J. Lipid Res.
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A more recent version of this article appeared on June 1, 2003 Originally published In Press as doi:10.1194/jlr.M300031-JLR200 on April 2, 2003

Papers In Press, published online ahead of print April 1, 2003
J. Lipid Res., doi:10.1194/jlr.M300031-JLR200
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Submitted on January 21, 2003
Revised on March 21, 2003
Accepted on March 21, 2003

A decreased expression of angiopoietin-like 3 is protective against atherosclerosis in apoE-deficient mice

Yosuke Ando, Tetsuya Shimizugawa, Shigehito Takeshita, Mitsuru Ono, Mitsuru Shimamura, Ryuta Koishi, and Hidehiko Furukawa

Medicinal Safety Research Laboratories, Sankyo Co., Ltd., Fukuroi, Shizuoka 437-0065

Corresponding Author: ysando{at}fuku.sankyo.co.jp

KK/Snk mice (previously KK/San) possessing a recessive mutation (hypl) of the angiopoietin-like 3 (Angptl3) gene homozygously exhibit a marked reduction of VLDL due to the decreased Angptl3 expression. Recently, we proposed that Angptl3 is a new class of lipid metabolism modulators regulating VLDL-TG levels through the inhibition of LPL activity. In this study, to elucidate the role of Angptl3 in atherogenesis, we investigated the effects of hypl mutation against hyperlipidemia and atherosclerosis in apolipoprotein E knockout (apoEKO) mice. ApoEKO mice with hypl mutation (apoEKO-hypl) exhibited a significant reduction of VLDL-TG, VLDL-cholesterol and plasma apoB levels compared with apoEKO mice. Hepatic VLDL-TG secretion was comparable between both apoE-deficient mice. Turnover studies revealed that the clearance of both 3H-TG-labeled and 125I-labeled VLDL was significantly enhanced in apoEKO-hypl mice. Postprandial plasma TG levels also decreased in apoEKO-hypl mice. Both LPL and hepatic lipase activities in the post-heparin plasma increased significantly in apoEKO-hypl mice, explaining the enhanced lipid metabolism. Furthermore, apoEKO-hypl mice developed 3-fold smaller atherogenic lesions in the aortic sinus compared with apoEKO mice. Taken together, the reduction of Angptl3 expression is protective against hyperlipidemia and atherosclerosis, even in the absence of apoE, owing to the enhanced catabolism and clearance of TG-rich lipoproteins.


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