Abstract 398: Bile Acid Receptor Activation Ameliorates Metabolic Disorders by Differentially Activating FXR or TGR5

Objectives: Activation of the bile acid (BA) receptors farnesoid X receptor (FXR) or TGR5 has beneficial effects on metabolic homeostasis. However, activation of FXR may increase obesity and activation of TGR5 has little effect on lipid metabolism. As such, dual activation of FXR and TGR5 appears to be a more attractive approach for treatment of common metabolic disorders. So far, the role of BA receptor activation in metabolic regulation is not well characterized. Methods: We utilized wild-type (WT) mice, Tgr5 -/- mice, Fxr -/- mice, Apoe -/- mice and Shp -/- mice to investigate whether and how BA receptor activation by INT-767, a semisynthetic agonist for both FXR and TGR5, can prevent or reverse diet-induced metabolic disorders. Results: INT-767 reversed HFD-induced obesity and hyperglycemia in a TGR5-dependent manner and inhibited the development of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Mechanistically, INT-767 improved lipid homeostasis by activation of FXR and increased energy expenditure. Furthermore, activation of FXR inhibited several lipogeneic genes in the liver. We identified peroxisome proliferation-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα) as novel downstream targets of FXR. FXR inhibited PPARγ expression by inducing SHP (small heterodimer partner) whereas the inhibition of CEBPα by FXR is SHP-independent. Conclusions: BA receptor activation can prevent and reverse obesity, NAFLD and atherosclerosis by specific activation of FXR or TGR5. Our data suggest that compared of activation of FXR or TGR5 alone, dual activation of both FXR and TGR5 is a more attractive strategy for treatment of common metabolic disorders. Key words: FXR; TGR5; Atherosclerosis; Obesity; NAFLD; Lipogenesis