Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4 alpha

Hepatocyte nuclear factor 4 alpha (HNF4 alpha) regulates many genes that are preferentially expressed in liver. Mice lacking hepatic expression of HNF4 alpha (HNF4 alpha(Delta L)) exhibited markedly increased levels of serum bile acids (BAs) compared with HNF4 alpha-floxed (HNF4 alpha(F/F)) mice. The expression of genes involved in the hydroxylation and side chain beta-oxidation of cholesterol, including oxysterol 7 alpha-hydroxylase, sterol 12 alpha-hydroxylase (CYP8B1), and sterol carrier protein x, was markedly decreased in HNF4 alpha(Delta L) mice. Cholesterol 7 alpha-hydroxylase mRNA and protein were diminished only during the dark cycle in HNF4(Delta L) mice, whereas expression in the light cycle was not different between HNF4 alpha(Delta L) and HNF4 alpha(F/F) mice. Because CYP8B1 expression was reduced in HNF4 alpha(Delta L) mice, it was studied in more detail. In agreement with the mRNA levels, CYP8B1 enzyme activity was absent in HNF4 alpha(Delta L) mice. An HNF4 alpha binding site was found in the mouse Cyp8b1 promoter that was able to direct HNF4 alpha-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 HNF4 alpha plays a central role in BA homeostasis by regulation of genes involved in BA biosynthesis, including hydroxylation and side chain beta-oxidation of cholesterol in vivo.