Hepatocyte Nuclear Factor 4α Prevents the Steatosis-to-NASH Progression by Regulating p53 and Bile Acid Signaling (in mice).

BACKGROUND AND AIMS: Hepatocyte nuclear factor 4α (HNF4α) is highly enriched in the liver, but its role in the progression of nonalcoholic liver steatosis (NAFL) to NASH has not been elucidated. In this study, we investigated the effect of gain or loss of HNF4α function on the development and progression of NAFLD in mice. APPROACH AND RESULTS: Overexpression of human HNF4α protected against high-fat/cholesterol/fructose (HFCF) diet-induced steatohepatitis, whereas loss of Hnf4α had opposite effects. HNF4α prevented hepatic triglyceride accumulation by promoting hepatic triglyceride lipolysis, fatty acid oxidation, and VLDL secretion. Furthermore, HNF4α suppressed the progression of NAFL to NASH. Overexpression of human HNF4α inhibited HFCF diet-induced steatohepatitis in control mice but not in hepatocyte-specific p53-/- mice. In HFCF diet-fed mice lacking hepatic Hnf4α, recapitulation of hepatic expression of HNF4α targets cholesterol 7α-hydroxylase and sterol 12α-hydroxylase and normalized hepatic triglyceride levels and attenuated steatohepatitis. CONCLUSIONS: The current study indicates that HNF4α protects against diet-induced development and progression of NAFLD by coordinating the regulation of lipolytic, p53, and bile acid signaling pathways. Targeting hepatic HNF4α may be useful for treatment of NASH.

Kinase/phosphatase regulation of CYP7A1.

Bile acid synthesis powerfully influences cholesterol homeostasis by providing an avenue for cholesterol disposal and by producing signaling molecules. Bile acids are multifaceted signals, regulating gene expression both by acting as a ligand for the nuclear hormone receptor, farnesoid X-receptor (FXR), and by activating cellular kinases. Though the exact identities and sequence of the signaling events are under investigation, there is mounting evidence for the involvement of c-Jun N-terminal kinase (JNK) and extracellular-regulated kinase (ERK) 1/2 pathway. The rate of bile acid synthesis is controlled by the activity of the enzyme, cholesterol 7alpha-hydroxylase, encoded on the CYP7A1 gene. Cholesterol 7alpha-hydroxylase activity and transcription of CYP7A1 gene promoter have been reported to be affected by protein kinases and phosphatases. Cellular protein kinases may provide the mechanisms for coordinate regulation of cholesterol transport, synthesis and breakdown to bile acids. Investigations into the interrelationships between various kinases/phosphatases and nuclear hormone receptors will clarify the roles that these pathways play in bile acid gene regulation and coordinate regulation of lipid metabolism, as well as in the connection of lipid metabolism with disease onset and progression of several human diseases.