Regulation of human sterol 27-hydroxylase gene (CYP27A1) by bile acids and hepatocyte nuclear factor 4α (HNF4α)

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.