Transgenic expression of cholesterol-7-α-hydroxylase prevents atherosclerosis in C57BL/6J mice
Transgenic expression of cholesterol-7-α-hydroxylase prevents atherosclerosis in C57BL/6J mice
复制标题
DOI：
10.1161/hq0102.102588
复制
发表时间：
2002-01-01
影响因子：
8.7
通讯作者：
Davis, RA
中科院分区：
文献类型：
--
作者：
Miyake, JH;Duong-Polk, XT;Davis, RA
当喂食由脂肪、胆固醇和牛磺胆酸盐组成的饮食时，C57 BL/6 J小鼠易患动脉粥样硬化。对饮食诱导的动脉粥样硬化的易感性与血浆高密度脂蛋白（HDL）的降低有关。饮食诱导的血浆HDL降低显示与胆固醇-7-α-羟化酶（调节胆固醇转化为胆汁酸的肝脏特异性酶）的抑制存在生理和遗传相关性。为了检验胆固醇-7-α-羟化酶的抑制负责启动导致动脉粥样硬化和胆结石形成的代谢改变的假设，我们确定了C57 BL/6 J小鼠中胆固醇-7-α-羟化酶的组成型转基因表达是否会赋予对这两种常见人类疾病的抵抗力。当喂食致动脉粥样硬化饮食时，非转基因同窝出生的小鼠，而不是胆固醇-7-α-羟化酶转基因小鼠，在肝脏和血浆中积累胆固醇和胆固醇酯。虽然致动脉粥样硬化饮食导致非转基因小鼠血浆HDL胆固醇显著降低，但转基因小鼠的HDL水平保持相对不变。此外，胆固醇-7-α-羟化酶转基因小鼠维持胆固醇和脂蛋白稳态的能力完全阻止了动脉粥样硬化和胆结石的形成。这些数据确立了胆固醇-7-α-羟化酶在维持肝脏胆固醇稳态中的不可或缺的作用，因此，在胆结石和动脉粥样硬化形成的易感性中。
C57BL/6J mice are susceptible to atherosclerosis when fed a diet consisting of fat, cholesterol, and taurocholate. The susceptibility to diet-induced atherosclerosis is linked to a reduction in plasma high density lipoprotein (HDL). Diet-induced reduction of plasma HDL shows a physiological and a genetic correlation with repression of cholesterol-7-alpha-hydroxylase, the liver-specific enzyme that regulates the conversion of cholesterol into bile acids. To examine the hypothesis that the repression of cholesterol-7-alpha-hydroxylase is responsible for initiating the metabolic alterations leading to the formation of atherosclerosis and gallstones, we determined whether constitutive transgenic expression of cholesterol-7-alpha-hydroxylase in C57BL/6J mice would confer resistance to these 2 common human diseases. When fed the atherogenic diet, nontransgenic littermates, but not cholesterol-7-alpha-hydroxylase transgenic mice, accumulated cholesterol and cholesterol esters in their livers and plasma. Although the atherogenic diet caused a marked decrease in plasma HDL cholesterol in nontransgenic mice, HDL levels in transgenic mice remained relatively unchanged. Moreover, the ability of cholesterol-7-alpha-hydroxylase transgenic mice to maintain cholesterol and lipoprotein homeostasis completely prevented the formation of atherosclerosis and gallstones. These data establish the integral role that cholesterol-7-alpha-hydroxylase has in maintaining hepatic cholesterol homeostasis and, thus, in the susceptibility to the formation of gallstones and atherosclerosis.