Knouff C, Hinsdale M E, Mezdour H, Altenburg M K, Watanabe M, Quarfordt S H, Sullivan P M, Maeda N
Department of Pathology and Laboratory Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599-7525, USA.
J Clin Invest. 1999 Jun;103(11):1579-86. doi: 10.1172/JCI6172.
We have generated mice expressing the human apo E4 isoform in place of the endogenous murine apo E protein and have compared them with mice expressing the human apo E3 isoform. Plasma lipid and apolipoprotein levels in the mice expressing only the apo E4 isoform (4/4) did not differ significantly from those in mice with the apo E3 isoform (3/3) on chow and were equally elevated in response to increased lipid and cholesterol in their diet. However, on all diets tested, the 4/4 mice had approximately twice the amount of cholesterol, apo E, and apo B-48 in their VLDL as did 3/3 mice. The 4/4 VLDL competed with human LDL for binding to the human LDL receptor slightly better than 3/3 VLDL, but the VLDL clearance rate in 4/4 mice was half that in 3/3 mice. On an atherogenic diet, there was a trend toward greater atherosclerotic plaque size in 4/4 mice compared with 3/3 mice. These data, together with our earlier observations in wild-type and human APOE*2-replacement mice, demonstrate a direct and highly significant correlation between VLDL clearance rate and mean atherosclerotic plaque size. Therefore, differences solely in apo E protein structure are sufficient to cause alterations in VLDL residence time and atherosclerosis risk in mice.
我们培育出了用人类载脂蛋白E4亚型替代内源性小鼠载脂蛋白E蛋白的小鼠，并将它们与表达人类载脂蛋白E3亚型的小鼠进行了比较。仅表达载脂蛋白E4亚型（4/4）的小鼠的血浆脂质和载脂蛋白水平与食用普通食物的载脂蛋白E3亚型（3/3）小鼠相比，没有显著差异，并且在饮食中脂质和胆固醇增加时同样升高。然而，在所有测试的饮食中，4/4小鼠极低密度脂蛋白（VLDL）中的胆固醇、载脂蛋白E和载脂蛋白B-48含量大约是3/3小鼠的两倍。4/4小鼠的VLDL与人类低密度脂蛋白（LDL）竞争结合人类LDL受体的能力略优于3/3小鼠的VLDL，但4/4小鼠的VLDL清除率是3/3小鼠的一半。在致动脉粥样化饮食条件下，与3/3小鼠相比，4/4小鼠的动脉粥样硬化斑块大小有增大的趋势。这些数据，连同我们早期在野生型和人类APOE*2替代小鼠中的观察结果，证明了VLDL清除率与平均动脉粥样硬化斑块大小之间存在直接且高度显著的相关性。因此，仅载脂蛋白E蛋白结构的差异就足以导致小鼠VLDL停留时间和动脉粥样硬化风险的改变。
