Transcriptional regulation of hum,an sterol 27-hydroxylase gene (CYP27A1) by nuclear receptors
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Chen W L; Chiang J
Faseb Journal
2001
2001-03
Journal Article or Conference Abstract Publication
n/a
Regulation of human sterol 27-hydroxylase gene (CYP27A1) by bile acids and hepatocyte nuclear factor 4 alpha (HNF4 alpha)
rat; liver; bile acid synthesis; down-regulation; hepatocytes; nuclear receptor; transcriptional regulation; negative feedback-regulation; Genetics & Heredity; cholesterol 7-alpha-hydroxylase; cholic-acid; farnesoid X receptor; heterodimer partner; x-receptor; small; alpha-fetoprotein transcription factor; cerebrotendinous xanthomatosis; factor 4-alpha
Mitochondrial sterol 27-hydroxylase (CYP27Al) catalyses sterol side-chain oxidation of bile acid synthesis front cholesterol, and the first reaction of the acidic bile acid biosynthetic pathway. Hydrophobic bile acids suppress human CYP27Al gene reporter activity when assayed in human hepatocellular blastoma HepG2 cells. Bile acids also inhibit CYP27Al reporter activity in human embryonic kidney 293 cells. A putative bile acid response element (BARE) was mapped to a region downstream of nt - 147 of the human CYP27Al gene, within which a binding site for a liver-specific nuclear receptor, HNF4alpha, is identified. HNF4alpha strongly stimulates CYP27Al gene transcription and mutation of its binding site markedly reduced promoter activity. Results suggest that human CYP27Al gene transcription is suppressed by bile acids and HNF4alpha plays a pivotal role in transcriptional regulation of this gene. (C) 2003 Elsevier Science B.V. All rights reserved.
Chen W L; Chiang J Y L
Gene
2003
2003-08
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/s0378-1119(03)00631-0" target="_blank" rel="noreferrer noopener">10.1016/s0378-1119(03)00631-0</a>
Nuclear receptor-mediated repression of human cholesterol 7 alpha-hydroxylase gene transcription by bile acids
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
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.
Chen W L; Owsley E; Yang Y Z; Stroup D; Chiang J Y L
Journal of Lipid Research
2001
2001-09
Journal Article or Conference Abstract Publication
n/a