Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α

Abstract

Hepatocyte nuclear factor 4α (HNF4α) regulates many genes that are preferentially expressed in liver. Mice lacking hepatic expression of HNF4α (HNF4αΔL) exhibited markedly increased levels of serum bile acids (BAs) compared with HNF4a-floxed (HNF4α F/F) mice. The expression of genes involved in the hydroxylation and side chain β-oxidation of cholesterol, including oxysterol 7α-hydroxylase, sterol 12α-hydroxylase (CYP8B1), and sterol carrier protein x, was markedly decreased in HNF4αΔL mice. Cholesterol 7α-hydroxylase mRNA and protein were diminished only during the dark cycle in HNF4αΔL mice, whereas expression in the light cycle was not different between HNF4αΔL and HNF4αF/F mice. Because CYP8B1 expression was reduced in HNF4αΔL mice, it was studied in more detail. In agreement with the mRNA levels, CYP8B1 enzyme activity was absent in HNF4α ΔL mice. An HNF4α binding site was found in the mouse Cyp8b1 promoter that was able to direct HNF4α-dependent transcription. Surprisingly, cholic acid-derived BAs, produced as a result of CYP8B1 activity, were still observed in the serum and gallbladder of these mice. These studies reveal that HNF4α plays a central role in BA homeostasis by regulation of genes involved in BA biosynthesis, including hydroxylation and side chain β-oxidation of cholesterol in vivo.