Bile acids repress cholesterol 7α‐hydroxylase gene transcription by recruiting histone deacetylases

Abstract

Cholesterol is disposed mainly via its conversion to bile acids, which repress their own synthesis by decreasing the expression of cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme of this metabolic pathway. Kinetic analysis of mRNA levels shows that bile acids, but not the farnesoid X receptor (FXR) selective ligand GW4064, decrease CYP7A1 expression within few minutes, suggesting a FXR independent mechanism of transcriptional repression. Chromatin immunoprecipitation assays demonstrate that bile acids promote the rapid dissociation of coactivators and the recruitment of corepressors and histone deacetylases (HDACs). Moreover, bile acids elicit the translocation of HDAC7 from the cytosol to the nucleus. The assembly of a repressive complex on CYP7A1 promoter leads to the deacetylation of the nuclear receptor hepatocyte nuclear factor 4, followed by the inactivation of RNA polymerase II and its subsequent dissociation from the promoter. Silencing of HDAC7 by RNAi abolishes the inhibition of CYP7A1 transcription by bile acids and treatment with HDAC inhibitors (HDACi) prevents bile acid-mediated repression of CYP7A1. Administration of HDACi to hypercholesterolemic mice (Ldl-r KO) increases Cyp7a1 mRNA levels, bile acids synthesis and reduces total plasma and LDL cholesterol. The effect is mostly mediated by induction of Cyp7a1, as mRNAs levels of other genes involved in lipid metabolism do not change. In conclusion, our study reveals a FXR independent regulation of CYP7A1 that involves the recruitment of HDACs on CYP7A1 promoter, highlighting a role of HDACi in the reduction of plasma cholesterol. Supported by EC QLG1-CT2001-01513 and Telethon GGP04252