Compared selleck chem inhibitor to cholesterol itself, oxysterols are highly mobile, but once the 3B hydroxy group has been attached to a long chain fatty acid the molecule becomes insoluble and prone to aggregation. Al though the major sterol in advanced ATH plaque appears to be 27OHC, and not appar ently esters of 25OHC itself, this may be explained by the fact that 25OHC acts here, not as a substrate, but as an allosteric activator of intracellular Inhibitors,Modulators,Libraries esterification. Work over many years, notably by Changs group, has revealed that ACAT enzymes contain two binding sites, the allosteric regulatory site, and the catalytic site. Once a sterol is bound to the A site the enzyme be comes highly active, with promiscuous substrate specifi city for a wide range of sterols and even some steroids.

Inhibitors,Modulators,Libraries Adding 25OHC to the culture medium caused a 20 60 fold increase in sterol esterification without change in enzyme content. Crucially, 25OHC is the most effective positive allosteric Inhibitors,Modulators,Libraries effector of ACAT, the enzyme is only poorly activated by close analogs such as 7 ketocholesterol, 6 ketocholestanol, 7 OHC, cholate, or cholesterol itself. 25OHC activation of ACAT takes place in multiple cell types including macrophages and neuronal cells. In addition, it has been suggested that 25OHC drives intracellular redistribution of cholesterols to the endoplasmic reticulum, where ACAT is located, this could afford a second mechanism underpinning the enhancement of esterification. Therefore, by these routes 25OHC triggers the conversion of the intracellular pool of cholesterols into insoluble choles teryl esters, and thus prevents their export.

Induction of cholesterol esterification by 25OHC was recently confirmed. In further confirmation of its key role, 25OHC has been shown to promote macrophage foam cell formation in mouse cell culture. It is interesting that 3 uM 25OHC is typically used to stimulate choles terol esterification, whereas foam cell Inhibitors,Modulators,Libraries formation was re ported to take place even at a 10 fold lower concentration, ACAT is thus a further contender as a receptor for 25OHC. The data suggest Inhibitors,Modulators,Libraries that chronic overexpression of CH25H is causally associated with disease. In direct support, CH25H gene expression is repressed by transcription fac tor ATF3 knockout of ATF3 in susceptible mice led to a marked increase in 25OHC levels and foam cell formation. Ablation of CYP7B1 increased ATH severity in mice, pointing to a specific predisposing effect of 25OHC itself. Circumstantially, the finding that the expression of CYP7B1, that efficiently metabolizes 25OHC, is downregulated in AD brain is consistent with the interpretation Erlotinib mechanism that excess 25OHC contributes to AD.