Hepatocytic activating transcription factor 3 protects against steatohepatitis via hepatocyte nuclear factor 4

Activating transcription factor 3 (ATF3) has been shown to play an important role in HDL metabolism, yet the role of hepatocytic ATF3 in the development of steatohepatitis remains elusive. Here we show that adeno-associated virus-mediated over-expression of human ATF3 in hepatocytes prevents diet-induced steatohepatitis in C57BL/6 mice and reverses steatohepatitis in db/db mice. Conversely, global or hepatocyte-specific loss of ATF3 aggravates diet-induced steatohepatitis. Mechanistically, hepatocytic ATF3 induces hepatic lipolysis and fatty acid oxidation and inhibits inflammation and apoptosis. We further show that hepatocyte nuclear factor 4a (HNF4a) is required for ATF3 to improve steatohepatitis. Thus, the current study indicates that ATF3 protects against steatohepatitis through, at least in part, hepatic HNF4a. Targeting hepatic ATF3 may be useful for treatment of steatohepatitis.