Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4alpha

doi:10.1194/jlr.M500430-JLR200

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Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4 $alpha$

Yusuke Inoue, Ai-Ming Yu, Sun Hee Yim, Xiaochao Ma, Kristopher W. Krausz, Junko Inoue, Charlie C. Xiang, Michael J. Brownstein, Gösta Eggertsen, Ingemar Björkhem, and Frank J. Gonzalez

Laboratory of Metabolism, National Cacner Institute, Bethesda, MD 20892

Corresponding Author: fjgonz{at}helix.nih.gov

Hepatocyte nuclear factor 4 $alpha$ (HNF4 $alpha$ ) regulates many genes that are preferentially expressed in liver. Mice lacking hepatic expression of HNF4 $alpha$ , HNF4 $alpha$ ^deltaL, exhibited markedly elevated levels of serum bile acids compared to HNF4 $alpha$ -floxed mice, HNF4 $alpha$ ^F/F. The expression of genes involved in the hydroxylation and side chain $beta$ -oxidation of cholesterol including oxysterol 7 $alpha$ -hydroxylase (CYP7B1), sterol 12 $alpha$ -hydroxylase (CYP8B1), and sterol carrier protein x (SCPx) was markedly decreased in liver-specific HNF4 $alpha$ ^deltaL mice. Cholesterol 7 $alpha$ -hydroxylase (CYP7A1) mRNA and protein were diminished only during the dark cycle in HNF4 $alpha$ ^deltaL mice, whereas expression in the light cycle was not different between HNF4 $alpha$ ^deltaL and HNF4 $alpha$ ^F/F mice. Since CYP8B1 expression was reduced in HNF4 $alpha$ ^deltaL mice, it was studied in more detail. In agreement with the mRNA levels, CYP8B1 enzyme activity was absent in HNF4 $alpha$ ^deltaL 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 b-oxidation of cholesterol in vivo.

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