Mortimer B C, Redgrave T G, Spangler E A, Verstuyft J G, Rubin E M
Department of Physiology, University of Western Australia, Nedlands.
Arterioscler Thromb. 1994 Oct;14(10):1542-52. doi: 10.1161/01.atv.14.10.1542.
Apolipoprotein (apo) E is a ligand for lipoprotein receptors and mediates the cellular uptake of several different lipoproteins. Human apoE occurs in three allelic forms designated E2, E3, and E4. The E2 isoform is associated with changes in lipoprotein metabolism, and the E4 isoform is associated with Alzheimer's disease and an increased risk of coronary heart disease. In this study transgenic mice were generated to assess the effect of a sustained increase in plasma apoE4 concentration. The transgenic animals had three- to sixfold increases in total plasma apoE, associated primarily with the non-high-density lipoprotein (HDL) fractions of plasma lipoproteins. In response to an atherogenic diet the transgenic mice developed hypercholesterolemia similar to that in nontransgenic mice but did not experience the decrease in HDL cholesterol normally observed in this strain of C57BL/6 mice. The rate of plasma clearance of a lipid emulsion mimicking lymph chylomicrons was measured in transgenic mice expressing the human apoE4 gene and compared with the clearance rate in nontransgenic control animals. In animals fed a low-fat diet the emulsion lipids were cleared significantly more rapidly from the plasma of transgenic than control mice. In animals adapted to a high-fat diet, the clearance of chylomicron remnants was slowed markedly in both transgenic and control mice and was not significantly accelerated in transgenic compared with control animals. We also investigated the effect of increasing the plasma concentration of apoE4 on the progression of atherosclerotic heart disease.(ABSTRACT TRUNCATED AT 250 WORDS)
载脂蛋白（apo）E是脂蛋白受体的配体，介导几种不同脂蛋白的细胞摄取。人类载脂蛋白E有三种等位基因形式，分别命名为E2、E3和E4。E2同工型与脂蛋白代谢变化有关，E4同工型与阿尔茨海默病和冠心病风险增加有关。在本研究中，通过基因工程培育了转基因小鼠，以评估血浆载脂蛋白E4浓度持续升高的影响。转基因动物的血浆总载脂蛋白E增加了三到六倍，主要与血浆脂蛋白的非高密度脂蛋白（HDL）部分有关。在接受致动脉粥样硬化饮食后，转基因小鼠出现了与非转基因小鼠类似的高胆固醇血症，但并未出现该品系C57BL/6小鼠通常观察到的高密度脂蛋白胆固醇降低情况。在表达人类载脂蛋白E4基因的转基因小鼠中，测定了模拟淋巴乳糜微粒的脂质乳剂的血浆清除率，并与非转基因对照动物的清除率进行了比较。在喂食低脂饮食的动物中，转基因小鼠血浆中乳剂脂质的清除速度明显快于对照小鼠。在适应高脂饮食的动物中，转基因小鼠和对照小鼠的乳糜微粒残粒清除均明显减慢，与对照动物相比，转基因小鼠的清除速度没有显著加快。我们还研究了提高血浆载脂蛋白E4浓度对动脉粥样硬化性心脏病进展的影响。（摘要截短于250字）
