• FXR, the bile acid receptor and its downstream target, small heterodimer partner (SHP), have recently been identified to play a central role in hepatic lipidmetabolism as BA administration lowers blood lipids and the TAGs hepatic content. This effect is partially reversed in SHP KO mice and is mediated by transcriptional repression of SREBP-1c [81]. Thus, FXR represses hepatic DNL and VLDL export. FXR KO mice develop hepatic steatosis, and treatment with FXR agonist attenuates hepatic steatosis in mice when fed a methionine- and choline- deficient diet (MCD), a model that induces steatosis and oxidative stress, rather than insulin resistance [82, 83]. Other studies also revealed that FXR agonists improve IR [64, 84]. In the intestine, FXR activation induces secretion of fibroblast growth factors 15 (mouse) and 19 (human) (FGF15/19), which activates hepatic FA oxidation and insulin response via activation of the FGF receptor 4 [85, 86]. BAs have additional effects on lipid and glucose metabolisms via a G-protein-coupled receptor (TGR5/GBAR), which regulates energy expenditure in brown adipose tissue (and possibly skeletal muscle), and promotes intestinal GLP-1 secretion [87]. Thus, BAs may now be viewed as enterohepatic hormones that circulate with absorbed dietary lipids and fine-tune their metabolism
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