van Vlijmen B J, van den Maagdenberg A M, Gijbels M J, van der Boom H, HogenEsch H, Frants R R, Hofker M H, Havekes L M
TNO Institute of Ageing and Vascular Research, Gaubius Laboratory, Leiden, The Netherlands.
J Clin Invest. 1994 Apr;93(4):1403-10. doi: 10.1172/JCI117117.
Apolipoprotein E3-Leiden (APOE3-Leiden) transgenic mice have been used to study the effect of different cholesterol-containing diets on the remnant lipoprotein levels and composition and on the possible concurrent development of atherosclerotic plaques. On high fat/cholesterol (HFC) diet, the high expressing lines 2 and 181 developed severe hypercholesterolemia (up to 40 and 60 mmol/liter, respectively), whereas triglyceride levels remained almost normal when compared with regular mouse diet. The addition of cholate increased the hypercholesterolemic effect of this diet. In lines 2 and 181, serum levels of apo E3-Leiden also increased dramatically upon cholesterol feeding (up to 107 and 300 mg/dl, respectively). In these high expressing APOE3-Leiden transgenic mice, the increase in both serum cholesterol and apo E3-Leiden occurred mainly in the VLDL/LDL-sized fractions, whereas a considerable increase in large, apo E-rich HDL particles also occurred. In contrast to the high expressing lines, the low expressing line 195 reacted only mildly upon HFC diet. On HFC diets, the high expresser APOE3-Leiden mice developed atherosclerotic lesions in the aortic arch, the descending aorta, and the carotid arteries, varying from fatty streaks containing foam cells to severe atherosclerotic plaques containing cholesterol crystals, fibrosis, and necrotic calcified tissue. Quantitative evaluation revealed that the atherogenesis is positively correlated with the serum level of cholesterol-rich VLDL/LDL particles. In conclusion, with APOE3-Leiden transgenic mice, factors can be studied that influence the metabolism of remnant VLDL and the development of atherosclerosis.
载脂蛋白E3-莱顿(APOE3-莱顿)转基因小鼠已被用于研究不同含胆固醇饮食对残余脂蛋白水平和组成以及动脉粥样硬化斑块可能同时发生发展的影响。在高脂肪/胆固醇(HFC)饮食条件下,高表达系2和181出现了严重的高胆固醇血症(分别高达40和60毫摩尔/升),而与常规小鼠饮食相比,甘油三酯水平几乎保持正常。添加胆酸盐增强了这种饮食的高胆固醇血症效应。在系2和181中,喂食胆固醇后血清中载脂蛋白E3-莱顿水平也显著升高(分别高达107和300毫克/分升)。在这些高表达APOE3-莱顿转基因小鼠中,血清胆固醇和载脂蛋白E3-莱顿的增加主要发生在极低密度脂蛋白/低密度脂蛋白大小的组分中,而富含载脂蛋白E的大高密度脂蛋白颗粒也有相当大的增加。与高表达系相比,低表达系195对HFC饮食的反应仅较为轻微。在HFC饮食条件下,高表达APOE3-莱顿小鼠在主动脉弓、降主动脉和颈动脉中出现了动脉粥样硬化病变,从含有泡沫细胞的脂肪条纹到含有胆固醇晶体、纤维化和坏死钙化组织的严重动脉粥样硬化斑块不等。定量评估显示,动脉粥样硬化的发生与富含胆固醇的极低密度脂蛋白/低密度脂蛋白颗粒的血清水平呈正相关。总之,利用APOE3-莱顿转基因小鼠,可以研究影响残余极低密度脂蛋白代谢和动脉粥样硬化发展的因素。