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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:269.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Isoform-Dependent Cholesterol Efflux From Macrophages by Apolipoprotein E Is Modulated by Cell Surface Proteoglycans

Masumi Hara; Teruhiko Matsushima; Hiroaki Satoh; Naoyuki Iso-o; Hiroshi Noto; Masako Togo; Satoshi Kimura; Yoshiaki Hashimoto; Kazuhisa Tsukamoto

From the Department of Metabolic Diseases (M.H., H.S., N.I., H.N., M.T., S.K., K.T.) and the Department of Clinical Laboratory Medicine (Y.H.), Graduate School of Medicine, University of Tokyo, Tokyo, and the Department of Internal Medicine (T.M.), Tsukuba Memorial Hospital, Ibaraki, Japan.

Correspondence to Kazuhisa Tsukamoto, MD, Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655 Japan. E-mail kazuhisa-tky{at}umin.ac.jp

Objective— Apolipoprotein E (apoE) mediates cellular cholesterol efflux and plays a crucial role in the inhibition of atherogenesis. We investigated whether there is an isoform-specific difference in its function for cholesterol efflux from cholesterol-loaded RAW264.7 cells, a murine macrophage cell line that lacks endogenous apoE expression.

Methods and Results— When human apoE was expressed in RAW264.7 cells, apoE2 reduced cellular total cholesterol (TC) and esterified cholesterol (EC) levels significantly, whereas apoE3 and apoE4 had no effect. However, treatment of cells with 4-methylumbelliferyl-7-ß-D-xyloside (ß-DX) resulted in all 3 isoforms’ reducing cellular TC and EC contents significantly. We also investigated the effect of exogenously derived apoE on cholesterol efflux by utilizing the medium harvested from HeLa cells expressing apoE. ApoE2 and E3 reduced both cellular TC and EC contents significantly, whereas apoE4 did not. However, treatment of the cells with ß-DX resulted in all 3 exogenously derived apoE isoforms’ reducing TC and EC contents significantly. The binding ability of apoE to heparan sulfate proteoglycans examined by heparinase I treatment revealed less binding ability of apoE2 compared with that of apoE3 or apoE4.

Conclusions— The present study clarified the differential cellular cholesterol-modulating effect of apoE isoforms in macrophages, which would be due to the difference in their binding to proteoglycans.

Key Words: apolipoprotein E • isoforms • cholesterol efflux • RAW264.7 cells • heparan-sulfate proteoglycans

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