCK) in experimental animals have been well documented. Recently, studies in humans showed that CCK is released into plasma following food ingestion, a phenomenon postulated to promote meal-related satiety. To explore whether abnormal CCK secretion during feeding may be related to pathophysiological mechanisms in disorders associated with appetite abnormalities, we report here studies of the plasma CCK response to a test meal in patients with bulimia nervosa, as well as seasonal (hyperphagic) and melancholic (anorexic) depression. Compared to controls, bulimic patients had impaired meal-related CCK secretion, correlated with an impaired sense of postprandial satiety. This defect resolved with tricyclic antidepressant-induced amelioration of bulimic behavior, suggesting that deficient CCK secretion may constitute a fundamental pathophysiologic derangement in this disorder. In contrast to patients with bulimia nervosa, hyperphagic patients with seasonal affective disorder failed to show abnormal meal-related CCK secretion. Preliminary evidence shows robust meal-related CCK secretion in melancholic depression with anorexia. We have also begun to explore the dynamics of CCK secretion into cerebrospinal fluid (CSF) utilizing an indwelling lumbar catheter. From studies in humans, we note that this peptide is secreted into the CSF in large (ng/ml) quantities in an episodic fashion that may bear some relationship to food ingestion. Further study of this parameter in volunteers and patients is now underway.

Authors
Geracioti, TD; Kling, MA; Joseph-Vanderpool, JR; Kanayama, S; Rosenthal, NE; Gold, PW; Liddle, RA
MLA Citation
Geracioti, TD, Kling, MA, Joseph-Vanderpool, JR, Kanayama, S, Rosenthal, NE, Gold, PW, and Liddle, RA. "Meal-related cholecystokinin secretion in eating and affective disorders." Psychopharmacol Bull 25.3 (1989): 444-449. (Review)
PMID
2697014
Source
pubmed
Published In
Psychopharmacology bulletin
Volume
25
Issue
3
Publish Date
1989
Start Page
444
End Page
449

Endogenous cholecystokinin does not decrease food intake or gastric emptying in fasted rats

To investigate the hypothesized inhibitory effect of cholecystokinin (CCK) released from the small intestine on food intake and gastric emptying, we infused soybean trypsin inhibitor (STI) into the stomach or duodenum of male rats deprived of food for 17 h. Intraduodenal infusions of STI (100-200 mg) before real or sham feeding, or during sham feeding, had no effect on food intake. Intragastric infusions of STI (100-200 mg) also had no effect on gastric emptying. Identical infusions of STI, however, increased bioassayable plasma CCK six to ninefold. The failure of endogenous, small intestinal CCK released by STI to decrease food intake or to decrease gastric emptying is evidence against the hypothesis that the inhibitions of food intake and of gastric emptying are physiological functions of small intestinal CCK in food-deprived rats. In contrast to the negative results with STI, administration of exogenous CCK-8 (2-4 μg/kg ip) significantly inhibited food intake and gastric emptying despite producing smaller increases of plasma CCK than STI produced. The reason for the differential effects of exogenous and endogenous CCK is not clear and requires further investigation.

Authors
Smith, GP; Greenberg, D; Falasco, JD; Avilion, AA; Gibbs, J; Liddle, RA; Williams, JA
MLA Citation
Smith, GP, Greenberg, D, Falasco, JD, Avilion, AA, Gibbs, J, Liddle, RA, and Williams, JA. "Endogenous cholecystokinin does not decrease food intake or gastric emptying in fasted rats." American Journal of Physiology - Regulatory Integrative and Comparative Physiology 257.6 (1989): 26/6-.
Source
scival
Published In
American Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume
257
Issue
6
Publish Date
1989
Start Page
26/6

Bulimia nervosa

Authors
Sigman, GS; Flanery, RC; Bernstein, J; Jr, TDG; Liddle, RA; Schwartz, HJ; Herzog, DB; Copeland, PM
MLA Citation
Sigman, GS, Flanery, RC, Bernstein, J, Jr, TDG, Liddle, RA, Schwartz, HJ, Herzog, DB, and Copeland, PM. "Bulimia nervosa." New England Journal of Medicine 320.11 (1989): 735-736.
PMID
2922018
Source
scival
Published In
New England Journal of Medicine
Volume
320
Issue
11
Publish Date
1989
Start Page
735
End Page
736

Inhibitory regulation of rat exocrine pancreas by peptide YY and pancreatic polypeptide

Peptide YY (PYY) and pancreatic polypeptide (PP) have been shown to inhibit exocrine pancreatic secretion in vivo in a variety of species. This study evaluates the type of stimulation inhibited by PYY and PP by examining, in urethan-anesthetized rats, the inhibition of pancreatic secretion when stimulated to a comparable extent by cholecystokinin (CCK), 2-deoxy-D-glucose (2DG), bethanecol, and electrical vagal nerve stimulation. PYY at maximal infusion rates inhibited stimulation by CCK by 83%, bethanecol by 55%, and electrical nerve stimulation by 40%. The inhibition of CCK stimulation was half maximal at 250 pmol · kg-1 · h-1. By contrast, PYY totally inhibited 2DG-stimulated secretion with half-maximal inhibition at 10 pmol · kg-1 · h-1. PP acted similarly to PYY in inhibiting CCK and 2DG-stimulated pancreatic protein secretion but was fivefold weaker in each case. These findings indicate that PYY and PP have multiple actions but preferentially inhibit neurally mediated pancreatic secretion at a preacinar cell locus, possibly at a central site of action.

Authors
Putnam, WS; Liddle, RA; Williams, JA
MLA Citation
Putnam, WS, Liddle, RA, and Williams, JA. "Inhibitory regulation of rat exocrine pancreas by peptide YY and pancreatic polypeptide." American Journal of Physiology - Gastrointestinal and Liver Physiology 256.4 (1989): 19/4-.
Source
scival
Published In
American Journal of Physiology - Gastrointestinal and Liver Physiology
Volume
256
Issue
4
Publish Date
1989
Start Page
19/4

Pancreatic digestive enzyme gene expression: Effects of CCK and soybean trypsin inhibitor

Regulation of pancreatic gene expression by cholecystokinin (CCK) was examined in the rat using cloned cDNA probes to quantify changes in specific mRNAs (amylase, trypsinogen I, chymotrypsinogen B, and ribonuclease). Rats were administered intraduodenally an elemental liquid diet. Plasma CCK levels were raised to levels comparable to physiological postprandial levels either by intraduodenal perfusion with soybean trypsin inhibitor (SBTI) (6.9 ± 1.0 pM, n = 8) or by continuous intravenous infusion with cholecystokinin octapeptide (CCK-8, 6.0 ± 0.9 pM, n = 6). SBTI infusion resulted in fivefold increases in trypsinogen I and chymotrypsinogen B mRNA levels after 48 h. In contrast SBTI infusion had no effect on amylase mRNA levels and led to a decrease in ribonuclease mRNA levels to ~ 50% of control after 48 h. Intravenous infusion with CCK-8 for 24 h resulted in plasma levels of CCK comparable to those obtained with SBTI and had similar effects on digestive enzyme mRNA levels. These data suggested that SBTI acted via its ability to raise plasma CCK levels. To further test the specificity of these effects, animals were infused intraduodenally with the specific CCK receptor antagonist L364,718. Although the antagonist itself had no effect on digestive enzyme mRNA levels, antagonist treatment totally abolished the effects of both CCK infusion and SBTI treatment. These data therefore indicate that CCK regulates digestive enzyme gene expression at plasma concentrations comparable to physiological postprandial levels. Furthermore, the ability of SBTI infusion to increase plasma CCK accounts for its effects on pancreatic digestive enzyme mRNA levels.

Authors
Rosewicz, S; Lewis, LD; Wang, X-Y; Liddle, RA; Logsdon, CD
MLA Citation
Rosewicz, S, Lewis, LD, Wang, X-Y, Liddle, RA, and Logsdon, CD. "Pancreatic digestive enzyme gene expression: Effects of CCK and soybean trypsin inhibitor." American Journal of Physiology - Gastrointestinal and Liver Physiology 256.4 (1989): 19/4-.
Source
scival
Published In
American Journal of Physiology - Gastrointestinal and Liver Physiology
Volume
256
Issue
4
Publish Date
1989
Start Page
19/4

Feedback regulation by trypsin: Evidence for intraluminal CCK-releasing peptide

The mechanism by which intraluminal proteases inhibit pancreatic secretion and CCK release was investigated in conscious rats. We hypothesized that the stimulation of pancreatic secretion and CCK release that occurs in the absence of luminal trypsin is caused by a trypsin-sensitive, cholecystokinin (CCK)-releasing peptide that is tonically secreted intraluminally by the small intestine. We tested whether rapid saline perfusion of the lumen of the proximal intestine in rats with jejunostomies would wash out the putative peptide, thereby inhibiting the spontaneous pancreatic secretion caused by diverting bile and pancreatic juice from the intestine. Rats were prepared with cannulas draining bile and pancreatic juice, a duodenal cannula and a jejunostomy 10-12 cm from the ligament of Treitz. During diversion of bile and pancreatic juice to the exterior, the proximal intestine was perfused with phosphate-buffered saline at 3 ml/min via the duodenal cannula and the intestinal washes collected from the jejunostomy outlet. Rapid intestinal perfusion significantly inhibited pancreatic protein and fluid secretion stimulated by diversion of bile and pancreatic juice to the exterior. Reinfusion of the concentrated intestinal washes prevented the 'washout' inhibition. The active factor in the intestinal washes was heat stable and trypsin sensitive. Rapid washout perfusion of isolated jejunal loops in Thiry-Vella fistula rats reduced plasma CCK from 20.4 ± 3.6 to 10.4 ± 1.8 pM, and reinfusion of the washes into the loop returned plasma CCK to 17.1 ± 3.8 pM. The results support the hypothesis that a trypsin-sensitive, CCK-releasing peptide in intestinal secretions mediates feedback regulation of pancreatic secretion in rats.

Authors
Miyasaka, K; Guan, D; Liddle, RA; Green, GM
MLA Citation
Miyasaka, K, Guan, D, Liddle, RA, and Green, GM. "Feedback regulation by trypsin: Evidence for intraluminal CCK-releasing peptide." American Journal of Physiology - Gastrointestinal and Liver Physiology 257.2 (1989): 20/2-.
Source
scival
Published In
American Journal of Physiology - Gastrointestinal and Liver Physiology
Volume
257
Issue
2
Publish Date
1989
Start Page
20/2

Intraventricular CCK inhibits food intake and gastric emptying in baboons

To evaluate the role of cholecystokinin (CCK) as a physiological regulator of meal size and gastric emptying in the baboon, we measured plasma CCK bioactivity during 30-min meals alone and after intravenous or intraventricular infusions of CCK COOH-terminal octapeptide (CCK-8). Both intravenous (2 μg/kg) and intraventricular (1 μg/kg) CCK-8 administration resulted in plasma CCK elevations comparable with normal prandial CCK levels: peak plasma levels were 4.1 ± 0.9, 7.1 ± 1.1, and 4.9 ± 2.2 pM for pooled intravenous and intraventricular control, intravenous, and intraventricular conditions. Also, both treatments appeared to reduce gastric emptying as indicated by a significant suppression of postprandial plasma insulin and glucose levels. However, only intravenous CCK reliably reduced meal size (percent of control meal size was 91 ± 5% or 43 ± 19% with intravenous or intraventricular CCK). We conclude that circulating endogenous CCK is a potent postprandial endocrine regulator of gastric emptying. However, the ability of CCK to decrease meal size may require direct interaction with the central nervous system.

Authors
Figlewicz, DP; Sipols, AJ; Jr, DP; Woods, SC; Liddle, RA
MLA Citation
Figlewicz, DP, Sipols, AJ, Jr, DP, Woods, SC, and Liddle, RA. "Intraventricular CCK inhibits food intake and gastric emptying in baboons." American Journal of Physiology - Regulatory Integrative and Comparative Physiology 256.6 (1989): 25/6-.
Source
scival
Published In
American Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume
256
Issue
6
Publish Date
1989
Start Page
25/6

Plasma secretin, CCK, and pancreatic secretion in response to dietary fat in the rat

The role of fat in regulation of pancreatic secretion was studied in conscious rats by measuring pancreatic secretion and plasma cholecystokinin (CCK) and secretin responses to intraluminal infusion of fat, protein, or trypsin inhibitor via the duodenum. In rats with pancreatic juice continuously returned to the intestine, intraduodenal infusion of 20% emulsified fat (Liposyn), 10% casein, and 0.4% ovomucoid trypsin inhibitor (OMTI) stimulated equivalent increases of approximately threefold in pancreatic protein output. Proglumide reduced fat-stimulated pancreatic protein secretion by >90% but did not inhibit the response to OMTI. Fat significantly increased plasma CCK from basal levels of 0.5 pM to 2-3 pM, but it was a weaker stimulant of CCK secretion than casein (peak CCK levels > 10 pM) or OMTI (peak CCK levels 5-6 pM). Fat significantly stimulated secretin release (21.7 pM) compared with casein (6.8 pM), OMTI (4.4 pM), and NaCl (3.5 pM). The inhibition of fat-stimulated pancreatic secretion by proglumide indicates that the small amounts of CCK released by fat are necessary for a normal pancreatic response, suggesting that this response may be the result of potentiation between secretin and small amounts of CCK.

Authors
Green, GM; Taguchi, S; Friestman, J; Chey, WY; Liddle, RA
MLA Citation
Green, GM, Taguchi, S, Friestman, J, Chey, WY, and Liddle, RA. "Plasma secretin, CCK, and pancreatic secretion in response to dietary fat in the rat." American Journal of Physiology - Gastrointestinal and Liver Physiology 256.6 (1989): 19/6-.
Source
scival
Published In
American Journal of Physiology - Gastrointestinal and Liver Physiology
Volume
256
Issue
6
Publish Date
1989
Start Page
19/6

Effects of cholecystokinin on pancreatic ornithine decarboxylase gene expression.

The effects of cholecystokinin (CCK) on pancreatic ornithine decarboxylase (ODC) gene expression were studied in the rat. Plasma CCK concentrations were raised to levels comparable to postprandial values either by intravenous infusion of CCK octapeptide (CCK-8) or by intraduodenal perfusion of soybean trypsin inhibitor (SBTI). ODC mRNA levels were quantified using a cloned cDNA probe. ODC mRNA increased to 166 +/- 34% (n = 4) of control after 1 h, peaked at 254 +/- 39% (n = 4) of control after 24 h, and remained significantly elevated for up to 48 h of SBTI infusion. Intravenous infusion of CCK-8 for 24 h increased ODC mRNA levels to the same extent observed with SBTI infusion. The CCK receptor antagonist L364,718 by itself had no effect on ODC mRNA levels but totally abolished the induction of ODC mRNA by both intravenous CCK infusion and intraduodenal infusion of SBTI. These data therefore indicate that CCK plasma concentrations comparable to postprandial values regulate pancreatic ODC at a pretranslational level and that SBTI exerts its effects on pancreatic ODC via an increase in plasma CCK.

Authors
Rosewicz, S; Lewis, LD; Liddle, RA; Logsdon, CD
MLA Citation
Rosewicz, S, Lewis, LD, Liddle, RA, and Logsdon, CD. "Effects of cholecystokinin on pancreatic ornithine decarboxylase gene expression." Am J Physiol 255.6 Pt 1 (December 1988): G818-G821.
PMID
3202175
Source
pubmed
Published In
The American journal of physiology
Volume
255
Issue
6 Pt 1
Publish Date
1988
Start Page
G818
End Page
G821

Impaired cholecystokinin secretion in bulimia nervosa.

Bulimia nervosa is a prevalent disorder of unknown cause, characterized by recurrent episodes of uncontrollable eating. In the light of recent evidence that the gastrointestinal hormone cholecystokinin induces satiety and reduces food intake in laboratory animals and humans, we investigated the hypothesis that abnormalities in cholecystokinin secretion and satiety may occur in patients with bulimia and contribute to their disturbed eating patterns. Blood levels of cholecystokinin and subjective satiety were measured in 14 women with bulimia and 10 normal women before and after a mixed-liquid meal. The total integrated plasma cholecystokinin response to eating was significantly impaired in patients with bulimia (P less than 0.05) as was postprandial satiety. Fasting cholecystokinin levels were similar in both populations (approximately 0.8 pmol per liter). After eating, however, mean (+/- SEM) peak plasma cholecystokinin levels increased to 4.1 +/- 0.9 pmol per liter in normal controls but to only 2.1 +/- 0.2 pmol per liter in patients with bulimia nervosa (P less than 0.05). After an open trial of tricyclic antidepressants in a subgroup of five patients with bulimia, the postprandial cholecystokinin response to eating increased significantly, to 6.6 +/- 1.2 pmol per liter (P less than 0.05), and there was an increase in the satiety response. We conclude that patients with bulimia do not have normal satiety and have impaired secretion of cholecystokinin in response to a meal. Preliminary evidence suggests that both these abnormalities may be improved by treatment with tricyclic antidepressants.

Authors
Geracioti, TD; Liddle, RA
MLA Citation
Geracioti, TD, and Liddle, RA. "Impaired cholecystokinin secretion in bulimia nervosa." N Engl J Med 319.11 (September 15, 1988): 683-688.
PMID
3412386
Source
pubmed
Published In
The New England journal of medicine
Volume
319
Issue
11
Publish Date
1988
Start Page
683
End Page
688
DOI
10.1056/NEJM198809153191105

Dietary regulation of rat intestinal cholecystokinin gene expression.

Cholecystokinin (CCK) is a gastrointestinal hormone produced by discrete endocrine cells in the upper small intestine and released after ingestion of a meal. The present study was designed to determine if enhanced CCK secretion is associated with increases in intestinal CCK mRNA levels. Rats, prepared with indwelling intraduodenal cannulae, were first fed an elemental diet that did not stimulate CCK release. Next, as a means of stimulating CCK secretion, soybean trypsin inhibitor was perfused for up to 24 h. Trypsin inhibitor administration increased plasma CCK levels from 0.9 +/- 0.1 to approximately 5 pmol/liter. RNA was prepared from the proximal small intestine at various times after trypsin inhibitor perfusion and mRNA levels analyzed by hybridization with a CCK cDNA probe. After 12 and 24 h of trypsin inhibitor treatment there were three- and fourfold increases, respectively, in CCK mRNA levels. In comparison, there was no change in beta-actin mRNA levels. To determine if regulation of CCK mRNA was at the level of CCK gene transcription, labeled transcripts from nuclear run-on incubations were hybridized to immobilized CCK cDNA. In trypsin inhibitor-treated rats, a two- to threefold increase in transcriptional activity was observed, whereas beta-actin gene transcription levels were unaltered. These studies indicate that stimulation of CCK secretion is associated with an increase in intestinal CCK mRNA content resulting from an increase in CCK gene transcription.

Authors
Liddle, RA; Carter, JD; McDonald, AR
MLA Citation
Liddle, RA, Carter, JD, and McDonald, AR. "Dietary regulation of rat intestinal cholecystokinin gene expression." J Clin Invest 81.6 (June 1988): 2015-2019.
PMID
2454954
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
81
Issue
6
Publish Date
1988
Start Page
2015
End Page
2019
DOI
10.1172/JCI113552

Physiological role for cholecystokinin in reducing postprandial hyperglycemia in humans.

It is known that the ingestion of glucose alone causes a greater increase in plasma glucose levels than ingestion of the same amount of glucose given with other nutrients. Since physiological plasma concentrations of cholecystokinin (CCK) prolong gastric emptying, it is proposed that after a meal, CCK may modify plasma glucose levels by delaying glucose delivery to the duodenum. To evaluate the effect of CCK on oral glucose tolerance, plasma CCK, insulin, and glucose levels and gastric emptying rates were measured in eight normal males before and after the ingestion of 60 g glucose with the simultaneous infusion of either saline or one of two doses of CCK-8 (12 or 24 pmol/kg per h). Gastric emptying rates were measured by gamma camera scintigraphy of technetium 99m sulfur colloid and plasma CCK levels were measured by a sensitive and specific bioassay. Basal CCK levels averaged 1.0 +/- 0.1 pM (mean +/- SEM, n = 8) and increased to 7.1 +/- 1.1 pM after a mixed liquid meal. After glucose ingestion, but without CCK infusion, CCK levels did not change from basal, and the gastric emptying t1/2 was 68 +/- 3 min. Plasma glucose levels increased from basal levels of 91 +/- 3.9 mg/dl to peak levels of 162 +/- 11 mg/dl and insulin levels increased from 10.7 +/- 1.8 microU/ml to peak levels of 58 +/- 11 microU/ml. After glucose ingestion, with CCK infused at 24 pmol/kg per h, plasma CCK levels increased to 8 pM and the gastric emptying t1/2 increased to 148 +/- 16 min. In concert with this delay in gastric emptying, peak glucose levels rose to only 129 +/- 17 mg% and peak insulin levels rose to only 24.2 +/- 4.2 microU/ml. With CCK at 12 pmol/kg per h, similar but less dramatic changes were seen. To demonstrate that endogenous CCK could modify the plasma glucose and insulin responses to oral glucose, oral glucose was given with 50 g of lipid containing long-chain triglycerides. This lipid increased peak CCK levels to 3.7 +/- 0.9 pM. Concomitant with this rise in CCK was a delay in gastric emptying and a lowering of plasma glucose and insulin values. To confirm that CCK reduced hyperglycemia by its effect on gastric motility, 36 g glucose was perfused directly into the duodenum through a nasal-duodenal feeding tube in four subjects. With duodenal perfusion of glucose, there was no change in plasma CCK levels, but plasma glucose levels increased from basal levels of 93+/-5 to 148+/-6 mg/dl and insulin levels rose from 10.6+/-3.5 to 29.5+/-5.2 microU/ml. When CCK was infused at 24 pmol/kg per h, neither the plasma glucose nor insulin responses to the duodenal administration of glucose were modified. Thus we conclude that CCK, in physiological concentrations, delays gastric emptying, slows the delivery of glucose to the duodenum, and reduces postprandial hyperglycemia. These data indicate, therefore, that CCK has a significant role in regulating glucose homeostasis in human.

Authors
Liddle, RA; Rushakoff, RJ; Morita, ET; Beccaria, L; Carter, JD; Goldfine, ID
MLA Citation
Liddle, RA, Rushakoff, RJ, Morita, ET, Beccaria, L, Carter, JD, and Goldfine, ID. "Physiological role for cholecystokinin in reducing postprandial hyperglycemia in humans." J Clin Invest 81.6 (June 1988): 1675-1681.
PMID
3290250
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
81
Issue
6
Publish Date
1988
Start Page
1675
End Page
1681
DOI
10.1172/JCI113505

Effects of cholecystokinin on pancreatic ornithine decarboxylase gene expression

The effects of cholecystokinin (CCK) on pancreatic ornithine decarboxylase (ODC) gene expression were studied in the rat. Plasma CCK concentrations were raised to levels comparable to postprandial values either by intravenous infusion of CCK octapeptide (CCK-8) or by intraduodenal perfusion of soybean trypsin inhibitor (SBTI). ODC mRNA levels were quantified using a cloned cDNA probe. ODC mRNA increased to 166 ± 34% (n = 4) of control after 1 h, peaked at 254 ± 39% (n = 4) of control after 24 h, and remained significantly elevated for up to 48 h of SBTI infusion. Intravenous infusion of CCK-8 for 24 h increased ODC mRNA levels of the same extent observed with SBTI infusion. The CCK receptor antagonist L364,718 by itself had no effect on ODC mRNA by both intravenous CCK infusion and intraduodenal infusion of SBTI. These data therefore indicate that CCK plasma concentrations comparable to postprandial values regulate pancreatic ODC at a pretranslational level and that SBTI exerts its effects on pancreatic ODC via an increase in plasma CCK.

Authors
Rosewicz, S; Lewis, LD; Liddle, RA; Logsdon, CD
MLA Citation
Rosewicz, S, Lewis, LD, Liddle, RA, and Logsdon, CD. "Effects of cholecystokinin on pancreatic ornithine decarboxylase gene expression." American Journal of Physiology - Gastrointestinal and Liver Physiology 255.6 (1988): 18/6-.
Source
scival
Published In
American Journal of Physiology - Gastrointestinal and Liver Physiology
Volume
255
Issue
6
Publish Date
1988
Start Page
18/6

Physiological concentrations of cholecystokinin stimulate amino acid-induced insulin release in humans.

After a meal, hormones released from the gut potentiate insulin release. This study was undertaken to determine if physiological concentrations of plasma cholecystokinin (CCK) stimulate insulin secretion in man. Employing a specific CCK bioassay, postprandial CCK levels were determined in normal subjects. Ingestion of a mixed liquid meal stimulated an increase in circulating CCK from a mean fasting level of 0.9 +/- 0.2 (SEM) pmol/L to a mean peak level of 7.1 +/- 1.1 pmol/L within 10 min of feeding. After 30 min the mean CCK level fell to 3.5 pmol/L and remained elevated for the remainder of the 90-min experiment. Eight subjects underwent 40-min infusions of either arginine (15 g), mixed amino acids (15 g), or glucose (30 g) with or without the simultaneous infusion of CCK-8. Since CCK-8 has full biological potency, this form was chosen for infusion to reproduce total CCK bioactivity in plasma. CCK-8 was infused at rates of 12 or 24 pmol/kg X h, producing steady state plasma CCK levels of 4.5 +/- 0.7 and 8.2 +/- 1.1 pmol/L, respectively, spanning the range of normal postprandial levels. CCK alone had no effect on insulin, glucose, or glucagon levels. Administration of arginine alone stimulated insulin from a mean basal level of 12.8 +/- 1.3 microU/mL to a peak level of 41.3 +/- 5.4 microU/mL. Infusion of CCK at 12 and 24 pmol/kg X h augmented arginine-stimulated insulin levels to peaks of 62.5 +/- 13.9 and 63.0 +/- 4.0 microU/mL, respectively. Moreover, CCK nearly doubled the total amount of insulin secreted during the arginine infusion. A similar potentiation of glucagon release was found with both doses of CCK. In addition, infusion of a mixture of amino acids with and without concomitant CCK infusions revealed that CCK potentiated the insulin release induced by mixed amino acids. In contrast to the potent effect of CCK on amino acid-induced insulin release, infusions of CCK together with glucose caused no enhancement of glucose-stimulated insulin release. These results demonstrate that physiological concentrations of CCK potentiate amino acid (but not glucose)-induced insulin secretion in man. These data suggest, therefore, that CCK may have a role in man as a modulator of insulin release.

Authors
Rushakoff, RJ; Goldfine, ID; Carter, JD; Liddle, RA
MLA Citation
Rushakoff, RJ, Goldfine, ID, Carter, JD, and Liddle, RA. "Physiological concentrations of cholecystokinin stimulate amino acid-induced insulin release in humans." J Clin Endocrinol Metab 65.3 (September 1987): 395-401.
PMID
3305550
Source
pubmed
Published In
Journal of Clinical Endocrinology and Metabolism
Volume
65
Issue
3
Publish Date
1987
Start Page
395
End Page
401
DOI
10.1210/jcem-65-3-395

Jejunal bypass stimulation of pancreatic growth and cholecystokinin secretion in rats: importance of luminal nutrients.

The effect of jejunal bypass on pancreatic growth and plasma cholecystokinin (CCK) was investigated in rats. Rats underwent bypass of jejunum or sham operation. Rats with jejunal bypass were further divided into three groups; one group received a continuous infusion of a partially hydrolysed liquid diet (Vital) into the bypassed jejunum; a second group received the nutrient solution mixed with trypsin and infused into the bypassed jejunum; the third bypass group did not receive infusion of nutrient or trypsin into the jejunum. Jejunal bypass alone did not significantly stimulate pancreatic growth or DNA content at one or two weeks postoperative. Infusion of nutrient solution into the bypassed jejunum stimulated pancreatic growth and DNA content, with maximal increases of 185% and 181% for pancreatic weight and DNA content, respectively, at two weeks. This coincided with significant increases in postabsorptive plasma CCK concentrations. Infusion of pancreatic proteases into the bypassed jejunum partially reversed the effects of nutrient infusion. These results suggest that exclusion of bile-pancreatic juice or pancreatic proteases from the jejunum does not lead to maximal release of CCK unless the jejunum receives luminal nutrients. It is proposed that CCK release from rat jejunum occurs spontaneously in the absence of pancreatic proteases, and that luminal nutrients in bypassed jejunum increase plasma CCK and stimulate pancreatic growth by maintaining synthesis of CCK.

Authors
Levan, VH; Liddle, RA; Green, GM
MLA Citation
Levan, VH, Liddle, RA, and Green, GM. "Jejunal bypass stimulation of pancreatic growth and cholecystokinin secretion in rats: importance of luminal nutrients." Gut 28 Suppl (1987): 25-29.
PMID
3692314
Source
pubmed
Published In
Gut
Volume
28 Suppl
Publish Date
1987
Start Page
25
End Page
29

Pancreatic growth: interaction of exogenous cholecystokinin, a protease inhibitor, and a cholecystokinin receptor antagonist in mice.

The effects on pancreatic growth and plasma CCK concentration of chronic feeding of camostate (400 mg/kg day for 10 days), a potent inhibitor of serine proteases including trypsin, were assessed in the mouse. For comparison, the trophic effects of chronic exogenous administration of CCK octapeptide (sc injection of 1 microgram/kg day every eight hours for 10 days) were also studied. In addition, the effects of a proglumide-analogue CCK-receptor antagonist (CR1409) on the stimulatory actions of camostate feeding and chronic administration of exogenous CCK were studied. The effects of the combination of chronic camostate feeding and sc injections of CCK, the effects of acute camostate feeding, and the effects of the CCK-receptor antagonist given without camostate or CCK were also studied. The results show that chronic camostate feeding markedly increased CCK plasma concentrations eight-fold over control values, and that acute camostate feeding increased plasma concentration to four fold of control values. Correspondingly, chronic camostate feeding markedly increased pancreatic weight, protein and DNA content. Exogenous CCK-8 also had qualitatively similar, but quantitatively less potent stimulatory effects. The combination of camostate and CCK-8 resulted in an additive stimulatory effect. The trophic actions of exogenous and endogenous CCK grossly increased chymotrypsinogen content, but left amylase content unaffected. The CCK-receptor antagonist CR 1409 completely abolished the trophic effects of exogenous CCK and greatly inhibited the effects of chronic camostate feeding. The CCK antagonist decreased pancreatic weight, DNA and protein content compared to control values when given without any CCK or camostate. We conclude that the protease inhibitor camostate is a very strong release effector of CCK and exerts a powerful trophic effect on mouse pancreas which is probably mediated by CCK. Furthermore, physiological increases of CCK during feeding of regular chow appear to exert trophic effects on the exocrine pancreas.

Authors
Niederau, C; Liddle, RA; Williams, JA; Grendell, JH
MLA Citation
Niederau, C, Liddle, RA, Williams, JA, and Grendell, JH. "Pancreatic growth: interaction of exogenous cholecystokinin, a protease inhibitor, and a cholecystokinin receptor antagonist in mice." Gut 28 Suppl (1987): 63-69.
PMID
2446964
Source
pubmed
Published In
Gut
Volume
28 Suppl
Publish Date
1987
Start Page
63
End Page
69

Beneficial effects of cholecystokinin-receptor blockade and inhibition of proteolytic enzyme activity in experimental acute hemorrhagic pancreatitis in mice. Evidence for cholecystokinin as a major factor in the development of acute pancreatitis.

The effects of the cholecystokinin (CCK)-receptor antagonist proglumide, the protease inhibitor gabexate, and the hormones secretin and cholecystokinin-octapeptide (CCK-8) were studied in a model of acute hemorrhagic pancreatitis induced by feeding mice a choline-deficient, ethionine-supplemented (CDE) diet. Injections of gabexate and proglumide from initiation of CDE diet (before induction of pancreatitis) increased survival from 37% (diet alone) to 85 and 75%, respectively, and also ameliorated histological alterations and increases in serum amylase concentration and pancreatic activated trypsin. Secretin had no major beneficial effect. When proglumide or gabexate were given after induction of pancreatitis, proglumide still increased survival to 75%, whereas gabexate no longer did. Injection of nontoxic doses of CCK-8 before proglumide or gabexate injections completely abolished all beneficial effects and also increased the severity of pancreatitis due to CDE diet alone. Blockade of CCK receptors and early inhibition of protease activity may be beneficial in severe acute pancreatitis. Cholecystokinin appears to play a contributory role in the development of pancreatitis.

Authors
Niederau, C; Liddle, RA; Ferrell, LD; Grendell, JH
MLA Citation
Niederau, C, Liddle, RA, Ferrell, LD, and Grendell, JH. "Beneficial effects of cholecystokinin-receptor blockade and inhibition of proteolytic enzyme activity in experimental acute hemorrhagic pancreatitis in mice. Evidence for cholecystokinin as a major factor in the development of acute pancreatitis." J Clin Invest 78.4 (October 1986): 1056-1063.
PMID
2428840
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
78
Issue
4
Publish Date
1986
Start Page
1056
End Page
1063
DOI
10.1172/JCI112661

Relative bioactivities of cholecystokinins-8 and -33 on rat pancreatic acini.

The relative potencies of cholecystokinin (CCK-33) and its carboxyl terminal octapeptide (CCK-8) for stimulation of amylase release from rat pancreatic acini was measured. Porcine CCK-33 and synthetic CCK-8 were initially subjected to high pressure liquid chromatography to assess purity. Concentrations of each peptide were determined by amino acid analysis. The relative immunoreactivities of CCK-33 and CCK-8 were compared using an antibody that recognizes the common carboxyl terminus of these forms. This antibody bound CCK-8 and CCK-33 with nearly equal affinity. The relative potencies of CCK-33 and CCK-8 were then measured by comparing their abilities to stimulate amylase release from isolated rat pancreatic acini. Statistical analysis of the relative potencies of the two hormones indicated that CCK-8 was 36% more potent than CCK-33 in this assay system. These data suggest that differences in biological activities between large and small forms of CCK are not as great as previously reported.

Authors
Liddle, RA; Elashoff, J; Reeve, JR
MLA Citation
Liddle, RA, Elashoff, J, and Reeve, JR. "Relative bioactivities of cholecystokinins-8 and -33 on rat pancreatic acini." Peptides 7.5 (September 1986): 723-727.
PMID
2432584
Source
pubmed
Published In
Peptides
Volume
7
Issue
5
Publish Date
1986
Start Page
723
End Page
727

Proteins but not amino acids, carbohydrates, or fats stimulate cholecystokinin secretion in the rat.

Because of prior difficulties in measuring plasma cholecystokinin (CCK) levels, it has not been established which components of food stimulate CCK secretion in rats. In the present study, we used a sensitive and specific bioassay for measuring plasma CCK and determined the effects of proteins, protein hydrolysates, amino acids, fats, starch, and glucose on CCK secretion in this species. Intact proteins were the only stimulants of CCK release. Solutions of 18% casein and 0.2% soybean trypsin inhibitor caused prompt increases in plasma CCK levels from 0.5 +/- 0.2 to 7.9 +/- 1.9 and 8.0 +/- 2.0 pM, respectively, within 5 min of orogastric administration. The proteins lactalbumin and bovine serum albumin caused smaller elevations in circulating CCK. In contrast, hydrolysates of casein and lactalbumin and the amino acids L-phenylalanine and L-tryptophan did not stimulate CCK release. In addition, plasma CCK levels did not increase with the feeding of fat, starch, or glucose. The ability of proteins to stimulate CCK secretion paralleled their ability to inhibit trypsin activity in vitro. Furthermore, the plasma CCK response to casein was completely abolished by the simultaneous administration of trypsin. These studies indicate that proteins are the major food stimulants of CCK release in the rat and that the effects of proteins are related to inhibition of intraluminal protease activity.

Authors
Liddle, RA; Green, GM; Conrad, CK; Williams, JA
MLA Citation
Liddle, RA, Green, GM, Conrad, CK, and Williams, JA. "Proteins but not amino acids, carbohydrates, or fats stimulate cholecystokinin secretion in the rat." Am J Physiol 251.2 Pt 1 (August 1986): G243-G248.
PMID
3740265
Source
pubmed
Published In
The American journal of physiology
Volume
251
Issue
2 Pt 1
Publish Date
1986
Start Page
G243
End Page
G248

Plasma cholecystokinin and pancreatic growth during adaptation to dietary protein.

The relationship among plasma cholecystokinin (CCK), pancreatic growth, and food intake was studied in rats over a 2-wk period of adaptation from a very low-protein to a very high-protein diet. Rats adapted to a control diet (5% casein) were killed at 0900 (without fasting) at 0 h, 12 h, 24 h, 48 h, 7 days, or 14 days after transfer to a high-protein diet (75% casein). CCK was measured by bioassay using isolated pancreatic acini. Plasma CCK in high protein-fed rats was increased approximately threefold in the first 24 h, but returned to control (approximately 2.5 pM) values by day 7. Pancreatic weight, DNA, protein, and chymotrypsin(ogen) significantly increased to maximal values by day 7 in high protein-fed rats. Food intake in high protein-fed rats was inhibited by 47% after 24 h but returned to control values by day 7. The results indicate that high-protein diets initially increase CCK release and increase pancreatic protease secretory capacity and that, when pancreatic protease secretion is sufficient to match protein digestive requirements, the stimulus for CCK secretion is reduced and plasma CCK returns to normal. The pronounced but transient inhibition of food intake in high protein-fed rats is consistent with a role for CCK in regulation of food intake.

Authors
Green, GM; Levan, VH; Liddle, RA
MLA Citation
Green, GM, Levan, VH, and Liddle, RA. "Plasma cholecystokinin and pancreatic growth during adaptation to dietary protein." Am J Physiol 251.1 Pt 1 (July 1986): G70-G74.
PMID
3524262
Source
pubmed
Published In
The American journal of physiology
Volume
251
Issue
1 Pt 1
Publish Date
1986
Start Page
G70
End Page
G74

Regulation of gastric emptying in humans by cholecystokinin.

In the present study we used a bioassay system for measuring plasma cholecystokinin (CCK) to evaluate whether CCK has a physiologic role in regulating gastric emptying in humans. Plasma CCK levels and gastric emptying after ingestion of a mixed liquid meal were determined in five normal male volunteers. Fasting CCK levels averaged 0.8 +/- 0.1 pM and increased to 6.5 +/- 1.0 pM within 10 min of drinking the mixed meal. CCK levels remained elevated for up to 90 min. Gastric emptying after a meal was slow; at the end of the 90 min 68% of the original volume remained in the stomach. The rate of gastric emptying of water was then measured in the same individuals with a simultaneous infusion of either saline, or one of two doses of CCK (12 pmol/kg per h and 24 pmol/kg per h). With the saline infusion, plasma CCK levels did not increase above basal and gastric contents emptied rapidly. At the end of 90 min only 7% of the original volume remained in the stomach. The lower dose of CCK resulted in a plasma level of 3.4 pM which both reproduced the average postprandial plasma level and caused a significant delay in gastric emptying. The higher dose of CCK achieved plasma levels of 8 pM and resulted in a delay in gastric emptying that was similar to that seen with the mixed meal. Since exogenous CCK at concentrations which occur postprandially delays gastric emptying, we conclude that CCK is a physiologic regulator of gastric emptying.

Authors
Liddle, RA; Morita, ET; Conrad, CK; Williams, JA
MLA Citation
Liddle, RA, Morita, ET, Conrad, CK, and Williams, JA. "Regulation of gastric emptying in humans by cholecystokinin." J Clin Invest 77.3 (March 1986): 992-996.
PMID
3949984
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
77
Issue
3
Publish Date
1986
Start Page
992
End Page
996
DOI
10.1172/JCI112401

Interaction of dietary protein and trypsin inhibitor on plasma cholecystokinin and pancreatic growth in rats.

Authors
Green, GM; Levan, VH; Liddle, RA
MLA Citation
Green, GM, Levan, VH, and Liddle, RA. "Interaction of dietary protein and trypsin inhibitor on plasma cholecystokinin and pancreatic growth in rats." Adv Exp Med Biol 199 (1986): 123-132.
PMID
3799272
Source
pubmed
Published In
Advances in experimental medicine and biology
Volume
199
Publish Date
1986
Start Page
123
End Page
132

Plasma cholecystokinin and pancreatic growth during adaptation to dietary protein

The relationship among plasma cholecystokinin (CCK), pancreatic growth, and food intake was studied in rats over a 2-wk period of adaptation from a very low-protein to a very high-protein diet. Rats adapted to a control diet (5% casein) were killed at 0900 (without fasting) at 0 h, 12 h, 24 h, 48 h, 7 days, or 14 days after transfer to a high-protein diet (75% casein). CCK was measured by bioassay using isolated pancreatic acini. Plasma CCK in high protein-fed rats was increased approximately threefold in the first 24 h, but returned to control (~2.5 pM) values by day 7. Pancreatic weight, DNA, protein, and chymotrypsin(ogen) significantly increased to maximal values by day 7 in high protein-fed rats. Food intake in high protein-fed rats was inhibited by 47% after 24 h but returned to control values by day 7. The results indicate that high-protein diets initially increase CCK release and increase pancreatic protease secretory capacity and that, when pancreatic protease secretion is sufficient to match protein digestive requirements, the stimulus for CCK secretion is reduced and plasma CCK returns to normal. The pronounced but transient inhibition of food intake in high protein-fed rats is consistent with a role for CCK in regulation of food intake.

Authors
Green, GM; Levan, VH; Liddle, RA
MLA Citation
Green, GM, Levan, VH, and Liddle, RA. "Plasma cholecystokinin and pancreatic growth during adaptation to dietary protein." American Journal of Physiology - Gastrointestinal and Liver Physiology 251.1 (1986): 14/1-.
Source
scival
Published In
American Journal of Physiology - Gastrointestinal and Liver Physiology
Volume
251
Issue
1
Publish Date
1986
Start Page
14/1

Proteins but not amino acids, carbohydrates, or fats stimulate cholecystokinin secretion in the rat

Because of prior difficulties in measuring plasma cholecystokinin (CCK) levels, it has not been established which components of food stimulate CCK secretion in rats. In the present study, we used a sensitive and specific bioassay for measuring plasma CCK and determined the effects of proteins, protein hydrolysates, amino acids, fats, starch, and glucose on CCK secretion in this species. Intact proteins were the only stimulants of CCK release. Solutions of 18% casein and 0.2% soybean trypsin inhibitor caused prompt increases in plasma CCK levels from 0.5 ± 0.2 to 7.9 ± 1.9 and 8.0 ± 2.0 pM, respectively, within 5 min of orogastric administration. The proteins lactalbumin and bovine serum albumin caused smaller elevations in circulating CCK. In contrast, hydrolysates of casein and lactalbumin and the amino acids L-phenylalanine and L-tryptophan did not stimulate CCK release. In addition, plasma CCK levels did not increase with the feeding of fat, starch, or glucose. The ability of proteins to stimulate CCK secretion paralleled their ability to inhibit trypsin activity in vitro. Furthermore, the plasma CCK response to casein was completely abolished by the simultaneous administration of trypsin. These studies indicate that proteins are the major food stimulants of CCK release in the rat and the effects of proteins are related to inhibition of intraluminal protease activity.

Authors
Liddle, RA; Green, GM; Conrad, CK; Williams, JA
MLA Citation
Liddle, RA, Green, GM, Conrad, CK, and Williams, JA. "Proteins but not amino acids, carbohydrates, or fats stimulate cholecystokinin secretion in the rat." American Journal of Physiology - Gastrointestinal and Liver Physiology 251.2 (1986): 14/2-.
Source
scival
Published In
American Journal of Physiology - Gastrointestinal and Liver Physiology
Volume
251
Issue
2
Publish Date
1986
Start Page
14/2

Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding, and relationship to gallbladder contraction.

A sensitive and specific bioassay for the measurement of cholecystokinin (CCK) in human plasma was developed to determine the molecular forms of CCK in circulation, CCK responses to feeding, and the physiologic role of CCK in gallbladder contraction. First, plasma was quantitatively extracted and concentrated with octadecylsilylsilica, and the extracts were then assayed for their ability to stimulate amylase release from isolated rat pancreatic acini. Acini were highly sensitive to CCK whereas gastrin reacted only weakly in this system. With the assay, plasma levels of cholecystokinin octapeptide (CCK-8) bioactivity as low as 0.2 pM were detectable. CCK bioactivity in plasma was inhibited by the CCK antagonist, bibutyryl cyclic guanosine monophosphate, and was eliminated by immunoadsorption with an antibody directed against the carboxyl terminus of CCK. Detection of fasting levels of CCK was possible in all individuals tested and averaged 1.0 +/- 0.2 pM (mean +/- SE, n = 22) CCK-8 equivalents. Plasma CCK biological activity was normal in patients with gastrin-secreting tumors. After being fed a mixed liquid meal, CCK levels rose within 15 min to 6.0 +/- 1.6 pM. The individual food components fat, protein, and amino acids were all potent stimulants of CCK secretion; in contrast, glucose caused a significant but smaller elevation in plasma CCK levels. Gel filtration studies identified three major forms of CCK bioactivity in human plasma: an abundant form that eluted with CCK-33, a smaller form that eluted with CCK-8, and an intermediate form that eluted between CCK-33 and CCK-8. Ultrasonic measurements of gallbladder volume indicated that this organ decreased 51% in size 30 min after feeding a mixed liquid meal. This contraction occurred coincidentally with the increase in plasma CCK levels. Next CCK-8 was infused to obtain CCK levels similar to postprandial levels. This infusion caused a decrease in gallbladder volume, similar to that seen with a meal. The present studies indicate, therefore, that CCK can be bioassayed in fasting and postprandial human plasma. These studies also suggest that CCK may be an important regulator of gallbladder contraction.

Authors
Liddle, RA; Goldfine, ID; Rosen, MS; Taplitz, RA; Williams, JA
MLA Citation
Liddle, RA, Goldfine, ID, Rosen, MS, Taplitz, RA, and Williams, JA. "Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding, and relationship to gallbladder contraction." J Clin Invest 75.4 (April 1985): 1144-1152.
PMID
2580857
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
75
Issue
4
Publish Date
1985
Start Page
1144
End Page
1152
DOI
10.1172/JCI111809

Bioassay of plasma cholecystokinin in rats: effects of food, trypsin inhibitor, and alcohol.

We report herein a specific, sensitive, and rapid bioassay for measuring plasma cholecystokinin in rats. Plasma was first passed through octadecylsilylsilica cartridges and the extracts were then tested for their content of cholecystokinin, based on their ability to stimulate amylase release from isolated rat pancreatic acini. Plasma levels of cholecystokinin-octapeptide as low as 0.18 pM were detectable. Gastrin, in contrast, reacted only weakly in this system. Cholecystokinin bioactivity was inhibited by the antagonist dibutyryl cyclic guanosine monophosphate and was eliminated by immunoadsorption with an antibody directed against the carboxyl terminus of cholecystokinin. Plasma cholecystokinin levels in fasting rats as cholecystokinin-octapeptide equivalents were 0.31 +/- 0.05 pM (mean +/- SE) and rose to 6.2 +/- 1.8 pM after feeding. Plasma cholecystokinin levels also increased 30-fold after intragastric instillation of soybean trypsin inhibitor and 15-fold after ethanol instillation. After column chromatography of plasma, two different forms of cholecystokinin were identifiable; one eluted with the octapeptide of cholecystokinin whereas the other most abundant form was intermediate in size between cholecystokinin-33 and cholecystokinin-octapeptide.

Authors
Liddle, RA; Goldfine, ID; Williams, JA
MLA Citation
Liddle, RA, Goldfine, ID, and Williams, JA. "Bioassay of plasma cholecystokinin in rats: effects of food, trypsin inhibitor, and alcohol." Gastroenterology 87.3 (September 1984): 542-549.
PMID
6204904
Source
pubmed
Published In
Gastroenterology
Volume
87
Issue
3
Publish Date
1984
Start Page
542
End Page
549

Adrenocorticotropic hormone biotransformation, clearance, and catabolism.

Authors
Nicholson, WE; Liddle, RA; Puett, D; Liddle, GW
MLA Citation
Nicholson, WE, Liddle, RA, Puett, D, and Liddle, GW. "Adrenocorticotropic hormone biotransformation, clearance, and catabolism." Endocrinology 103.4 (October 1978): 1344-1351.
PMID
217674
Source
pubmed
Published In
Endocrinology
Volume
103
Issue
4
Publish Date
1978
Start Page
1344
End Page
1351
DOI
10.1210/endo-103-4-1344

Renal uptake of lutropin. Studies based on electron microscopic autoradiography and nephrectomy.

Nephrectomy of mature rats was found to result in a significant increase in the circulatory half-life of tritiated ovine lutropin. The interaction of the glycoprotein hormone with the kidneys was studied in a more direct fashion using electron microscopic autoradiography. Evidence is presented showing the transfer of the hormone from microvilli into tubular epithelia (probably via vesicular transport), where radioactivity then becomes associated with lysosomes. This provides direct support for related results based on subcellular fractionation in which renal lysosomal catabolism was suggested as being important in the degradation of tritiated lutropin (M. Ascoli, R. A. Liddle, and D. Puett, Molecular and Cellular Endocrinology 4, 297, 1976). These results add substantial weight to the growing evidence that the kidneys assume a major role in controlling the concentration of circulating macromolecules.

Authors
Robinson, JP; Derreberry, S; Liddle, RA; Ascoli, M; Puett, D
MLA Citation
Robinson, JP, Derreberry, S, Liddle, RA, Ascoli, M, and Puett, D. "Renal uptake of lutropin. Studies based on electron microscopic autoradiography and nephrectomy." Mol Cell Biochem 15.1 (March 21, 1977): 63-66.
PMID
865484
Source
pubmed
Published In
Molecular and Cellular Biochemistry
Volume
15
Issue
1
Publish Date
1977
Start Page
63
End Page
66

Renal and hepatic lysosomal catabolism of luteinizing hormone.

Following an intravenous injection of tritiated ovine lutenizing hormone (LH) into mature male rats, the liver and kidneys accumulate a significant portion of the non-excreted hormone. The subcellular distribution of total radioactivity in both tissues was found to be similar to that of beta-galactosidase, a lysosomal enzyme marker. Moreover, the subcellular fraction with the highest relative specific activity of beta-galactosidase exhibited the highest degradation rate of endogenous hormone under in vitro conditions. Based on these and other observations, it is concluded that the intracellular catabolism of LH by these tissues is due to lysosomal enzymes. An analysis of the radioactive degradation products produced by a lysosomal-rich subcellular fraction showed the presence of free amino acids and oligopeptides. Thus, the uptake and degradation of the hormone by these tissues appear to occur by endocytosis followed by lysosomal catabolism. This phenomenon may represent a regulatory role in the control of (circulating) hormone concenttrations.

Authors
Ascoli, M; Liddle, RA; Puett, D
MLA Citation
Ascoli, M, Liddle, RA, and Puett, D. "Renal and hepatic lysosomal catabolism of luteinizing hormone." Mol Cell Endocrinol 4.5 (May 1976): 297-310.
PMID
950069
Source
pubmed
Published In
Molecular and Cellular Endocrinology
Volume
4
Issue
5
Publish Date
1976
Start Page
297
End Page
310

The metabolism of luteinizing hormone. Plasma clearance, urinary excretion, and tissue uptake.

The kinetics of plasma clearance, tissue uptake, and urinary excretion of tritiated ovine pituitary luteinizing hormone in adult male rats are reported. Most of the intravenously injected tritiated gonadotropin is cleared from circulation with a half-life of five minutes, and this is independent of the injected amount of hormone over a wide dose range. It was found that the hormone is rapidly removed from circulation by the kidneys, probably by glomerular filtration, and excreted in the urine. The radioactivity present in the urine is associated with material of the same molecular size as the native hormone and, moreover, the urinary hormone retains a significant amount of biological activity. A small amount of the hormone is catabolized by the kidney and liver, and our data suggest that this occurs in the cortex and hepatocytes, respectively.

Authors
Ascoli, M; Liddle, RA; Puett, D
MLA Citation
Ascoli, M, Liddle, RA, and Puett, D. "The metabolism of luteinizing hormone. Plasma clearance, urinary excretion, and tissue uptake." Mol Cell Endocrinol 3.1 (July 1975): 21-36.
PMID
168103
Source
pubmed
Published In
Molecular and Cellular Endocrinology
Volume
3
Issue
1
Publish Date
1975
Start Page
21
End Page
36

Adenosine 3',5'-monophosphate (cyclic AMP) as the mediator of the actions of melanocyte stimulating hormone (MSH) and norepinephrine on the frog skin.

Authors
Abe, K; Butcher, RW; Nicholson, WE; Baird, CE; Liddle, RA; Liddle, GW
MLA Citation
Abe, K, Butcher, RW, Nicholson, WE, Baird, CE, Liddle, RA, and Liddle, GW. "Adenosine 3',5'-monophosphate (cyclic AMP) as the mediator of the actions of melanocyte stimulating hormone (MSH) and norepinephrine on the frog skin." Endocrinology 84.2 (February 1969): 362-368.
PMID
4303528
Source
pubmed
Published In
Endocrinology
Volume
84
Issue
2
Publish Date
1969
Start Page
362
End Page
368
DOI
10.1210/endo-84-2-362
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