Figure 8. Recapitulation of hepatic CYP7A1 and CYP8B1 expression attenuates diet-induced steatohepatitis in Hnf4α^Hep−/− mice.

Hnf4α^fl/fl mice and Hnf4α^Hep−/− mice were injected i.v. with 0.5×10¹¹ GC of AAV8-ALB-Null or AAV8-ALB-hCYP7A1 plus AAV8-ALB-hCYP8B1, and then fed an HFCF diet for 20 weeks (n=8 per group). (A) Plasma ALT levels. (B) Liver sections were stained with Sirius Red (left panel) and hepatic hydroxyproline levels were quantified (right panel). (C) Hepatic apoptosis was analyzed by TUNEL assays. (D) Hepatic proteins were analyzed by Western blot assays (left panel) and then quantified (middle and right panels). (E) Hepatic mRNA levels. (F) A model for hepatic HNF4α to regulate the development and progression of NAFLD. HNF4α regulates VLDL secretion, lipolysis, fatty acid oxidation (FAO), bile acid synthesis and p53 expression. As a result, FXR is activated, hepatic free fatty acid, free cholesterol and triglyceride (TG) levels are decreased, and hepatic apoptosis, inflammation, and ROS production are inhibited. These multifacted effects of HNF4α lead to inhibition of development and progression of NAFLD. *P<0.05, **P<0.01