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Journal of Lipid Research, Vol. 44, 1216-1223, June 2003
Copyright © 2003 by Lipid Research, Inc.

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

Yosuke Ando^1,*, Tetsuya Shimizugawa, Shigehito Takeshita^*, Mitsuru Ono, Mitsuru Shimamura, Ryuta Koishi and Hidehiko Furukawa

^* Medicinal Safety Research Laboratories, Sankyo Co., Ltd., 717, Horikoshi, Fukuroi, Shizuoka 437-0065, Japan
Pharmacology & Molecular Biology Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
Biomedical Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan

¹ To whom correspondence should be addressed. e-mail: 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 modulator regulating VLDL triglyceride (TG) levels through the inhibition of lipoprotein lipase (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 postheparin 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.

Abbreviations: Angptl3, angiopoietin-like 3; apoEKO, homozygous for apoE gene knockout allele; apoEKO-hypl, homozygous for both apoE gene knockout and hypl allele; HL, hepatic lipase; hypl, a recessive mutation in Angptl3 gene causing hypolipidemia

Supplementary key words hypolipidemia • hyperlipidemia • triglyceride-rich lipoproteins • very low density lipoprotein • apolipoprotein B • lipoprotein lipase • hepatic lipase

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