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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:366.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Angiopoietin-Like Protein3 Regulates Plasma HDL Cholesterol Through Suppression of Endothelial Lipase

Mitsuru Shimamura; Morihiro Matsuda; Hiroaki Yasumo; Mitsuyo Okazaki; Kazunori Fujimoto; Keita Kono; Tetsuya Shimizugawa; Yosuke Ando; Ryuta Koishi; Takafumi Kohama; Naohiko Sakai; Kazuaki Kotani; Ryutaro Komuro; Tatsuo Ishida; Kenichi Hirata; Shizuya Yamashita; Hidehiko Furukawa; Iichiro Shimomura

From the Department of Medicine and Pathophysiology (M.S., M.M., I.S.), Graduate School of Frontier Bioscience; Department of Metabolic Medicine (M.M., N.S., R.Komuro, I.S.), Department of Cardiovascular Medicine (S.Y.), Graduate School of Medicine, Osaka University, Osaka, Japan; Biomedical Research Laboratories (M.S., H.Y., R.Koishi, T.K., H.F.), Pharmacology and Molecular Biology Research Laboratories (K.Kono, T.S., T.K.), Sankyo Co. Ltd., Tokyo, Japan; Medical Safety Research Laboratories (K.F., Y.A.), Sankyo Co. Ltd., Shizuoka, Japan; Laboratory of Chemistry (M.O.), College of Liberal Arts and Sciences, Tokyo Medical and Dental University, Chiba, Japan; Sekiyama Clinic, Osaka Health Club (K.Kotani), Osaka, Japan; Division of Cardiovascular and Respiratory Medicine (T.I., K.H.), Kobe University Graduate School of Medicine, Kobe, Japan. Current affiliation (N.S.), Itami City Hospital, Hyogo, Japan.

Correspondence to Morihiro Matsuda, MD, PhD, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan. E-mail mmatsuda{at}imed2.med.osaka-u.ac.jp

Objectives— A low level of high-density lipoprotein (HDL) in plasma has been recognized as an aspect of metabolic syndrome and as a crucial risk factor of cardiovascular events. However, the physiological regulation of plasma HDL levels has not been completely defined. Current studies aim to reveal the contribution of angiopoietin-like protein3 (angptl3), previously known as a plasma suppressor of lipoprotein lipase, to HDL metabolism.

Methods and Results— Angptl3-deficient mice showed low plasma HDL cholesterol and HDL phospholipid (PL), and which were increased by ANGPTL3 supplementation via adenovirus. In vitro, ANGPTL3 inhibited the phospholipase activity of endothelial lipase (EL), which hydrolyzes HDL-PL and hence decreases plasma HDL levels, through a putative heparin-binding site in the N-terminal domain of ANGPTL3. Post-heparin plasma in Angptl3-knockout mice had higher phospholipase activity than did that in wild-type mice, suggesting that the activity of endogenous EL is elevated in Angptl3-deficient mice. Furthermore, we established an ELISA system for human ANGPTL3 and found that plasma ANGPTL3 levels significantly correlated with plasma HDL cholesterol and HDL-PL levels in human subjects.

Conclusions— Angptl3 acts as an inhibitor of EL and may be involved in the regulation of plasma HDL cholesterol and HDL-PL levels in humans and rodents.

Current studies investigated the potential involvement of angptl3, previously known as a plasma suppressor of lipoprotein lipase, in HDL metabolism and its effects on endothelial lipase (EL) activity. The results suggest that angptl3 should be involved in the regulation of plasma HDL levels through the inhibition of EL activity.

Key Words: angptl3 • high density lipoprotein • endothelial lipase • phospholipase • triglyceride

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