Structure, Evolution, and Liver-Specific Expression of Sterol 12 -Hydroxylase P450 (CYP8B)

Ishida, Hiroko; Kuruta, Yoshihiro; Gotoh, Osamu; Yamashita, Chika; Yoshida, Yuzo; Noshiro, Mitsuhide

doi:10.1093/oxfordjournals.jbchem.a022422

Cited by 32 publications

(27 citation statements)

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“…These investigators suggest that SHP is a candidate MODY gene that may regulate HNF4 activity in pancreas and control energy metabolism and body weight. In diabetes, bile acid synthesis and pool size increase in association with an increase in CYP8B1 activity (48,49). This is consistent with our results that SHP and HNF4␣ play important roles in regulating human CYP8B1 transcription.…”

Section: Discussionsupporting

confidence: 91%

Transcriptional Regulation of the Human Sterol 12α-Hydroxylase Gene (CYP8B1)

Zhang

Chiang

2001

Journal of Biological Chemistry

217

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Sterol 12␣-hydroxylase catalyzes the synthesis of cholic acid and controls the ratio of cholic acid over chenodeoxycholic acid in the bile. Transcription of CYP8B1 is inhibited by bile acids, cholesterol, and insulin. To study the mechanism of CYP8B1 transcription by bile acids, we have cloned and determined 3389 base pairs of the 5-upstream nucleotide sequences of the human CYP8B1. Deletion analysis of CYP8B1/luciferase reporter activity in HepG2 cells revealed that the sequences from ؊57 to ؉300 were important for basal and liver-specific promoter activities. Hepatocyte nuclear factor 4␣ (HNF4␣) strongly activated human CYP8B1 promoter activities, whereas cholesterol 7␣-hydroxylase promoter factor (CPF), an NR5A2 family of nuclear receptors, had much less effect. Electrophoretic mobility shift assay identified an overlapping HNF4␣-and CPFbinding site in the ؉198/؉227 region. The human CYP8B1 promoter activities were strongly repressed by bile acids, and the bile acid response element was localized between ؉137 and ؉220. Site-directed mutagenesis of the HNF4␣-binding site markedly reduced promoter activity and its response to bile acid repression. On the other hand, mutation of the CPF-binding site had little effect on promoter activity and bile acid inhibition. A negative nuclear receptor, small heterodimer partner markedly inhibited transactivation of CYP8B1 by HNF4␣. Mammalian two-hybrid assay confirmed that HNF4␣ interacted with small heterodimer partner. Furthermore, bile acids and farnesoid X receptor reduced the expression of nuclear HNF4␣ in HepG2 cells and rat livers and its binding to DNA. Bile acids and farnesoid X receptor also inhibited mouse HNF4␣ gene transcription. In summary, our data revealed the critical roles HNF4␣ play on CYP8B1 transcription and its repression by bile acids. Bile acids repress human CYP8B1 transcription by reducing the transactivation activity of HNF4␣ through interaction of HNF4␣ with SHP and reduction of HNF4␣ expression in the liver.

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Section: Discussionsupporting

confidence: 91%

Transcriptional Regulation of the Human Sterol 12α-Hydroxylase Gene (CYP8B1)

Zhang

Chiang

2001

Journal of Biological Chemistry

217

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“…Several other mechanisms have also been described that downregulate CYP7A1 expression, involving PXR, the cJun N-terminal kinase (1), and insulin (19), all of which are independent of SHP. It seems likely, however, that 1/1 and CYP8B1 2/2 mice with the same diet or the same treatment; ¤, significant differences between the diet-treated groups and the chow groups, or two agonist groups, compared with vehicle group having the same genotype.…”

Section: Discussionmentioning

confidence: 99%

Studies on LXR- and FXR-mediated effects on cholesterol homeostasis in normal and cholic acid-depleted mice

Wang

Einarsson

Murphy

et al. 2006

Journal of Lipid Research

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As previously reported by us, mice with targeted disruption of the CYP8B1 gene (CYP8B1 2/2 ) fail to produce cholic acid (CA), upregulate their bile acid synthesis, reduce the absorption of dietary cholesterol and, after cholesterol feeding, accumulate less liver cholesterol than wild-type (CYP8B1 1/1 ) mice. In the present study, cholesterol-enriched diet (0.5%) or administration of a synthetic liver X receptor (LXR) agonist strongly upregulated CYP7A1 expression in CYP8B1 2/2 mice, compared to CYP8B1mice. Cholesterol-fed CYP8B1 2/2 mice also showed a significant rise in HDL cholesterol and increased levels of liver ABCA1 mRNA. A combined CA (0.25%)/cholesterol (0.5%) diet enhanced absorption of intestinal cholesterol in both groups of mice, increased their liver cholesterol content, and reduced their expression of CYP7A1 mRNA. The ABCG5/G8 liver mRNA was increased in both groups of mice, but cholesterol crystals were only observed in bile from the CYP8B1 1/1 mice. The results demonstrate the cholesterol-sparing effects of CA: enhanced absorption and reduced conversion into bile acids. Farnesoid X receptor (FXR)-mediated suppression of CYP7A1 in mice seems to be a predominant mechanism for regulation of bile acid synthesis under normal conditions and, as confirmed, able to override LXR-mediated mechanisms. Interaction between FXR-and LXR-mediated stimuli might also regulate expression of liver ABCG5/G8.-Wang, J., C. Einarsson, C. Murphy, P. Parini, I. Björkhem, M. Gåfvels, and G. Eggertsen. Studies on LXR-and FXR-mediated effects on cholesterol homeostasis in normal and cholic acid-depleted mice. J. Lipid Res. 2006. 47: 421-430. Supplementary key words bile acids . farnesoid X receptor . liver X receptor . cholesterol 7a-hydroxylase . sterol 12a-hydroxylase

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“…Because CYP8B1 is expressed mainly in liver (38), the possibility was investigated that HNF4a can directly bind to and regulate the promoter of the mouse Cyp8b1 gene. The mouse Cyp8b1 promoter contains a direct repeat 1 (DR1) motif (at position 2109 to 294 from the translation start site) that is a potential binding site for nuclear receptors such as HNF4a and PPARa.…”

Section: Hnf4a Directly Binds To the Promoter Region Of The Mouse Cypmentioning

confidence: 99%

Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α

Inoue

Yim

et al. 2006

Journal of Lipid Research

127

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Hepatocyte nuclear factor 4a (HNF4a) regulates many genes that are preferentially expressed in liver. Mice lacking hepatic expression of HNF4a (HNF4a DL ) exhibited markedly increased levels of serum bile acids (BAs) compared with HNF4a-floxed (HNF4a F/F ) mice. The expression of genes involved in the hydroxylation and side chain b-oxidation of cholesterol, including oxysterol 7a-hydroxylase, sterol 12a-hydroxylase (CYP8B1), and sterol carrier protein x, was markedly decreased in HNF4a DL mice. Cholesterol 7a-hydroxylase mRNA and protein were diminished only during the dark cycle in HNF4a DL mice, whereas expression in the light cycle was not different between HNF4a DL and HNF4a F/F mice. Because CYP8B1 expression was reduced in HNF4a DL mice, it was studied in more detail. In agreement with the mRNA levels, CYP8B1 enzyme activity was absent in HNF4a DL mice. An HNF4a binding site was found in the mouse Cyp8b1 promoter that was able to direct HNF4a-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 HNF4a plays a central role in BA homeostasis by regulation of genes involved in BA biosynthesis, including hydroxylation and side chain b-oxidation of cholesterol in vivo.-Inoue, Y., A

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Structure, Evolution, and Liver-Specific Expression of Sterol 12 -Hydroxylase P450 (CYP8B)

Cited by 32 publications

References 0 publications

Transcriptional Regulation of the Human Sterol 12α-Hydroxylase Gene (CYP8B1)

Transcriptional Regulation of the Human Sterol 12α-Hydroxylase Gene (CYP8B1)

Studies on LXR- and FXR-mediated effects on cholesterol homeostasis in normal and cholic acid-depleted mice

Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α

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