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J. Biol. Chem., Vol. 279, Issue 9, 7521-7529, February 27, 2004

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Overexpression of Lipoprotein Lipase in Transgenic Watanabe Heritable Hyperlipidemic Rabbits Improves Hyperlipidemia and Obesity^*

Tomonari Koike, Jingyan Liang, Xiaofei Wang, Tomonaga Ichikawa, Masashi Shiomi, George Liu¶, Huijun Sun||, Shuji Kitajima**, Masatoshi Morimoto**, Teruo Watanabe**, Nobuhiro Yamada, and Jianglin Fan

From the Cardiovascular Disease Laboratory, Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan, the Institute for Experimental Animals, Kobe University School of Medicine, Kobe 650-0017, Japan, the ^¶Institute of Cardiovascular Sciences, Peking University, Beijing 100083, China, the ^||Department of Pharmacology, Dalian Medical University, Dalian 116027, China, ^**Saga University School of Medicine, Saga 849-8502, Japan, and the Division of Metabolism and Endocrinology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba 305-8575, Japan

Lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of the triglyceride-rich lipoproteins and plays a critical role in lipoprotein and free fatty acid metabolism. Genetic manipulation of LPL may be beneficial in the treatment of hypertriglyceridemias, but it is unknown whether increased LPL activity may be effective in lowering plasma cholesterol and improving insulin resistance in familial hypercholesterolemic patients. To test the hypothesis that stimulation of LPL expression may be used as an adjunctive therapy for treatment of homozygous familial hypercholesterolemia, we have generated transgenic (Tg) Watanabe heritable hyperlipidemic (WHHL) rabbits that overexpress the human LPL transgene and compared their plasma lipid levels, glucose metabolism, and body fat accumulation with those of non-Tg WHHL rabbits. Overexpression of LPL dramatically ameliorated hypertriglyceridemia in Tg WHHL rabbits. Furthermore, increased LPL activity in male Tg WHHL rabbits also corrected hypercholesterolemia (544 ± 52 in non-Tg versus 227 ± 29 mg/dl in Tg, p < 0.01) and reduced body fat accumulation by 61% (323 ± 27 in non-Tg versus 125 ± 21ginTg, p < 0.01), suggesting that LPL plays an important role in mediating plasma cholesterol homeostasis and adipose accumulation. In addition, overexpression of LPL significantly suppressed high fat diet-induced obesity and insulin resistance in Tg WHHL rabbits. These results imply that systemic elevation of LPL expression may be potentially useful for the treatment of hyperlipidemias, obesity, and insulin resistance.

Received for publication, October 21, 2003

^* This work was supported in part by grants-in-aid for scientific research from the Ministry of Education, Science, and Culture of Japan, by Grant JSPS-RFTF 96I00202 from the Japan Society for the Promotion of Sciences, by the Mochida Memorial Foundation and Uehara Memorial Foundation, and by a grant from the Center for Tsukuba Advanced Research Alliance at the University of Tsukuba. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 81-298-53-3165; Fax: 81-298-53-3262; E-mail: j-lfan{at}md.tsukuba.ac.jp.

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