Overexpression of apolipoprotein E3 in transgenic rabbits causes combined hyperlipidemia by stimulating hepatic VLDL production and impairing VLDL lipolysis.
Overexpression of apolipoprotein E3 in transgenic rabbits causes combined hyperlipidemia by stimulating hepatic VLDL production and impairing VLDL lipolysis.
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DOI：
10.1161/01.atv.19.12.2952
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发表时间：
1999-12
期刊：
影响因子：
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通讯作者：
Yadong Huang;Z. Ji;W. Brecht;S. C. Rall;John Taylor;R. Mahley
中科院分区：
文献类型：
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作者：
Yadong Huang;Z. Ji;W. Brecht;S. C. Rall;John Taylor;R. Mahley
在表达低水平（20 mg/dL）apoE 3的转基因兔中研究了人载脂蛋白（apo）E3过表达对血浆胆固醇和甘油三酯代谢的不同影响。胆固醇水平随着apoE 3水平的增加而逐渐增加，而甘油三酯水平在apoE 3水平高达20 mg/dL时不受显著影响，但在apoE 3>20 mg/dL时显著增加。中等表达者有明显的高胆固醇血症（比非转基因者高3- 4倍），其特征是低密度脂蛋白（LDL）胆固醇增加，而低表达者的血浆胆固醇水平仅略有增加。中等表达者显示LDL增加18倍，但肝脏极低密度脂蛋白（VLDL）甘油三酯产生增加2倍，VLDL apoB增加8倍，VLDL脂解能力中度降低。然而，血浆VLDL清除率增加，可能是因为apoE 3含量增加。LDL的增加似乎是由于VLDL对LDL受体结合和摄取的竞争增强，导致LDL蓄积。apoE 3高表达者（>20 mg/dL）的混合型高脂血症的特征是LDL胆固醇增加19倍，但肝脏VLDL甘油三酯产生增加4倍，与血浆VLDL甘油三酯、胆固醇和apoB 100显著升高相关（分别为非转基因者的4倍、9倍和25倍）。来自高表达者的VLDL更富含apoE 3而显著缺乏apoC-II，这有助于>60%的VLDL脂解抑制。刺激的VLDL产生和受损的VLDL脂解的联合作用导致apoE 3高表达者血浆甘油三酯和VLDL浓度的增加。高脂血症apoE 3兔具有与家族性混合型高脂血症相似的表型，其中VLDL过量产生是主要生化特征。总体而言，apoE 3的表达升高似乎通过刺激肝脏VLDL产生、增强VLDL清除和抑制VLDL脂解来决定血浆脂质水平。因此，apoE的差异表达可能在相当窄的浓度范围内，在调节血浆胆固醇和甘油三酯水平中起关键作用，并且可能代表特定类型的高脂蛋白血症的重要决定因素。
The differential effects of overexpression of human apolipoprotein (apo) E3 on plasma cholesterol and triglyceride metabolism were investigated in transgenic rabbits expressing low (20 mg/dL) levels of apoE3. Cholesterol levels increased progressively with increasing levels of apoE3, whereas triglyceride levels were not significantly affected at apoE3 levels up to 20 mg/dL but were markedly increased at levels of apoE3 >20 mg/dL. The medium expressers had marked hypercholesterolemia (up to 3- to 4-fold over nontransgenics), characterized by an increase in low density lipoprotein (LDL) cholesterol, while the low expressers had only slightly increased plasma cholesterol levels. The medium expressers displayed an 18-fold increase in LDL but also had a 2-fold increase in hepatic very low density lipoprotein (VLDL) triglyceride production, an 8-fold increase in VLDL apoB, and a moderate decrease in the ability of the VLDL to be lipolyzed. However, plasma clearance of VLDL was increased, likely because of the increased apoE3 content. The increase in LDL appears to be due to an enhanced competition of VLDL for LDL receptor binding and uptake, resulting in the accumulation of LDL. The combined hyperlipidemia of the apoE3 high expressers (>20 mg/dL) was characterized by a 19-fold increase in LDL cholesterol but also a 4-fold increase in hepatic VLDL triglyceride production associated with a marked elevation of plasma VLDL triglycerides, cholesterol, and apoB100 (4-, 9-, and 25-fold over nontransgenics, respectively). The VLDL from the high expressers was much more enriched in apoE3 and markedly depleted in apoC-II, which contributed to a >60% inhibition of VLDL lipolysis. The combined effects of stimulated VLDL production and impaired VLDL lipolysis accounted for the increases in plasma triglyceride and VLDL concentrations in the apoE3 high expressers. The hyperlipidemic apoE3 rabbits have phenotypes similar to those of familial combined hyperlipidemia, in which VLDL overproduction is a major biochemical feature. Overall, elevated expression of apoE3 appears to determine plasma lipid levels by stimulating hepatic VLDL production, enhancing VLDL clearance, and inhibiting VLDL lipolysis. Thus, the differential expression of apoE may, within a rather narrow range of concentrations, play a critical role in modulating plasma cholesterol and triglyceride levels and may represent an important determinant of specific types of hyperlipoproteinemia.