Document Detail


Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice.
MedLine Citation:
PMID:  23257920     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Bile acid sequestrants are nonabsorbable 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 glucagon-like peptide-1 (GLP-1) release. A GLP-1 receptor antagonist blocked suppression of hepatic glycogenolysis and blunted but did not eliminate the effect of colesevelam on glycemia. The ability of colesevelam 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 farnesoid X 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.
Authors:
Matthew J Potthoff; Austin Potts; Tianteng He; João A G Duarte; Ronald Taussig; David J Mangelsdorf; Steven A Kliewer; Shawn C Burgess
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-12-20
Journal Detail:
Title:  American journal of physiology. Gastrointestinal and liver physiology     Volume:  304     ISSN:  1522-1547     ISO Abbreviation:  Am. J. Physiol. Gastrointest. Liver Physiol.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-18     Completed Date:  2013-04-19     Revised Date:  2014-02-18    
Medline Journal Info:
Nlm Unique ID:  100901227     Medline TA:  Am J Physiol Gastrointest Liver Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  G371-80     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Allylamine / analogs & derivatives*,  pharmacology
Animals
Bile Acids and Salts / pharmacology
Blood Glucose / drug effects,  metabolism
Cholesterol / metabolism
Diet, High-Fat
Glucagon-Like Peptide 1 / metabolism*
Glycogenolysis / drug effects
Liver / drug effects
Male
Mice
Mice, Obese
Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
Receptors, G-Protein-Coupled / physiology*
Receptors, Glucagon / metabolism
Grant Support
ID/Acronym/Agency:
DK-059630/DK/NIDDK NIH HHS; DK-059637/DK/NIDDK NIH HHS; P41 RR002584/RR/NCRR NIH HHS; R01 DK078184/DK/NIDDK NIH HHS; R01DK078184/DK/NIDDK NIH HHS; RR02584/RR/NCRR NIH HHS; U19 DK62434/DK/NIDDK NIH HHS; UL1-DE019584/DE/NIDCR NIH HHS; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/Bile Acids and Salts; 0/Blood Glucose; 0/Gpbar1 protein, mouse; 0/Receptors, Cytoplasmic and Nuclear; 0/Receptors, G-Protein-Coupled; 0/Receptors, Glucagon; 0/farnesoid X-activated receptor; 0/glucagon-like peptide-1 receptor; 182815-44-7/colesevelam; 48G762T011/Allylamine; 89750-14-1/Glucagon-Like Peptide 1; 97C5T2UQ7J/Cholesterol
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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