The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling

Tingting Li, Sam R. Holmstrom, Serkan Kir, Michihisa Umetani, Daniel R. Schmidt, Steven A. Kliewer, David J. Mangelsdorf

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

TGR5 is a G protein-coupled bile acid receptor present in brown adipose tissue and intestine, where its agonism increases energy expenditure and lowers blood glucose. Thus, it is an attractive drug target for treating human metabolic disease. However, TGR5 is also highly expressed in gallbladder, where its functions are less well characterized. Here, we demonstrate that TGR5 stimulates the filling of the gallbladder with bile. Gallbladder volume was increased in wild-type but not Tgr5-/- mice by administration of either the naturally occurring TGR5 agonist, lithocholic acid, or the synthetic TGR5 agonist, INT-777. These effects were independent of fibroblast growth factor 15, an enteric hormone previously shown to stimulate gallbladder filling. Ex vivo analyses using gallbladder tissue showed that TGR5 activation increased cAMP concentrations and caused smooth muscle relaxation in a TGR5-dependent manner. These data reveal a novel, gallbladder-intrinsic mechanism for regulating gallbladder contractility. They further suggest that TGR5 agonists should be assessed for effects on human gallbladder as they are developed for treating metabolic disease.

Original languageEnglish (US)
Pages (from-to)1066-1071
Number of pages6
JournalMolecular Endocrinology
Volume25
Issue number6
DOIs
StatePublished - Jun 2011

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Gallbladder
Bile Acids and Salts
GTP-Binding Proteins
Metabolic Diseases
Lithocholic Acid
Gastrointestinal Hormones
Muscle Relaxation
Brown Adipose Tissue
Fibroblast Growth Factors
Bile
Energy Metabolism
Intestines
Smooth Muscle
Blood Glucose
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling. / Li, Tingting; Holmstrom, Sam R.; Kir, Serkan; Umetani, Michihisa; Schmidt, Daniel R.; Kliewer, Steven A.; Mangelsdorf, David J.

In: Molecular Endocrinology, Vol. 25, No. 6, 06.2011, p. 1066-1071.

Research output: Contribution to journalArticle

Li, Tingting ; Holmstrom, Sam R. ; Kir, Serkan ; Umetani, Michihisa ; Schmidt, Daniel R. ; Kliewer, Steven A. ; Mangelsdorf, David J. / The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling. In: Molecular Endocrinology. 2011 ; Vol. 25, No. 6. pp. 1066-1071.
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