Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human APOE*2
Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human APOE*2
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DOI：
10.1172/jci2673
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发表时间：
1998-07-01
影响因子：
15.9
通讯作者：
Maeda, N
中科院分区：
文献类型：
--
作者：
Sullivan, PM;Mezdour, H;Maeda, N
为了研究载脂蛋白E（apoE）在体内的同种型特异性作用，我们通过在胚胎干细胞中进行靶向基因置换，用人类APOE*2等位基因代替小鼠Apoe基因，产生小鼠。表达人apoE 2（2/2）的小鼠几乎具有III型高脂蛋白血症的所有特征。它们的血浆胆固醇和甘油三酯水平都是以相同方式制备的表达人apoE 3（3/3）的（血脂正常）小鼠的两倍至三倍。2/2小鼠在清除β-迁移VLDL颗粒方面明显缺陷，并且自发地发展动脉粥样硬化斑块，即使在常规饮食下也是如此。高脂肪和高胆固醇的致动脉粥样硬化饮食加剧了2/2小鼠中动脉粥样硬化和黄瘤的发展。因此，2/2和3/3小鼠之间的比较明确表明，apoE蛋白中的单个氨基酸差异（Arg 158 Cys）足以引起小鼠中的III型HLP和自发性动脉粥样硬化。
To study isoform-specific effects of apolipoprotein E (apoE) in vivo, we generated mice with a human APOE*2 allele in place of the mouse Apoe gene via targeted gene replacement in embryonic stem cells. Mice expressing human apoE2 (2/2) have virtually all the characteristics of type III hyperlipoproteinemia. Their plasma cholesterol and triglyceride levels are both twice to three times those in (normolipidemic) mice that are expressing human apoE3 (3/3) made in an identical manner. The 2/2 mice are markedly defective in clearing beta-migrating VLDL particles, and spontaneously develop atherosclerotic plaques, even on a regular diet. An atherogenic diet, high in fat and cholesterol, exacerbates development of atherosclerosis and xanthomas in the 2/2 mice. Thus, comparisons between the 2/2 and 3/3 mice unequivocally demonstrate that a single amino acid difference (Arg158 Cys) in the apoE protein is sufficient to cause type III HLP and spontaneous atherosclerosis in mice.