Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover
Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover
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DOI：
10.1074/jbc.m303415200
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发表时间：
2003-06-20
影响因子：
4.8
通讯作者：
Russell, DW
中科院分区：
文献类型：
--
作者：
Lund, EG;Xie, CL;Russell, DW
大多数胆固醇的周转发生在肝脏，包括将胆固醇转化为可溶的、容易排出的胆汁酸。胆汁酸的合成仅限于肝脏，但胆汁酸生物合成途径中的几种酶在肝外组织中表达，也可能有助于胆固醇的转化。后一种酶的一个例子是胆固醇24-羟基酶，这是一种细胞色素P450(CYP46A1)，在大脑中的表达水平是肝脏的100倍。胆固醇24-羟基酶催化合成氧化甾醇24(S)-羟基胆固醇。为了评估24-羟化途径对胆固醇转化的相对贡献，我们在缺乏胆固醇24-羟基酶基因的小鼠(Cyp46a1(-/-)小鼠)中进行了平衡研究。与野生型对照相比，突变小鼠的肝脏胆固醇和胆汁酸代谢参数保持不变。与肝脏相反，大脑中新胆固醇的合成减少了40%，尽管基因敲除小鼠的胆固醇水平稳定在40%左右。这些数据表明，新胆固醇的合成和24(S)-羟基胆固醇的分泌是紧密耦合的，大脑中至少有40%的胆固醇周转依赖于胆固醇24-羟基酶的作用。我们得出结论，胆固醇24-羟基酶构成了胆固醇在大脑中转化的主要组织特异性途径。
Most cholesterol turnover takes place in the liver and involves the conversion of cholesterol into soluble and readily excreted bile acids. The synthesis of bile acids is limited to the liver, but several enzymes in the bile acid biosynthetic pathway are expressed in extra-hepatic tissues and there also may contribute to cholesterol turnover. An example of the latter type of enzyme is cholesterol 24-hydroxylase, a cytochrome P450 (CYP46A1) that is expressed at 100-fold higher levels in the brain than in the liver. Cholesterol 24-hydroxylase catalyzes the synthesis of the oxysterol 24(S)-hydroxycholesterol. To assess the relative contribution of the 24-hydroxylation pathway to cholesterol turnover, we performed balance studies in mice lacking the cholesterol 24-hydroxylase gene (Cyp46a1(-/-) mice). Parameters of hepatic cholesterol and bile acid metabolism in the mutant mice remained unchanged relative to wild type controls. In contrast to the liver, the synthesis of new cholesterol was reduced by similar to40% in the brain, despite steady-state levels of cholesterol being similar in the knockout mice. These data suggest that the synthesis of new cholesterol and the secretion of 24(S)-hydroxycholesterol are closely coupled and that at least 40% of cholesterol turnover in the brain is dependent on the action of cholesterol 24-hydroxylase. We conclude that cholesterol 24-hydroxylase constitutes a major tissue-specific pathway for cholesterol turnover in the brain.