Huang Y, Rall S C, Mahley R W
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, USA.
Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2817-24. doi: 10.1161/01.atv.17.11.2817.
Several factors are hypothesized to precipitate or exacerbate type III hyperlipoproteinemia (HLP) in humans. Among such factors are those that directly overload remnant lipoprotein production or disrupt removal pathways, including an increased ratio of apolipoprotein (apo) E2 to normal apoE, overproduction of apoB-containing lipoproteins, and decreased LDL receptor activity. Hypolipidemic apoE2-transgenic mice bred onto an apoE-null background had dramatically higher plasma total cholesterol (192 +/- 26 mg/dL for males, 203 +/- 40 mg/dL for females) and triglyceride (295 +/- 51 mg/dL for males, 277 +/- 58 mg/dL for females) levels than apoE2 mice with endogenous mouse apoE. Thus, eliminating normal apoE in the presence of apoE2 (thereby increasing the relative abundance of the defective ligand) can convert a hypolipidemic to a hyperlipidemic phenotype. Hypolipidemic apoE2 transgenic mice overexpressing human apoB had moderate remnant accumulation compared with apoE2-only or apoB-only transgenic mice, indicating that overproduction of apoB-containing lipoproteins in the presence of apoE2 can augment remnant production. Hypolipidemic apoE2 transgenic mice bred-onto an LDL receptor-null background had markedly higher plasma total cholesterol (288 +/- 51 mg/dL for males, 298 +/- 73 mg/dL for females) and triglyceride (356 +/- 72 mg/dL for males, 317 +/- 88 mg/dL for females) levels than apoE2-only mice, and remnant accumulation increased even in apoE2 mice with a heterozygous LDL receptor-knockout background (compared with apoE2-only mice), suggesting that reducing or eliminating a major receptor-mediated remnant-removal pathway in the presence of apoE2 can also precipitate a hyperlipidemic phenotype. In all cases where either lipoprotein remnant production or removal pathways were severely stressed, increased remnant accumulation was apparent. As judged by the chemical characteristics of the remnant lipoproteins, the lipoprotein phenotype was quite similar to that of human type III HLP, especially in the apoE2-expressing mice with no endogenous apoE or LDL receptors, and thus these mice represent improved models of the disorder.
有几种因素被认为会引发或加剧人类的III型高脂蛋白血症（HLP）。这些因素包括直接使残余脂蛋白生成过载或破坏清除途径的因素，其中有载脂蛋白（apo）E2与正常apoE的比例增加、含apoB脂蛋白的过量生成以及低密度脂蛋白受体活性降低。在apoE基因敲除背景下培育的低脂血症apoE2转基因小鼠，其血浆总胆固醇水平（雄性为192±26mg/dL，雌性为203±40mg/dL）和甘油三酯水平（雄性为295±51mg/dL，雌性为277±58mg/dL）显著高于具有内源性小鼠apoE的apoE2小鼠。因此，在存在apoE2的情况下消除正常apoE（从而增加缺陷配体的相对丰度）可使低脂血症表型转变为高脂血症表型。与仅表达apoE2或仅表达apoB的转基因小鼠相比，过度表达人apoB的低脂血症apoE2转基因小鼠有中度的残余物蓄积，这表明在apoE2存在的情况下含apoB脂蛋白的过量生成可增加残余物的产生。在低密度脂蛋白受体基因敲除背景下培育的低脂血症apoE2转基因小鼠，其血浆总胆固醇水平（雄性为288±51mg/dL，雌性为298±73mg/dL）和甘油三酯水平（雄性为356±72mg/dL，雌性为317±88mg/dL）明显高于仅表达apoE2的小鼠，并且即使在具有杂合低密度脂蛋白受体敲除背景的apoE2小鼠中（与仅表达apoE2的小鼠相比）残余物蓄积也增加了，这表明在apoE2存在的情况下减少或消除主要的受体介导的残余物清除途径也可引发高脂血症表型。在脂蛋白残余物生成或清除途径受到严重影响的所有情况下，残余物蓄积增加都很明显。根据残余脂蛋白的化学特性判断，脂蛋白表型与人类III型HLP非常相似，尤其是在没有内源性apoE或低密度脂蛋白受体的表达apoE2的小鼠中，因此这些小鼠代表了该疾病更好的模型。
