Hepatocyte nuclear factor 4 alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis

The numerous functions of the liver are controlled primarily at the transcr iptional level by the concerted actions of a limited number of hepatocyte-e nriched transcription factors (hepatocyte nuclear factor 1 alpha [HNF1 alph a], -1 beta, -3 alpha, -3 beta, -3 gamma, 4 alpha, and -6 and members of th e c/ebp family). Of these, only HNF4 alpha (nuclear receptor 2A1) and HNF1 alpha appear to be correlated with the differentiated phenotype of cultured hepatoma cells. HNF1 alpha -null mice are viable, indicating that this fac tor is not an absolute requirement for the formation of an active hepatic p arenchyma. In contrast, HNF4 alpha -null mice die during embryogenesis. Mor eover, recent in vitro experiments using tetraploid aggregation suggest tha t HNF4 alpha is indispensable for hepatocyte differentiation, However, the function of HNF4 alpha in the maintenance of hepatocyte differentiation and function is less well understood. To address the function of HNF4 alpha in the mature hepatocyte, a conditional gene knockout was produced using the Cre-loxP system. Mice lacking hepatic HNF4 alpha expression accumulated lip id in the liver and exhibited greatly reduced serum cholesterol and triglyc eride levels and increased serum bile acid concentrations. The observed phe notypes may be explained by (i) a selective disruption of very-low-density lipoprotein secretion due to decreased expression of genes encoding apolipo protein B and microsomal triglyceride transfer protein, (ii) an increase in hepatic cholesterol uptake due to increased expression of the major high-d ensity lipoprotein receptor, scavenger receptor BI, and (iii) a decrease in bile acid uptake to the liver due to down-regulation of the major basolate ral bile acid transporters sodium taurocholate cotransporter protein and or ganic anion transporter protein 1. These data indicate that HNF4 alpha is c entral to the maintenance of hepatocyte differentiation and is a major in v ivo regulator of genes involved in the control of lipid homeostasis.