Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia
Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia
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DOI：
10.1074/jbc.273.41.26388
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发表时间：
1998-10-09
影响因子：
4.8
通讯作者：
Mahley, RW
中科院分区：
文献类型：
--
作者：
Huang, YD;Liu, XQ;Mahley, RW
高甘油三酯血症(HTG)是一种常见的人类脂代谢紊乱，通常由遗传因素引起，其分子机制尚不清楚。在研究载脂蛋白E对富含甘油三酯的脂蛋白代谢的影响时，我们发现，在缺乏内源性小鼠载脂蛋白E的转基因小鼠中，表达高水平的人载脂蛋白E会引起HTG。这些转基因小鼠的血浆甘油三酯水平是非转基因小鼠的3倍，高密度脂蛋白(VLDL)水平高于非转基因小鼠，高密度脂蛋白(HDLP)水平低于非转基因小鼠，去除apoE3过表达小鼠中的一个或两个低密度脂蛋白受体等位基因会导致严重的HTG(是非转基因小鼠的8-11倍)，增加VLDL并降低低密度脂蛋白和高密度脂蛋白，而apoE3丰富的VLDL在apoC-II中显著耗尽。至少有两种机制可以解释HTG与apoE3的过度表达有关：刺激的VLDL甘油三酯的产生和VLDL的脂解受损。服用HTG的apoE3小鼠肝脏VLDL甘油三酯的生成增加了50%。此外，在培养的肝细胞(MCA-RH7777细胞)中apoE(E2、E3或E4)的过度表达与VLDL的分泌呈正相关。然而，与apoE3过度表达相关的HTG只能部分地用VLDL的过度产生来解释，因为脂蛋白脂酶介导的VLDL脂解也根据apoE3的水平而降低20%-86%，这很可能是通过置换或掩盖颗粒上的apoC-II来实现的。在受试者中，HTG与升高的极低密度脂蛋白甘油三酯、血浆和极低密度脂蛋白载脂蛋白E水平呈正相关。而血浆和VLDL载脂蛋白E水平与载脂蛋白C-II水平和脂蛋白脂酶介导的极低密度脂蛋白脂解呈负相关。因此，apoE的最佳表达对于富含甘油三酯的脂蛋白的正常代谢至关重要，apoE的过度表达和/或积累可能通过刺激VLDL甘油三酯的产生和通过损害VLDL脂解而促进ATG。ApoE3过表达的小鼠将有助于研究这种疾病的病理生理学。
The molecular mechanisms of hypertriglyceridemia (HTG), a common lipid metabolic disorder in humans, often of genetic origin, are not well understood. In studying the effect of apolipoprotein (apo) E on the metabolism of triglyceride-rich lipoproteins, we found that expressing high plasma levels of human apoE3 in transgenic mice lacking endogenous mouse apoE caused HTG. These transgenic animals had 3-fold higher plasma triglyceride levels, higher very law density lipoproteins (VLDL), and lower high density lipoproteins than did non-transgenics, Removing one or both low density lipoprotein receptor alleles in the apoE3-overexpressing mice caused severe HTG (8-11-fold over nontransgenics) and increased VLDL and decreased low and high density lipoproteins, and apoE3-enriched VLDL were markedly depleted in apoC-II. At least two mechanisms could explain HTG associated with apoE3 overexpression: stimulated VLDL triglyceride production and impaired VLDL lipolysis. The apoE3 mice with HTG had a 50% increase in hepatic VLDL triglyceride production. Furthermore, overexpression of apoE (E2, E3, or E4) in cultured hepatocytes (McA-RH7777 cells) correlated positively with secretion of VLDL into the medium. However, apoE3 overexpression-associated HTG was only partially explained by VLDL overproduction, as lipoprotein lipase-mediated VLDL lipolysis was also decreased 20-86% depending on apoE3 levels, most likely by displacing or masking apoC-II on the particles. In human subjects, HTG correlated positively with increased VLDL triglyceride and plasma and VLDL apoE levels. However, plasma and VLDL apoE correlated negatively with VLDL apoC-II levels and lipoprotein lipase-mediated VLDL lipolysis. Thus, optimal expression of apoE is crucial for normal metabolism of triglyceride-rich lipoproteins, and overexpression and/or accumulation of apoE may contribute to ATG by stimulating VLDL triglyceride production and by impairing VLDL lipolysis. The apoE3-overexpressing mice will be useful for studying the pathophysiology of this disorder.