Ratliff Eric P, Gutierrez Alejandra, Davis Roger A
Heart Institute, BioScience Center, San Diego State University, CA 92182, USA.
J Lipid Res. 2006 Jul;47(7):1513-20. doi: 10.1194/jlr.M600120-JLR200. Epub 2006 Apr 11.
Constitutive expression of a cholesterol-7alpha-hydroxylase (CYP7A1) transgene in LDL receptor-deficient mice blocked the ability of a cholesterol-enriched diet to increase plasma levels of apolipoprotein B-containing lipoproteins. LDL receptor-deficient mice expressing the CYP7A1 transgene exhibited complete resistance to diet-induced hypercholesterolemia and to the accumulation of cholesterol in the liver. Hepatic mRNA expression of liver X receptor-inducible ABCG5 and ABCG8 was decreased in CYP7A1 transgenic, LDL receptor-deficient mice fed a cholesterol-enriched diet. Thus, increased biliary cholesterol excretion could not account for the maintenance of cholesterol homeostasis. CYP7A1 transgenic, LDL receptor-deficient mice fed the cholesterol-enriched diet exhibited decreased jejunal Niemann-Pick C1-Like 1 protein (NPC1L1) mRNA expression, an important mediator of intestinal cholesterol absorption. A taurocholate-enriched diet also decreased NPC1L1 mRNA expression in a farnesoid X receptor-independent manner. Reduced expression of NPC1L1 mRNA was associated with decreased cholesterol absorption ( approximately 20%; P < 0.05) exhibited by CYP7A1 transgenic LDL receptor-deficient mice fed the cholesterol-enriched diet. The combined data show that enhanced expression of CYP7A1 is an effective means to prevent the accumulation of cholesterol in the liver and of atherogenic apolipoprotein B-containing lipoproteins in plasma.
在低密度脂蛋白受体缺陷小鼠中组成型表达胆固醇7α-羟化酶（CYP7A1）转基因，可阻断高胆固醇饮食增加含载脂蛋白B脂蛋白血浆水平的能力。表达CYP7A1转基因的低密度脂蛋白受体缺陷小鼠对饮食诱导的高胆固醇血症以及肝脏中胆固醇的积累表现出完全抗性。在喂食高胆固醇饮食的CYP7A1转基因、低密度脂蛋白受体缺陷小鼠中，肝脏X受体诱导的ABCG5和ABCG8的肝脏mRNA表达降低。因此，胆汁胆固醇排泄增加并不能解释胆固醇稳态的维持。喂食高胆固醇饮食的CYP7A1转基因、低密度脂蛋白受体缺陷小鼠空肠中尼曼-匹克C1样1蛋白（NPC1L1）mRNA表达降低，NPC1L1是肠道胆固醇吸收的重要介质。富含牛磺胆酸盐的饮食也以法尼醇X受体非依赖的方式降低NPC1L1 mRNA表达。NPC1L1 mRNA表达降低与喂食高胆固醇饮食的CYP7A1转基因低密度脂蛋白受体缺陷小鼠胆固醇吸收减少（约20%；P<0.05）相关。综合数据表明，增强CYP7A1表达是预防肝脏中胆固醇积累以及血浆中致动脉粥样硬化的含载脂蛋白B脂蛋白积累的有效手段。
