| Colesevelam Suppresses Hepatic Glycogenolysis by TGR5-mediated Induction of GLP-1 Action in DIO mice. | |
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MedLine Citation:
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PMID: 23257920 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Bile acid sequestrants are non-absorbable resins designed to treat hypercholesterolemia by preventing ileal uptake of bile acids, thus increasing catabolism of cholesterol into bile acids. However, sequestrants also improve hyperglycemia and hyperinsulinemia through less characterized metabolic and molecular mechanisms. Here we demonstrate that the bile acid sequestrant, colesevelam, significantly reduced hepatic glucose production by suppressing hepatic glycogenolysis in diet induced obese mice, and that this was partially mediated by activation of the G-protein coupled bile acid receptor TGR5 and GLP-1 release. The GLP-1 receptor agonist ex-9 blocked suppression of hepatic glycogenolysis and blunted, but did not eliminate colesevelam's effect on glycemia. Colesevelam's ability to induce GLP-1, lower glycemia and spare hepatic glycogen content was compromised in mice lacking TGR5. In vitro assays revealed that bile acid activation of TGR5 initiates a prolonged cAMP signaling cascade, and that this signaling was maintained even when the bile acid was complexed to colesevelam. Intestinal TGR5 was most abundantly expressed in the colon, and rectal administration of a colesevelam/bile acid complex was sufficient to induce portal GLP-1 concentration but did not activate the nuclear bile acid receptor FXR. The beneficial effects of colesevelam on cholesterol metabolism were mediated by FXR, and were independent of TGR5/GLP-1. We conclude that colesevelam administration functions through a dual mechanism which includes TGR5/GLP-1 dependent suppression of hepatic glycogenolysis and FXR dependent cholesterol reduction. |
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Authors:
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Matthew J Potthoff; Austin Potts; Tianteng He; Joao A G Duarte; Ronald Taussig; David J Mangelsdorf; Steven A Kliewer; Shawn C Burgess |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-12-20 |
Journal Detail:
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Title: American journal of physiology. Gastrointestinal and liver physiology Volume: - ISSN: 1522-1547 ISO Abbreviation: Am. J. Physiol. Gastrointest. Liver Physiol. Publication Date: 2012 Dec |
Date Detail:
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Created Date: 2012-12-21 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100901227 Medline TA: Am J Physiol Gastrointest Liver Physiol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1University of Texas Southwestern Medical Center. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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