J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M500430-JLR200 on November 1, 2005

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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{alpha}

Yusuke Inoue*, Ai-Ming Yu*, Sun Hee Yim*, Xiaochao Ma*, Kristopher W. Krausz*, Junko Inoue*, Charlie C. Xiang{dagger}, Michael J. Brownstein{dagger}, Gösta Eggertsen§, Ingemar Björkhem§ and Frank J. Gonzalez1,*

* Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
{dagger} 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{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 ß-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{alpha}{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 ß-oxidation of cholesterol in vivo.

Supplementary key words conditional knockout mice • sterol 12{alpha}-hydroxylase • oxysterol 7{alpha}-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{alpha}-hydroxylase promoter factor; CYP7A1, cholesterol 7{alpha}-hydroxylase promoter factor; CYP7B1, oxysterol 7{alpha}-hydroxylase; CYP8B1, sterol 12{alpha}-hydroxylase; CYP27A1, sterol 27-hydroxylase; CYP39A1, oxysterol 7{alpha}-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{alpha}, hepatocyte nuclear factor 4{alpha}; HNF4{alpha}{Delta}L, liver-specific hepatocyte nuclear factor 4{alpha}-null; HNF4{alpha}F/F, hepatocyte nuclear factor 4{alpha}-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{alpha}, peroxisome proliferator-activated receptor {alpha}; PXR, pregnane X receptor; RXR{alpha}, retinoid X receptor {alpha}; 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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