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Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice
Journal article   Open access

Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice

Matthew J Potthoff, Austin Potts, Tianteng He, João A G Duarte, Ronald Taussig, David J Mangelsdorf, Steven A Kliewer and Shawn C Burgess
American journal of physiology: Gastrointestinal and liver physiology, Vol.304(4), pp.G371-380
02/15/2013
DOI: 10.1152/ajpgi.00400.2012
PMCID: PMC3566618
PMID: 23257920
url
https://doi.org/10.1152/ajpgi.00400.2012View
Published (Version of record) Open Access

Abstract

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.
 Bile Acids and Salts - pharmacology Glucagon-Like Peptide 1 - metabolism Allylamine - analogs & derivatives Receptors, Glucagon - metabolism Male Cholesterol - metabolism Blood Glucose - drug effects Animals Glucagon-Like Peptide-1 Receptor Liver - drug effects Diet, High-Fat Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors Allylamine - pharmacology Mice, Obese Mice Glycogenolysis - drug effects Blood Glucose - metabolism Colesevelam Hydrochloride Receptors, G-Protein-Coupled - physiology

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