Hepatic Hepatocyte Nuclear Factor 4α Is Essential for Maintaining Triglyceride and Cholesterol Homeostasis

Objective-Loss-of-function mutations in human hepatocyte nuclear factor 4 alpha (HNF4 alpha) are associated with maturity-onset diabetes of the young and lipid disorders. However, the mechanisms underlying the lipid disorders are poorly understood. In this study, we determined the effect of acute loss or augmentation of hepatic HNF4 alpha function on lipid homeostasis. Methods and Results-We generated an adenovirus expressing LacZ (Ad-shLacZ) or short hairpin RNA of Hnf4 alpha (Ad-shHnf4 alpha). Tail vain injection of C57BL/6J mice with Ad-shHnf4 alpha reduced hepatic Hnf4 alpha expression and resulted in striking phenotypes, including the development of fatty liver and a >80% decrease in plasma levels of triglycerides, total cholesterol, and high-density lipoprotein cholesterol. These latter changes were associated with reduced hepatic lipogenesis and impaired very-low-density lipoprotein secretion. Deficiency in hepatic Hnf4 alpha did not affect intestinal cholesterol absorption despite decreased expression of genes involved in bile acid synthesis. Consistent with the loss-of-function data, overexpression of Hnf4 alpha induced numerous genes involved in lipid metabolism in isolated primary hepatocytes. Interestingly, many of these HNF4 alpha-regulated genes were not induced in wild-type mice that overexpressed hepatic Hnf4 alpha. Because of selective gene regulation, mice overexpressing hepatic Hnf4 alpha had unchanged plasma triglyceride levels and decreased plasma cholesterol levels. Conclusion-Loss of hepatic HNF4 alpha results in severe lipid disorder as a result of dysregulation of multiple genes involved in lipid metabolism. In contrast, augmentation of hepatic HNF4 alpha activity lowers plasma cholesterol levels but has no effect on plasma triglyceride levels because of selective gene regulation. Our data indicate that hepatic HNF4 alpha is essential for controlling the basal expression of numerous genes involved in lipid metabolism and is indispensable for maintaining normal lipid homeostasis. (Arterioscler Thromb Vasc Biol. 2011;31:328-336.)