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FUNCTIONAL ROLE OF LIPOPROTEIN LIPASE IN ATHEROGENESIS - A STUDY ON TRANSGENIC RABBITS EXPRESSING HUMAN LIPOPROTEIN LIPASE

脂蛋白脂肪酶在动脉粥样硬化形成中的功能作用——表达人脂蛋白脂肪酶的转基因兔的研究

基本信息

批准号：
11470048
负责人：
FAN Jianglin
金额：
$ 9.09万
依托单位：
UNVERSITY OF TSUKUBA
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of TG-rich lipoprbteins. To elucidate the physiological roles of LPL in lipid and lipoprotein metabolism, we generated transgenic rabbits expressing human LPL. In post-heparinized plasma of transgenic rabbits, the human LPL protein levels were about 650 ng/ml and LPL enzymatic activity was found at levels up to 4-fold greater than that in nontransgenic littermates. Increased LPL activity in transgenic rabbits was associated with as much as 80% decrease in plasma triglycerides and 59% decrease in HDL-cholesterol. Analysis of the lipoprotein density fractions revealed that increased expression of the LPL transgene resulted in a remarkable reduction in the level of very low density lipoproteins as well as in the level of intermediate density lipoproteins. In addition, LDL cholesterol levels in transgenic rabbits were significantly increased. When transgenic rabbits were fed a cholesterol-rich diet, the development of hypercholesterolemia and aortic atherosclerosis was dramatically suppressed in transgenic rabbits. These results demonstrate that systemically increased LPL activity functions in the metabolism of all classes of lipoproteins, thereby playing a crucial role in plasma triglyceride hydrolysis and lipoprotein conversion, and that overexpression of LPL protects against diet-induced hypercholesterolemia and atherosclerosis.

脂蛋白脂肪酶（LPL）是富含TG的脂蛋白水解的关键酶。为了阐明 LPL 在脂质和脂蛋白代谢中的生理作用，我们培育了表达人类 LPL 的转基因兔子。在转基因兔子的肝素化后血浆中，人LPL蛋白水平约为650ng/ml，并且发现LPL酶活性水平比非转基因同窝兔子高4倍。转基因兔子中 LPL 活性的增加与血浆甘油三酯降低 80% 和 HDL 胆固醇降低 59% 相关。脂蛋白密度级分的分析表明，LPL转基因表达的增加导致极低密度脂蛋白的水平以及中密度脂蛋白的水平显着降低。此外，转基因兔子的低密度脂蛋白胆固醇水平显着增加。当给转基因兔子喂食富含胆固醇的饮食时，转基因兔子中高胆固醇血症和主动脉粥样硬化的发展受到显着抑制。这些结果表明，系统性增加的 LPL 活性在所有类别脂蛋白的代谢中发挥作用，从而在血浆甘油三酯水解和脂蛋白转化中发挥关键作用，并且 LPL 的过度表达可以防止饮食诱导的高胆固醇血症和动脉粥样硬化。