HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: M500430-JLR200v1 47/1/215    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Inoue, Y. Articles by Gonzalez, F. J. Search for Related Content PubMed PubMed Citation Articles by Inoue, Y. Articles by Gonzalez, F. J. Social Bookmarking                      What's this?

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

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. P. Martinez-Jimenez, I. Kyrmizi, P. Cardot, F. J. Gonzalez, and I. Talianidis Hepatocyte Nuclear Factor 4{alpha} Coordinates a Transcription Factor Network Regulating Hepatic Fatty Acid Metabolism Mol. Cell. Biol., February 1, 2010; 30(3): 565 - 577. [Abstract] [Full Text] [PDF]

				Y. Zhang, L. Yin, J. Anderson, H. Ma, F. J. Gonzalez, T. M. Willson, and P. A. Edwards Identification of Novel Pathways That Control Farnesoid X Receptor-mediated Hypocholesterolemia J. Biol. Chem., January 29, 2010; 285(5): 3035 - 3043. [Abstract] [Full Text] [PDF]

				B. Nedumaran, S. Hong, Y.-B. Xie, Y.-H. Kim, W.-Y. Seo, M.-W. Lee, C. H. Lee, S.-H. Koo, and H.-S. Choi DAX-1 Acts as a Novel Corepressor of Orphan Nuclear Receptor HNF4{alpha} and Negatively Regulates Gluconeogenic Enzyme Gene Expression J. Biol. Chem., October 2, 2009; 284(40): 27511 - 27523. [Abstract] [Full Text] [PDF]

				D. J. Waxman and M. G. Holloway Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes Mol. Pharmacol., August 1, 2009; 76(2): 215 - 228. [Abstract] [Full Text] [PDF]

				P. Lu, G. B. Rha, M. Melikishvili, G. Wu, B. C. Adkins, M. G. Fried, and Y.-I. Chi Structural Basis of Natural Promoter Recognition by a Unique Nuclear Receptor, HNF4{alpha}: DIABETES GENE PRODUCT J. Biol. Chem., November 28, 2008; 283(48): 33685 - 33697. [Abstract] [Full Text] [PDF]

				H. Ohguchi, T. Tanaka, A. Uchida, K. Magoori, H. Kudo, I. Kim, K. Daigo, I. Sakakibara, M. Okamura, H. Harigae, et al. Hepatocyte Nuclear Factor 4{alpha} Contributes to Thyroid Hormone Homeostasis by Cooperatively Regulating the Type 1 Iodothyronine Deiodinase Gene with GATA4 and Kruppel-Like Transcription Factor 9 Mol. Cell. Biol., June 15, 2008; 28(12): 3917 - 3931. [Abstract] [Full Text] [PDF]

				Y.-K. Lee, D. R. Schmidt, C. L. Cummins, M. Choi, L. Peng, Y. Zhang, B. Goodwin, R. E. Hammer, D. J. Mangelsdorf, and S. A. Kliewer Liver Receptor Homolog-1 Regulates Bile Acid Homeostasis but Is Not Essential for Feedback Regulation of Bile Acid Synthesis Mol. Endocrinol., June 1, 2008; 22(6): 1345 - 1356. [Abstract] [Full Text] [PDF]

				L. W. Harries, J. M. Locke, B. Shields, N. A. Hanley, K. P. Hanley, A. Steele, P. R. Njolstad, S. Ellard, and A. T. Hattersley The Diabetic Phenotype in HNF4A Mutation Carriers Is Moderated By the Expression of HNF4A Isoforms From the P1 Promoter During Fetal Development Diabetes, June 1, 2008; 57(6): 1745 - 1752. [Abstract] [Full Text] [PDF]

				D.-J. Shin and T. F. Osborne Peroxisome Proliferator-activated Receptor-{gamma} Coactivator-1{alpha} Activation of CYP7A1 during Food Restriction and Diabetes Is Still Inhibited by Small Heterodimer Partner J. Biol. Chem., May 30, 2008; 283(22): 15089 - 15096. [Abstract] [Full Text] [PDF]

				M. G. Holloway, G. D. Miles, A. A. Dombkowski, and D. J. Waxman Liver-Specific Hepatocyte Nuclear Factor-4{alpha} Deficiency: Greater Impact on Gene Expression in Male than in Female Mouse Liver Mol. Endocrinol., May 1, 2008; 22(5): 1274 - 1286. [Abstract] [Full Text] [PDF]

				Z. Xu, O. L. Tavares-Sanchez, Q. Li, J. Fernando, C. M. Rodriguez, E. J. Studer, W. M. Pandak, P. B. Hylemon, and G. Gil Activation of Bile Acid Biosynthesis by the p38 Mitogen-activated Protein Kinase (MAPK): HEPATOCYTE NUCLEAR FACTOR-4{alpha} PHOSPHORYLATION BY THE p38 MAPK IS REQUIRED FOR CHOLESTEROL 7{alpha}-HYDROXYLASE EXPRESSION J. Biol. Chem., August 24, 2007; 282(34): 24607 - 24614. [Abstract] [Full Text] [PDF]

				X. Ding, K. Lichti, I. Kim, F. J. Gonzalez, and J. L. Staudinger Regulation of Constitutive Androstane Receptor and Its Target Genes by Fasting, cAMP, Hepatocyte Nuclear Factor {alpha}, and the Coactivator Peroxisome Proliferator-activated Receptor {gamma} Coactivator-1{alpha} J. Biol. Chem., September 8, 2006; 281(36): 26540 - 26551. [Abstract] [Full Text] [PDF]