Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α
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 h...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2006-01-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520336701 |
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doaj-2e0d84da66da4c6894602d2415ebe533 |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α Journal of Lipid Research conditional knockout mice sterol 12α-hydroxylase oxysterol 7α-hydroxylase sterol carrier protein x cholic acid |
| author_facet |
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 |
| author_sort |
Yusuke Inoue |
| title |
Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α |
| title_short |
Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α |
| title_full |
Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α |
| title_fullStr |
Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α |
| title_full_unstemmed |
Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α |
| title_sort |
regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α |
| publisher |
Elsevier |
| series |
Journal of Lipid Research |
| issn |
0022-2275 |
| publishDate |
2006-01-01 |
| description |
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. |
| topic |
conditional knockout mice sterol 12α-hydroxylase oxysterol 7α-hydroxylase sterol carrier protein x cholic acid |
| url |
http://www.sciencedirect.com/science/article/pii/S0022227520336701 |
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doaj-2e0d84da66da4c6894602d2415ebe5332021-04-27T04:45:42ZengElsevierJournal of Lipid Research0022-22752006-01-01471215227Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4αYusuke Inoue0Ai-Ming Yu1Sun Hee Yim2Xiaochao Ma3Kristopher W. Krausz4Junko Inoue5Charlie C. Xiang6Michael J. Brownstein7Gösta Eggertsen8Ingemar Björkhem9Frank J. Gonzalez10Laboratory 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, SwedenLaboratory 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, SwedenLaboratory 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, SwedenLaboratory 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, SwedenLaboratory 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, SwedenLaboratory 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, SwedenLaboratory 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, SwedenLaboratory 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, SwedenLaboratory 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, SwedenLaboratory 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, SwedenLaboratory 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, SwedenHepatocyte 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.http://www.sciencedirect.com/science/article/pii/S0022227520336701conditional knockout micesterol 12α-hydroxylaseoxysterol 7α-hydroxylasesterol carrier protein xcholic acid |