Purcell-Huynh D A, Farese R V, Johnson D F, Flynn L M, Pierotti V, Newland D L, Linton M F, Sanan D A, Young S G
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94141-9100, USA.
J Clin Invest. 1995 May;95(5):2246-57. doi: 10.1172/JCI117915.
We previously generated transgenic mice expressing human apolipoprotein (apo-) B and demonstrated that the plasma of chow-fed transgenic animals contained markedly increased amounts of LDL (Linton, M. F., R. V. Farese, Jr., G. Chiesa, D. S. Grass, P. Chin, R. E. Hammer, H. H. Hobbs, and S. G. Young 1992. J. Clin. Invest. 92:3029-3037). In this study, we fed groups of transgenic and nontransgenic mice either a chow diet or a diet high in fat (16%) and cholesterol (1.25%). Lipid and lipoprotein levels were assessed, and after 18 wk of diet, the extent of aortic atherosclerotic lesions in each group of animals was quantified. Compared with the female transgenic mice on the chow diet, female transgenic mice on the high-fat diet had higher plasma levels of cholesterol (312 +/- 17 vs 144 +/- 7 mg/dl; P < 0.0001) and human apo-B (120 +/- 8 vs 84 +/- 3 mg/dl; P < 0.0001). The higher human apo-B levels were due to increased plasma levels of human apo-B48; the human apo-B100 levels did not differ in animals on the two diets. In mice on the high-fat diet, most of the human apo-B48 and apo-B100 was found in LDL-sized particles. Compared with nontransgenic mice on the high-fat diet, the transgenic animals on the high-fat diet had significantly increased levels of total cholesterol (312 +/- 17 vs 230 +/- 19 mg/dl; P < 0.0001) and non-HDL cholesterol (283 +/- 17 vs 193 +/- 19 mg/dl; P < 0.0001). The extent of atherosclerotic lesion development within the ascending aorta was quantified by measuring total lesion area in 60 progressive sections, using computer-assisted image analysis. Neither the chow-fed transgenic mice nor the chow-fed nontransgenic mice had significant atherosclerotic lesions. Nontransgenic animals on the high-fat diet had relatively small atherosclerotic lesions (< 15,000 microns 2/section), almost all of which were confined to the proximal 400 microns of the aorta near the aortic valve. In contrast, transgenic animals on the high-fat diet had extensive atherosclerotic lesions (> 160,000 microns 2/section) that were widely distributed throughout the proximal 1,200 microns of the aorta. Thus, human apo-B expression, in the setting of a diet rich in fats, causes severe atherosclerosis in mice.
我们之前培育出了表达人类载脂蛋白（apo-）B的转基因小鼠，并证明以普通饲料喂养的转基因动物血浆中低密度脂蛋白（LDL）含量显著增加（林顿，M.F.，R.V.法雷斯，Jr.，G.基耶萨，D.S.格拉斯，P.钦，R.E.哈默，H.H.霍布斯，以及S.G.扬，1992年。《临床研究杂志》92:3029 - 3037）。在本研究中，我们给几组转基因和非转基因小鼠分别喂食普通饲料或高脂肪（16%）高胆固醇（1.25%）饲料。评估脂质和脂蛋白水平，在饮食18周后，对每组动物主动脉粥样硬化病变程度进行量化。与喂食普通饲料的雌性转基因小鼠相比，喂食高脂肪饲料的雌性转基因小鼠血浆胆固醇水平更高（312±17 vs 144±7mg/dl；P<0.0001），人类apo-B水平也更高（120±8 vs 84±3mg/dl；P<0.0001）。人类apo-B水平升高是由于血浆中人类apo-B48水平增加；两种饮食的动物中人类apo-B100水平没有差异。在喂食高脂肪饲料的小鼠中，大部分人类apo-B48和apo-B100存在于LDL大小的颗粒中。与喂食高脂肪饲料的非转基因小鼠相比，喂食高脂肪饲料的转基因动物总胆固醇水平显著升高（312±17 vs 230±19mg/dl；P<0.0001），非HDL胆固醇水平也显著升高（283±17 vs 193±19mg/dl；P<0.0001）。通过计算机辅助图像分析测量60个连续切片中的总病变面积，对升主动脉内动脉粥样硬化病变发展程度进行量化。喂食普通饲料的转基因小鼠和非转基因小鼠均无明显的动脉粥样硬化病变。喂食高脂肪饲料的非转基因动物有相对较小的动脉粥样硬化病变（<15,000平方微米/切片），几乎所有病变都局限于主动脉瓣附近主动脉近端400微米处。相比之下，喂食高脂肪饲料的转基因动物有广泛的动脉粥样硬化病变（>160,000平方微米/切片），广泛分布于主动脉近端1200微米处。因此，在富含脂肪的饮食环境下，人类apo-B的表达会导致小鼠发生严重的动脉粥样硬化。
