Transcriptional regulation of the human sterol 12alpha-hydroxylase gene (CYP8B1): roles of heaptocyte nuclear factor 4alpha in mediating bile acid repression.

Title

Transcriptional regulation of the human sterol 12alpha-hydroxylase gene (CYP8B1): roles of heaptocyte nuclear factor 4alpha in mediating bile acid repression.

Creator

Zhang M; Chiang J Y

Publisher

The Journal of biological chemistry

Date

2001
2001-11

Description

Sterol 12alpha-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 4alpha (HNF4alpha) strongly activated human CYP8B1 promoter activities, whereas cholesterol 7alpha-hydroxylase promoter factor (CPF), an NR5A2 family of nuclear receptors, had much less effect. Electrophoretic mobility shift assay identified an overlapping HNF4alpha- and CPF-binding 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 HNF4alpha-binding site markedly reduced promoter activity and its response to bile acid repression. On the other hand, mutation of the

Subject

*DNA-Binding Proteins; *Transcription; Base Sequence; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Bile Acids and Salts/*pharmacology; Binding Sites; Cholesterol 7-alpha-Hydroxylase/genetics; Cultured; Cytochrome P-450 Enzyme System/*genetics; Cytoplasmic and Nuclear/physiology; Genetic; Genetic/physiology; Hepatocyte Nuclear Factor 4; Humans; Molecular Sequence Data; Phosphoproteins/*physiology; Promoter Regions; Receptors; Repressor Proteins/*pharmacology; Steroid 12-alpha-Hydroxylase; Steroid Hydroxylases/*genetics; Transcription Factors/*physiology; Tumor Cells

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

41690–41699

Issue

45

Volume

276

Citation

Zhang M; Chiang J Y, “Transcriptional regulation of the human sterol 12alpha-hydroxylase gene (CYP8B1): roles of heaptocyte nuclear factor 4alpha in mediating bile acid repression.,” NEOMED Bibliography Database, accessed September 25, 2021, https://neomed.omeka.net/items/show/4061.

Social Bookmarking