Project Summary Project Summary: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, which includes simple steatosis (NAFL) and non-alcoholic steatohepatitis (NASH). NAFLD not only causes liver dysfunctions but also induces extra-hepatic complications. Accumulating data indicate that cardiovascular disease (CVD) is the major cause of deaths in NAFLD patients. So far, the mechanism underlying the development of NAFLD is poorly understood. In addition, it is unclear why NAFLD patients have increased incidence of CAD. Forkhead box A3 (FOXA3) is a transcription factor whose function in lipid or lipoprotein metabolism has not been established. Our preliminary studies show that hepatic FOXA3 expression is markedly reduced under common metabolic stress. Using over-expression or knockdown approaches, we show that hepatic FOXA3 regulates hepatic lipid and plasma HDL levels as well as the expression of HDL-associated proteins. These novel data suggest that dysregulation of hepatic FOXA3 may play an important role in the pathogenesis of both NAFLD and CVD. To test this hypothesis, we will use both gain- and loss-of-function approaches. Completion of the proposed studies may uncover a novel role of hepatic FOXA3 in the development of NAFLD and atherosclerosis and may offer novel insights into the mechanism by which NAFLD is a risk factor for CAD.