Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism.

Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism.

Pathak Preeti; Liu Hailiang; Boehme Shannon; Xie Cen; Krausz Kristopher W; Gonzalez Frank; Chiang John Y L

The Journal of biological chemistry

2017

2017-06

The bile acid-activated receptors, nuclear farnesoid X receptor (FXR) and the membrane Takeda G-protein receptor 5 (TGR5), are known to improve glucose and insulin sensitivity in obese and diabetic mice. However, the metabolic roles of these two receptors and the underlying mechanisms are incompletely understood. Here, we studied the effects of the dual FXR and TGR5 agonist INT-767 on hepatic bile acid synthesis and intestinal secretion of glucagon-like peptide-1 (GLP-1) in wild-type, Fxr(-/-), and Tgr5(-/-) mice. INT-767 efficaciously stimulated intracellular Ca(2+) levels, cAMP activity, and GLP-1 secretion and improved glucose and lipid metabolism more than did the FXR-selective obeticholic acid and

*bile acid; *bile acid metabolism; *FXR; *Gene Expression Regulation; *GLP-1; *lipid metabolism; *liver metabolism; *non-alcoholic fatty liver disease; *obesity; *TGR5; *type 2 diabetes; Animals; Bile Acids and Salts/*biosynthesis/genetics; Cytoplasmic and Nuclear/genetics/*metabolism; Dietary Fats; G-Protein-Coupled/genetics/*metabolism; Glucagon-Like Peptide 1/genetics/metabolism; Glucose/metabolism; Knockout; Lipid Metabolism; Liver/*metabolism; Mice; Obesity/genetics/*metabolism/pathology; Receptors

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