Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α

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

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

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 HNF4a-floxed (HNF4α F/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 HNF4α ΔL 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.

Original languageEnglish (US)
Pages (from-to)215-227
Number of pages13
JournalJournal of Lipid Research
Volume47
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

Fingerprint

Hepatocyte Nuclear Factor 4
Biosynthesis
Steroid 12-alpha-Hydroxylase
Bile Acids and Salts
Hydroxylation
Genes
Mixed Function Oxygenases
Cholesterol
Cholesterol 7-alpha-Hydroxylase
Cholic Acid
Oxidation
Messenger RNA
Enzyme activity
Sterols
Transcription
Liver
Photoperiod
Gallbladder
Serum
Binding Sites

Keywords

  • Cholic acid
  • Conditional knockout mice
  • Oxysterol 7α-hydroxylase
  • Sterol 12α-hydroxylase
  • Sterol carrier protein x

ASJC Scopus subject areas

  • Endocrinology

Cite this

Inoue, Y., Yu, A., Sun, H. Y., Ma, X., Krausz, K. W., Inoue, J., ... Gonzalez, F. J. (2006). Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α. Journal of Lipid Research, 47(1), 215-227. https://doi.org/10.1194/jlr.M500430-JLR200

Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α. / Inoue, Yusuke; Yu, Aiming; Sun, Hee Yim; Ma, Xiaochao; Krausz, Kristopher W.; Inoue, Junko; Xiang, Charlie C.; Brownstein, Michael J.; Eggertsen, Gösta; Björkhem, Ingemar; Gonzalez, Frank J.

In: Journal of Lipid Research, Vol. 47, No. 1, 01.2006, p. 215-227.

Research output: Contribution to journalArticle

Inoue, Y, Yu, A, Sun, HY, Ma, X, Krausz, KW, Inoue, J, Xiang, CC, Brownstein, MJ, Eggertsen, G, Björkhem, I & Gonzalez, FJ 2006, 'Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α', Journal of Lipid Research, vol. 47, no. 1, pp. 215-227. https://doi.org/10.1194/jlr.M500430-JLR200
Inoue, Yusuke ; Yu, Aiming ; Sun, Hee Yim ; Ma, Xiaochao ; Krausz, Kristopher W. ; Inoue, Junko ; Xiang, Charlie C. ; Brownstein, Michael J. ; Eggertsen, Gösta ; Björkhem, Ingemar ; Gonzalez, Frank J. / Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α. In: Journal of Lipid Research. 2006 ; Vol. 47, No. 1. pp. 215-227.
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abstract = "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 HNF4a-floxed (HNF4α F/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 HNF4α ΔL 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.",
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