Insights in the regulation of cholesterol 7α-hydroxylase gene reveal a target for modulating bile acid synthesis

• DOI: 10.1002/hep.21819
• Publication Date: 2007-07-25T18:47:22Z
• Authors: Nico Mitro; Cristina Godio; Emma De Fabiani; Elena Scotti; Andrea Galmozzi; Federica Gilardi; Donatella Caruso; Ana Belen Vigil C...; Maurizio Crestani
• Keywords: Cell Nucleus; Feedback, Physiological; Male; 0303 health sciences; Receptors, Cytoplasmic and Nuclear; Isoxazoles; Histone Deacetylases; Bile Acids and Salts; DNA-Binding Proteins; Lipoproteins, LDL; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Gene Expression Regulation; Animals; Humans; Nuclear Receptor Co-Repressor 2; RNA, Messenger; RNA, Small Interfering; Cholesterol 7-alpha-Hydroxylase; Promoter Regions, Genetic; Histone Acetyltransferases

The transcription of the gene (CYP7A1) encoding cholesterol 7alpha-hydroxylase, a key enzyme in homeostasis, is repressed by bile acids via multiple mechanisms involving members nuclear receptor superfamily. Here, we describe regulatory mechanism that can be exploited for modulating acid synthesis. By dissecting CYP7A1 transcription, found stimulate sequential recruitment histone deacetylases (HDACs) 7, 3, and 1, corepressor SMRTalpha (silencing mediator retinoid thyroid receptors-alpha) corepressor. Bile acids, but not farnesoid X receptor-selective agonist GW4064, increase concentration HDAC7, which promotes assembly repressive complex ultimately represses transcription. Interestingly, despite its high basal expression level, small heterodimer partner (SHP) associated with promoter only at later stage repression. Gene silencing interfering RNA confirms HDAC7 factor required repression whereas knockdown SHP does prevent down-regulation CYP7A1. Administration HDAC inhibitors valproic or trichostatin A to genetically hypercholesterolemic mice increases Cyp7a1 messenger synthesis consequently markedly reduces total plasma low-density lipoprotein cholesterol.By using combination molecular, cellular, animal models, our study highlights importance HDACs feedback regulation identifies these enzymes as potential targets modulate treatment hypercholesterolemia.