Transcriptional regulation of cholesterol 24-hydroxylase by histone deacetylase inhibitors.
The mechanistic basis for the tissue specific expression of cholesterol elimination pathways is poorly understood. To gain additional insight into this phenomenon we considered it of interest to investigate if epigenetic mechanisms are involved in the regulation of the brain-specific enzyme cholesterol 24-hydroxylase (CYP46A1), a key regulator of brain cholesterol elimination. We demonstrated a marked time-dependent derepression of the expression of CYP46A1, in response to treatment with the potent histone deacetylase (HDAC) inhibitor Trichostatin A. The pattern of expression of the genes in the genomic region surrounding CYP46A1 was found to be diametrically opposite in brain and liver. Intraperitoneal injection of HDAC inhibitors in mice led to a significant derepression of hepatic Cyp46a1 mRNA expression and tissue specific changes in Hmgcr and Cyp39a1 mRNA expression. These results are discussed in the context of the phenomenology of tissue specific cholesterol balance.
Shafaati
Marjan
M
Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska University Hospital-Huddinge, Karolinska Institutet, Stockholm, Sweden.
O'Driscoll
Riona
R
Björkhem
Ingemar
I
Meaney
Steve
S
D000818:Animals; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D000072556:Cholesterol 24-Hydroxylase; D002843:Chromatin / Q000378:metabolism / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013250:Steroid Hydroxylases / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology
D002843:Chromatin; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase; D006655:Histone Deacetylases