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首页> 美国卫生研究院文献>other >Inhibition of intestinal absorption of cholesterol by ezetimibe or bile acids by SC-435 alters lipoprotein metabolism and extends the lifespan of SR-BI/apoE double knockout mice
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Inhibition of intestinal absorption of cholesterol by ezetimibe or bile acids by SC-435 alters lipoprotein metabolism and extends the lifespan of SR-BI/apoE double knockout mice

机译：依泽替米贝或胆汁酸通过SC-435抑制肠道对胆固醇的吸收可改变脂蛋白代谢并延长SR-BI / apoE双敲除小鼠的寿命

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SR-BI/apoE double knockout (dKO) mice exhibit many features of human coronary heart disease (CHD), including hypercholesterolemia, occlusive coronary atherosclerosis, cardiac hypertrophy, myocardial infarctions, cardiac dysfunction and premature death. Ezetimibe is a FDA-approved, intestinal cholesterol-absorption inhibitor that lowers plasma LDL cholesterol in humans and animals and inhibits aortic root atherosclerosis in apoE KO mice, but has not been proven to reduce CHD. Three week-ezetimibe treatment of dKO mice (0.005% (wt/wt) in standard chow administered from weaning) resulted in a 35% decrease in cholesterol in IDL/LDL-size lipoproteins, but not in VLDL- and HDL-size lipoproteins. Ezetimibe treatment significantly reduced aortic root (57%) and coronary arterial (68%) atherosclerosis, cardiomegaly (24%) and cardiac fibrosis (57%), and prolonged the lives of the mice (27%). This represents the first demonstration of beneficial effects of ezetimibe treatment on CHD. The dKO mice were similarly treated with SC-435 (0.01% (wt/wt)), an apical sodium-codependent bile acid transporter (ASBT) inhibitor, that blocks intestinal absorption of bile acids, lowers plasma cholesterol in animals, and reduces aortic root atherosclerosis in apoE KO mice. The effects of SC-435 treatment were similar to those of ezetimibe: 37% decrease in ILD/LDL-size lipoprotein cholesterol and 57% prolongation in median lifespan. Thus, inhibition of intestinal absorption of either cholesterol (ezetimibe) or bile acids (SC-435) significantly reduced plasma IDL/LDL-size lipoprotein cholesterol levels and improved survival of SR-BI/apoE dKO mice. The SR-BI/apoE dKO murine model of atherosclerotic occlusive, arterial CHD appears to provide a useful system to evaluate compounds that modulate cholesterol homeostasis and atherosclerosis.
机译：SR-BI / apoE双敲除（dKO）小鼠表现出人类冠心病（CHD）的许多特征，包括高胆固醇血症，闭塞性冠状动脉粥样硬化，心脏肥大，心肌梗塞，心脏功能障碍和过早死亡。依泽替米贝是经FDA批准的肠道胆固醇吸收抑制剂，可降低人和动物的血浆LDL胆固醇，并抑制apoE KO小鼠的主动脉根动脉粥样硬化，但尚未被证明能降低CHD。对dKO小鼠进行三周的依泽替米贝治疗（断奶后给予标准食物的0.005％（wt / wt））使IDL / LDL大小的脂蛋白中的胆固醇降低了35％，但VLDL和HDL大小的脂蛋白中没有。依泽替米贝治疗显着减少了主动脉根（57％）和冠状动脉（68％）的动脉粥样硬化，心脏肥大（24％）和心脏纤维化（57％），并延长了小鼠的寿命（27％）。这代表了依泽替米贝治疗对冠心病的有益作用的首次证明。 dKO小鼠也同样接受了根尖钠依赖性胆汁酸转运蛋白（ASBT）抑制剂SC-435（0.01％（wt / wt））的治疗，该抑制剂可阻止肠道对胆汁酸的吸收，降低动物血浆胆固醇并减少主动脉apoE KO小鼠的根动脉粥样硬化。 SC-435的治疗效果与依泽替米贝相似：ILD / LDL大小的脂蛋白胆固醇降低37％，中位寿命延长57％。因此，抑制肠道吸收胆固醇（依泽替米贝）或胆汁酸（SC-435）可显着降低血浆IDL / LDL大小的脂蛋白胆固醇水平，并改善SR-BI / apoE dKO小鼠的存活率。 SR-BI / apoE dKO小鼠动脉粥样硬化闭塞性冠心病模型似乎为评估可调节胆固醇稳态和动脉粥样硬化的化合物提供了有用的系统。

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