Abstract 248: Hepatocyte Nuclear Factor 4α Regulates Lipoprotein Metabolism and Atherosclerosis

Hepatocyte nuclear factor 4alpha (HNF4a) is a nuclear hormone receptor and highly expressed in the liver. Mutations in human HNF4a causes maturity-onset diabetes of the young type 1 (MODY1) and lipid disorder. We investigated the role of loss of hepatic HNF4a in lipid and lipoprotein metabolism using both adenovirus-mediated gene knockdown (Ad-shHNF4a) and liver-specific HNF4a knockout (L-HNF4a-/-) mice. Our data show that loss of hepatic HNF4a caused hypolipidemia and fatty liver disease. Plasma total cholesterol and triglyceride levels were significantly reduced whereas hepatic triglyceride levels were markedly increased. There effects were caused by impaired VLDL secretion. We further determined the effect of loss of hepatic HNF4a in atherosclerosis using ApoE-/- or Ldlr-/- mice. Our data show that loss of hepatic HNF4a caused a marked reduction in the atherosclerotic lesions when mice were challenged with a Western diet. Our data indicate that hepatic HNF4a plays a critical role in modulating lipid and lipoprotein metabolism and the development of atherosclerosis. Since human HNF4a mutations are found in MODY1 patients, this study may be of clinical importance.