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J. Biol. Chem., Vol. 276, Issue 43, 40071-40079, October 26, 2001

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Overexpression of Lipoprotein Lipase in Transgenic Rabbits Inhibits Diet-induced Hypercholesterolemia and Atherosclerosis^*

Jianglin Fan^§, Hiroyuki Unoki, Noriaki Kojima, Huijun Sun, Hiroaki Shimoyamada, Huayun Deng, Mitsuyo Okazaki^¶, Hisataka Shikama, Nobuhiro Yamada^**, and Teruo Watanabe

From the  Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan, the ^¶ Laboratory of Chemistry, College of Liberal Arts and Sciences, Tokyo Medical and Dental University, Chiba, 282-0827, Japan,  Yamanouchi Pharmaceutical Company, Tsukuba Research Institute, Tsukuba 305-8585, Japan, and the ^** Division of Metabolism and Endocrinology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba 305-8575, Japan

Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of TG-rich lipoproteins. To elucidate the physiological roles of LPL in lipid and lipoprotein metabolism, we generated transgenic rabbits expressing human LPL. In postheparinized 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 an 80% decrease in plasma triglycerides and a 59% decrease in high density lipoprotein-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.

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