Department of Gastroenterology, Center for Collaborative Research, Ibaraki 300-0395, Japan.
J Lipid Res. 2011 Aug;52(8):1509-16. doi: 10.1194/jlr.M014084. Epub 2011 May 16.
To date, many studies have been conducted using 25-hydroxycholesterol, which is a potent regulator of lipid metabolism. However, the origins of this oxysterol have not been entirely elucidated. Cholesterol 25-hydroxylase is one of the enzymes responsible for the metabolism of 25-hydroxycholesterol, but the expression of this enzyme is very low in humans. This oxysterol is also synthesized by sterol 27-hydroxylase (CYP27A1) and cholesterol 24-hydroxylase(CYP46A1), but it is only a minor product of these enzymes. We now report that CYP3A synthesizes a significant amount of 25-hydroxycholesterol and may participate in the regulation of lipid metabolism. Induction of CYP3A by pregnenolone-16α-carbonitrile caused the accumulation of 25-hydroxycholesterol in a cell line derived from mouse liver. Furthermore, treatment of the cells with troleandomycin, a specific inhibitor of CYP3A, significantly reduced cellular 25-hydroxycholesterol concentrations. In cells that overexpressed human recombinant CYP3A4, the activity of cholesterol 25-hydroxylation was found to be higher than that of cholesterol 4β-hydroxylation, a known marker activity of CYP3A4. In addition, 25-hydroxycholesterol concentrations in normal human sera correlated positively with the levels of 4β-hydroxycholesterol (r = 0.650, P < 0.0001, n = 78), but did not significantly correlate with the levels of 27-hydroxycholesterol or 24S-hydroxycholesterol. These results demonstrate the significance of CYP3A on the production of 25-hydroxycholesterol.
迄今为止，已有许多研究使用 25-羟胆固醇进行，该物质是脂代谢的强效调节剂。然而，这种氧化固醇的来源尚未完全阐明。胆固醇 25-羟化酶是负责代谢 25-羟胆固醇的酶之一，但这种酶在人类中的表达水平非常低。这种氧化固醇也由固醇 27-羟化酶（CYP27A1）和胆固醇 24-羟化酶（CYP46A1）合成，但它只是这些酶的次要产物。我们现在报告 CYP3A 合成大量的 25-羟胆固醇，并可能参与脂质代谢的调节。孕烯醇酮-16α-氰化物诱导 CYP3A 的表达导致源自小鼠肝脏的细胞系中 25-羟胆固醇的积累。此外，用特非那定（CYP3A 的特异性抑制剂）处理细胞，可显著降低细胞内 25-羟胆固醇浓度。在过表达人重组 CYP3A4 的细胞中，胆固醇 25-羟化酶的活性高于胆固醇 4β-羟化酶（已知的 CYP3A4 标志物活性）。此外，正常人血清中的 25-羟胆固醇浓度与 4β-羟胆固醇水平呈正相关（r = 0.650，P <0.0001，n = 78），但与 27-羟胆固醇或 24S-羟胆固醇水平无显著相关性。这些结果表明 CYP3A 在 25-羟胆固醇的生成中具有重要意义。
