Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α

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; Frank J. Gonzalez

Journal of Lipid Research (Jan 2006)

Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α

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,
Frank J. Gonzalez

Affiliations

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

Journal volume & issue: Vol. 47, no. 1
pp. 215 – 227

Abstract

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Hepatocyte nuclear factor 4α (HNF4α) regulates many genes that are preferentially expressed in liver. Mice lacking hepatic expression of HNF4α (HNF4αΔL) exhibited markedly increased levels of serum bile acids (BAs) compared with HNF4α-floxed (HNF4αF/F) mice. The expression of genes involved in the hydroxylation and side chain β-oxidation of cholesterol, including oxysterol 7α-hydroxylase, sterol 12α-hydroxylase (CYP8B1), and sterol carrier protein x, was markedly decreased in HNF4αΔL mice. Cholesterol 7α-hydroxylase mRNA and protein were diminished only during the dark cycle in HNF4αΔL mice, whereas expression in the light cycle was not different between HNF4αΔL and HNF4αF/F mice. Because CYP8B1 expression was reduced in HNF4αΔL mice, it was studied in more detail. In agreement with the mRNA levels, CYP8B1 enzyme activity was absent in HNF4αΔL mice. An HNF4α binding site was found in the mouse Cyp8b1 promoter that was able to direct HNF4α-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 HNF4α plays a central role in BA homeostasis by regulation of genes involved in BA biosynthesis, including hydroxylation and side chain β-oxidation of cholesterol in vivo.

Published in Journal of Lipid Research

ISSN: 0022-2275 (Print); 1539-7262 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Chemistry: Organic chemistry: Biochemistry
Website: https://www.journals.elsevier.com/journal-of-lipid-research

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