Small heterodimer partner deletion prevents hepatic steatosis and when combined with farnesoid X receptor loss protects against type 2 diabetes in mice

Nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP) are important regulators of bile acid, lipid, and glucose homeostasis. Here, we show that global Fxr –/– Shp –/– double knockout (DKO) mice are refractory to weight gain, glucose intolerance, and hepatic steatosis when challenged with high‐fat diet. DKO mice display an inherently increased capacity to burn fat and suppress de novo hepatic lipid synthesis. Moreover, DKO mice were also very active and that correlated well with the observed increase in phosphoenolpyruvate carboxykinase expression, type IA fibers, and mitochondrial function in skeletal muscle. Mechanistically, we demonstrate that liver‐specific Shp deletion protects against fatty liver development by suppressing expression of peroxisome proliferator‐activated receptor gamma 2 and lipid‐droplet protein fat‐specific protein 27 beta. Conclusion: These data suggest that Fxr and Shp inactivation may be beneficial to combat diet‐induced obesity and uncover that hepatic SHP is necessary to promote fatty liver disease. (Hepatology 2017;66:1854–1865)