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Journal of Lipid Research, Vol. 47, 215-227, January 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4

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^1,*

^* Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
Laboratory of Genetics, National Institute of Mental Health, National Institutes of Health, Bethesda, MD
Department of Medical Laboratory Sciences and Technology, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden

Published, JLR Papers in Press, November 1, 2005.

¹ To whom correspondence should be addressed. e-mail: fjgonz{at}helix.nih.gov

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

Supplementary key words conditional knockout mice • sterol 12-hydroxylase • oxysterol 7-hydroxylase • sterol carrier protein x • cholic acid

Abbreviations: ACOX2, trihydroxycoprostancyl-coenzyme A oxidase 2; BA, bile acid; CA, cholic acid; CDCA, chenodeoxycholic acid; CPF, cholesterol 7-hydroxylase promoter factor; CYP7A1, cholesterol 7-hydroxylase promoter factor; CYP7B1, oxysterol 7-hydroxylase; CYP8B1, sterol 12-hydroxylase; CYP27A1, sterol 27-hydroxylase; CYP39A1, oxysterol 7-hydroxylase; DBP, albumin D site-binding protein; DCA, deoxycholic acid; D-PBE, D-type peroxisomal bifunctional enzyme; DR1, direct repeat 1; FXR, farnesoid X receptor; HNF4, hepatocyte nuclear factor 4; HNF4^L, liver-specific hepatocyte nuclear factor 4-null; HNF4^F/F, hepatocyte nuclear factor 4-floxed; LC-MS/MS, liquid chromatography tandem mass spectrometry; LRH-1, liver receptor homologue-1; MCA, muricholic acid; NTCP, sodium taurocholate cotransporter polypeptide; OATP1, organic anion transporter polypeptide 1; PPAR, peroxisome proliferator-activated receptor ; PXR, pregnane X receptor; RXR, retinoid X receptor ; SCPx, sterol carrier protein x; SCP2, sterol carrier protein 2; SHP, small heterodimer partner; UDCA, ursodeoxycholic acid; VLACSR, very long chain acyl-coenzyme A synthase-related gene

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