Abstract
Hydrophobic bile acids strongly repressed transcription of the human cholesterol 7α-hydroxylase gene (CYP7A1) in the bile acid biosynthetic pathway in the liver. 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 α-fetoprotein transcription factor (FTF) and small heterodimer partner (SHP) mRNA expression in HepG2 cells. Feeding of rats with chenodeoxycholic acid repressed CYP7A1, induced FTF, but had no effect on SHP mRNA expression in the liver. FTF 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 FTF 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., E. Owsley, Y. Yang, D. Stroup, and J. Y. L. Chiang. Nuclear receptor-mediated repression of human cholesterol 7α-hydroxylase gene transcription by bile acids.
Highlights
Hydrophobic bile acids strongly repressed transcription of the human cholesterol 7␣-hydroxylase gene (CYP7A1) in the bile acid biosynthetic pathway in the liver
We have shown that Farnesoid X receptor (FXR) represses rat CYP7A1 transcription through the BARE-bile acid response elements I and II (II), but FXR does not bind to this sequence [15]
It is well recognized that FXR is a highly specific bile acid receptor that is activated by hydrophobic bile acids at physiological concentrations to regulate the genes involved in bile acid synthesis and transport
Summary
Hydrophobic bile acids strongly repressed transcription of the human cholesterol 7␣-hydroxylase gene (CYP7A1) in the bile acid biosynthetic pathway in the liver. Bile acids and FXR repressed endogenous CYP7A1 but stimulated ␣-fetoprotein transcription factor (FTF) and small heterodimer partner (SHP) mRNA expression 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. Tion, in transient transfection assays in confluent HepG2 cells, and identified a bile acid response element (BARE-II, nucleotides Ϫ148 to 118) [6, 7] This sequence contains a direct repeat of an AGGTCA-like motif separated by one base (DR1) that has been identified as a binding site for hepatocyte nuclear factor 4 (HNF4) [8].
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