Hepatocyte nuclear factor 4α (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 transcriptional level by the concerted actions of a limited number of hepatocyte-enriched transcription factors (hepatocyte nuclear factor 1 alpha [HNF1 alpha], -1 beta, -3 alpha, -3 beta, -3 gamma, 4 alpha, and -6 and members of the 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 factor is not an absolute requirement for the formation of an active hepatic parenchyma. In contrast, HNF4 alpha -null mice die during embryogenesis. Moreover, recent in vitro experiments using tetraploid aggregation suggest that 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 lipid in the liver and exhibited greatly reduced serum cholesterol and triglyceride levels and increased serum bile acid concentrations. The observed phenotypes may be explained by (i) a selective disruption of very-low-density lipoprotein secretion due to decreased expression of genes encoding apolipoprotein B and microsomal triglyceride transfer protein, (ii) an increase in hepatic cholesterol uptake due to increased expression of the major high-density lipoprotein receptor, scavenger receptor BI, and (iii) a decrease in bile acid uptake to the liver due to down-regulation of the major basolateral bile acid transporters sodium taurocholate cotransporter protein and organic anion transporter protein 1. These data indicate that HNF4 alpha is central to the maintenance of hepatocyte differentiation and is a major in vivo regulator of genes involved in the control of lipid homeostasis.