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

脂蛋白脂酶（LPL）是水解富含TG的脂蛋白的关键酶。为了阐明LPL在脂质和脂蛋白代谢中的生理作用，我们制备了表达人LPL的转基因兔。在转基因兔肝素化后的血浆中，人LPL蛋白水平约为650 ng/ml，LPL酶活性的水平比非转基因同窝出生兔高4倍。转基因兔中LPL活性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显示，LPL转基因的表达增加导致极低密度脂蛋白水平和中密度脂蛋白水平显著降低。此外，转基因兔的LDL胆固醇水平显著升高。当转基因兔被喂食富含胆固醇的饮食时，转基因兔的高胆固醇血症和主动脉粥样硬化的发展被显著抑制。这些结果表明，系统性增加的LPL活性在所有类型的脂蛋白的代谢中起作用，从而在血浆甘油三酯水解和脂蛋白转化中起关键作用，并且LPL的过表达防止饮食诱导的高胆固醇血症和动脉粥样硬化。

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.