On the mechanism of bile acid inhibition of rat sterol 12 -hydroxylase gene transcription by nuclear receptors, -fetoprotein transcription factor and hepatocyte nuclear receptor 4

Chiang, J.Y.L.; Yang, Y.; Zhang, M.; Eggertsen, G.

FASEB Journal 16(4): A562-A563

2002


ISSN/ISBN: 0892-6638
Accession: 035425813

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Abstract
The sterol 12(alpha)-hydroxylase is a key enzyme in the synthesis of cholic acid in the liver. In similarity with cholesterol 7(alpha)-hydroxylase (CYP7A1), CYP8B1 is subjected to a negative feedback regulation by bile acids. It has been reported that hydrophobic bile acids bind to and activate a nuclear receptor, farnesoid X receptor (FXR) in mouse liver. FXR induces a negative nuclear receptor, small heterodimer partner (SHP), which then interacts with an orphan receptor, FTF and down-regulates CYP7A1 transcription. We studied the molecular mechanism of bile acid regulation of rat CYP8B1 gene transcription. Feeding rats with CDCA caused a decrease of CYP8B1 and HNF4(alpha) mRNA expression. This was associated with an increase in FTF mRNA expression, but SHP mRNA expression was not altered. Electrophoretic mobility shift assay, promoter/reporter assay, and mutagenesis analysis identified an HNF4(alpha) binding site embedded in two overlapping FTF binding sites. Mutation of the HNF4(alpha) binding site markedly reduced basal promoter activity and its repression by bile acids. FXR did not affect, whereas FTF strongly repressed CYP8B1 transcription. We conclude that FTF and HNF4(alpha) play critical roles in regulating CYP8B1 gene transcription by bile acids and reveal an FXR/SHP-independent mechanism by which bile acids inhibit rat CYP8B1 gene transcription by inducing FTF and inhibiting HNF4(alpha) expression.