Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed countries, which ranges from simple steatosis to non-alcoholic steatohepatitis (NASH). So far, the mechanisms underlying the development of NAFLD is poorly understood. Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP response element-binding (ATF/CREB) family of transcription factors, and inhibits inflammatory response in macrophages. Until now, nothing has been known about the role of hepatic ATF3 in lipid metabolism. Our preliminary studies have shown that hepatic ATF3 expression is markedly reduced under common metabolic stress. Over-expression of ATF3 in the liver improves lipid homeostasis whereas loss of hepatic ATF3 has opposite effects. In this project, we will investigate whether and how hepatic ATF3 regulates the development of NAFLD. We will use both gain- and loss-of-function approaches to complete this project. Completion of the proposed studies may help identify hepatocyte ATF3 as a key regulator of lipid metabolism and the development of NAFLD.
Relevance: NAFLD is one of the most common chronic liver diseases worldwide. Completion of the proposed studies will help determine the role of hepatic ATF3 in the development of NAFLD and may lead to a new strategy for treatment of NAFLD. Thus, the studies proposed in this application are highly relevant to human health.