Nuclear receptor-mediated repression of human cholesterol 7 alpha-hydroxylase gene transcription by bile acids

Title

Nuclear receptor-mediated repression of human cholesterol 7 alpha-hydroxylase gene transcription by bile acids

Creator

Chen W L; Owsley E; Yang Y Z; Stroup D; Chiang J Y L

Publisher

Journal of Lipid Research

Date

2001
2001-09

Description

Hydrophobic bile acids strongly repressed transcription of the human cholesterol 7 alpha -hydroxylase gene (CYP7A1) in the bile acid biosynthetic pathway in the Ever. Farnesoid X receptor (FXR) repressed CYP7A1/Luc reporter activity in a transfection assay in human liver-derived HepG2 cells, but not in human embryonic kidney (HEK) 293 cells. FXR-binding activity was required for bile acid repression of CYP7A1 transcription despite the fact that FXR did not bind to the CYP7A1 promoter. FXR-induced liver-specific factors must be required for mediating bile acid repression. Bile acids and FXR repressed endogenous CYP7A1 but stimulated a-fetoprotein transcription factor (FTF) and small heterodimer partner (SHP) mRNA expression in HepG2 cells. Feeding of rats with chenodeoxycholic acid repressed CYP7A1, induced FIT, but had no effect on SHP mRNA expression in the liver. FIT strongly repressed CYP7A1 transcription in a dose-dependent manner, and SHP further inhibited CYP7A1 in HepG2 cells, but not in HEK 293 cells. FXR only moderately stimulated SHP transcription, whereas FIT strongly inhibited SHP transcription in HepG2 cells. Results revealed that FTF was a dominant negative factor that was induced by bile acid-activated FXR to inhibit both CYP7A1 and SHP transcription. Differential regulation of FTF and SHP expression by bile acids may explain the wide variation in CYP7A1 expression and the rate of bile acid synthesis and regulation in different species.

Subject

liver; bile acid synthesis; Biochemistry & Molecular Biology; expression; messenger-rna; activation; identification; promoter; cytochrome P450; shp; cyp7a; hepg2 cells; mechanism of gene regulation; orphan receptor

Identifier

n/a

Format

Journal Article or Conference Abstract Publication

URL Address

n/a

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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

1402-1412

Issue

9

Volume

42

Citation

Chen W L; Owsley E; Yang Y Z; Stroup D; Chiang J Y L, “Nuclear receptor-mediated repression of human cholesterol 7 alpha-hydroxylase gene transcription by bile acids,” NEOMED Bibliography Database, accessed June 23, 2021, https://neomed.omeka.net/items/show/8879.

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