Huang Y, Schwendner S W, Rall S C, Mahley R W
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94141-9100, USA.
J Biol Chem. 1996 Nov 15;271(46):29146-51. doi: 10.1074/jbc.271.46.29146.
Transgenic mice were produced that expressed different plasma levels (3-60 mg/dl) of human apolipoprotein (apo) E2(Arg158 --> Cys), which is associated with the recessive form of human type III hyperlipoproteinemia (HLP). In transgenic mice fed a normal chow diet, low levels of apoE2 (<10 mg/dl) did not significantly alter the lipid phenotype. Mice expressing intermediate levels of apoE2 (10-30 mg/dl) had a 50-60% decrease in total cholesterol compared with nontransgenic mice. The decrease was almost entirely due to a reduction in high density lipoprotein (HDL) cholesterol. These hypolipidemic apoE2 transgenic mice were cross-bred with human apoB transgenic mice, which have increased total cholesterol and low density lipoprotein (LDL) levels. The apoE2/apoB double transgenics revealed that expression of apoE2 on the background of human apoB overexpression resulted in a substantial decrease in LDL and HDL cholesterol and a corresponding accumulation of very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL). Thus, the double transgenics had a lipid phenotype resembling human type III HLP. In contrast to the hypolipidemic mice, mice expressing high levels of apoE2 (>50 mg/dl) were hyperlipidemic. The VLDL and IDL in these mice were significantly increased and cholesterol-enriched and had other characteristics of remnant lipoproteins. Upon agarose gel electrophoresis, the VLDL and IDL from both intermediate and high expressers migrated more slowly toward the beta position compared with the pre-beta-mobility of nontransgenic mouse VLDL and IDL. Thus, depending on plasma apoE2 levels, the expression of human apoE2 in the transgenic mice leads to either a hypolipidemic or hyperlipidemic phenotype. This animal model provides the opportunity to study the factors that cause hypolipidemia and those that precipitate the hyperlipidemia of type III HLP.
构建了转基因小鼠，其表达不同血浆水平（3 - 60毫克/分升）的人载脂蛋白（apo）E2（Arg158→Cys），该蛋白与人类III型高脂蛋白血症（HLP）的隐性形式相关。在喂食正常饲料的转基因小鼠中，低水平的apoE2（<10毫克/分升）并未显著改变脂质表型。表达中等水平apoE2（10 - 30毫克/分升）的小鼠与非转基因小鼠相比，总胆固醇降低了50 - 60%。这种降低几乎完全是由于高密度脂蛋白（HDL）胆固醇的减少。这些低脂血症的apoE2转基因小鼠与人类apoB转基因小鼠杂交，后者的总胆固醇和低密度脂蛋白（LDL）水平升高。apoE2/apoB双转基因小鼠显示，在人类apoB过表达的背景下，apoE2的表达导致LDL和HDL胆固醇大幅降低，以及极低密度脂蛋白（VLDL）和中间密度脂蛋白（IDL）相应积累。因此，双转基因小鼠具有类似于人类III型HLP的脂质表型。与低脂血症小鼠相反，表达高水平apoE2（>50毫克/分升）的小鼠出现高脂血症。这些小鼠的VLDL和IDL显著增加且富含胆固醇，并具有残余脂蛋白的其他特征。在琼脂糖凝胶电泳中，与非转基因小鼠VLDL和IDL的前β迁移率相比，中等和高表达者的VLDL和IDL向β位置迁移得更慢。因此，根据血浆apoE2水平，转基因小鼠中人类apoE2的表达会导致低脂血症或高脂血症表型。这个动物模型为研究导致低脂血症的因素以及引发III型HLP高脂血症的因素提供了机会。
