Shp deletion prevents hepatic steatosis and when combined with Fxr loss protects against type 2 diabetes

ABSTRACT

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 are also very active and that correlates well with the observed increase in Pepck expression, type IA fibers and mitochondrial function in the skeletal muscle. Mechanistically, we demonstrate that liver-specific Shp deletion protects against fatty liver development by suppressing the expression of Pparγ2 and lipid-droplet protein Fsp27β. Conclusions: 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. This article is protected by copyright. All rights reserved.

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