Keywords:24S-hydroxycholesterol CYP46A1 CYP39A1 Epigentics Histone deacetylase inhibitor Oxysterol Brain cholesterol a b s t r a c tThe 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.Ó 2008 Elsevier Inc. All rights reserved.Although all nucleated cells are capable of cholesterol synthesis, their ability to do so varies over several orders of magnitude. In the adult state most organisms have established a certain level of tissue specialisation [1]. The rate of cholesterol synthesis and the cholesterol content of a given tissue are not necessarily directly related, e.g. the adult brain contains more than 25% of whole body cholesterol but turns over only 0.03% of its cholesterol content each day. This turnover is much lower than the developing brain [1] where cholesterol rich myelin is being formed. The slow turnover of brain cholesterol is in marked contrast to that in most other organs [1,2]. The mechanistic basis for these differences is unknown, although they are probably a result of the functional isolation of brain and blood cholesterol [3][4][5].According to current concepts, the synthesis and elimination of cholesterol in the adult brain is compartmentalised-astroglial cells are believed to be responsible for the majority of synthesis in the adult brain while they contribute relatively little to brain elimination. The neuron specific cytochrome P450 cholesterol 24-hydroxylase (CYP46A1) is responsible for the elimination of about two thirds of the cholesterol synthesised by the brain [6,7]. Recently it was shown that deletion of this gene led to a reduction in the rate of brain cholesterol synthesis while the level of brain cholesterol was maintained [8]. Due to the importance of this enzyme for brain cholesterol balance we have previously investigated its transcriptional regulation [9], with an expectation that a gene so important for brain cholesterol balance would be subject to complex mechanisms of regulation. Surprisingly we found the opposite-expression of CYP46A1 was insensitive to mechanisms known to regulate the key genes in cholesterol synthesis and elimination, HMGCR and CYP7A1,...