Ichikawa Tomonaga, Kitajima Shuji, Liang Jingyan, Koike Tomonari, Wang Xiaofei, Sun Huijun, Okazaki Mitsuyo, Morimoto Masatoshi, Shikama Hisataka, Watanabe Teruo, Yamada Nobuhiro, Fan Jianglin
Cardiovascular Disease Laboratory, Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan.
Lab Invest. 2004 Jun;84(6):715-26. doi: 10.1038/labinvest.3700102.
Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. Previous studies using transgenic mice and rabbits have demonstrated that high level of LPL activity in adipose and skeletal muscle protects against diet-induced hypercholesterolemia and subsequently prevents aortic atherosclerosis. However, it is unknown, per se, whether increased LPL activity itself is antiatherogenic, or whether the antiatherogenic effect of LPL is dependent upon the LPL lipid-lowering effect. To address this issue, we fed LPL transgenic and littermate rabbits diets containing different amounts of cholesterol (0.3-0.6%) adjusted to maintain their plasma cholesterol concentrations at similarly high levels for 16 weeks. We analyzed their lipoprotein profiles and compared their susceptibility to atherosclerosis. The results showed that the overexpression of LPL in transgenic rabbits reduced remnant lipoproteins (beta-VLDL, d<1.006 g/ml) but concomitantly led to a significant increase of the large (d=1.02-1.04 g/ml) and small LDLs (d=1.04-1.06 g/ml) compared to the amounts in control rabbits. Furthermore, we found that with equally high hypercholesterolemia, transgenic rabbits developed 1.8-fold more extensive aortic atherosclerosis than control rabbits. To examine the hypothesis that altered lipoprotein profiles may be responsible for the enhanced atherosclerosis in transgenic rabbits, we studied the atherogenic properties of apoB-containing lipoproteins in vitro. These studies revealed that small-sized LDLs of transgenic rabbits were more susceptible to copper-induced oxidation and had higher affinity to biglycan than large remnant lipoproteins. We conclude, therefore, that LPL exerts a dual function in terms of its atherogenicity, namely antiatherogenicity, through enhancing receptor-mediated remnant lipoprotein catabolism and proatherogenicity via the generation of a large amount of small-sized LDLs. At an equal atherogenic-cholesterol level, small and dense LDLs are more atherogenic than large remnant lipoproteins.
脂蛋白脂肪酶（LPL）是富含甘油三酯脂蛋白水解过程中的关键酶。以往利用转基因小鼠和兔子开展的研究表明，脂肪组织和骨骼肌中高水平的LPL活性可预防饮食诱导的高胆固醇血症，并随后预防主动脉粥样硬化。然而，就其本身而言，尚不清楚LPL活性增加本身是否具有抗动脉粥样硬化作用，或者LPL的抗动脉粥样硬化作用是否依赖于其降低血脂的作用。为解决这一问题，我们给LPL转基因兔子及其同窝出生的对照兔子喂食含有不同胆固醇量（0.3 - 0.6%）的饲料，调整饲料以使其血浆胆固醇浓度在16周内维持在相似的高水平。我们分析了它们的脂蛋白谱，并比较了它们对动脉粥样硬化的易感性。结果显示，与对照兔子相比，转基因兔子中LPL的过表达降低了残余脂蛋白（β-VLDL，d<1.006 g/ml），但同时导致大颗粒（d = 1.02 - 1.04 g/ml）和小颗粒低密度脂蛋白（d = 1.04 - 1.06 g/ml）显著增加。此外，我们发现，在同样高度的高胆固醇血症情况下，转基因兔子发生的主动脉粥样硬化程度比对照兔子高1.8倍。为检验脂蛋白谱改变可能是转基因兔子动脉粥样硬化加重原因这一假说，我们在体外研究了含载脂蛋白B脂蛋白的致动脉粥样硬化特性。这些研究表明，转基因兔子的小颗粒低密度脂蛋白比大颗粒残余脂蛋白更容易受到铜诱导的氧化作用影响，并且与双糖链蛋白聚糖的亲和力更高。因此，我们得出结论，就其致动脉粥样硬化性而言，LPL发挥双重作用，即通过增强受体介导的残余脂蛋白分解代谢具有抗动脉粥样硬化作用，以及通过产生大量小颗粒低密度脂蛋白具有促动脉粥样硬化作用。在同等致动脉粥样硬化胆固醇水平下，小而密的低密度脂蛋白比大颗粒残余脂蛋白更具致动脉粥样硬化性。
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