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Journal of Lipid Research, Vol. 46, 2214-2220, October 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Effects of cholesterol in chylomicron remnant models of lipid emulsions on apoE-mediated uptake and cytotoxicity of macrophages

Atsushi Sakurai, Shin-ya Morita, Kyoko Wakita, Yuko Deharu, Minoru Nakano and Tetsurou Handa¹

Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan

Published, JLR Papers in Press, June 1, 2005. DOI 10.1194/jlr.M500167-JLR200

¹ To whom correspondence should be addressed. e-mail: handatsr{at}pharm.kyoto-u.ac.jp

Chylomicron remnants have been suggested to be involved in the development of atherosclerosis. To investigate the mechanisms of chylomicron remnant-induced atherosclerosis, we prepared cholesterol (Chol)-containing emulsion particles as models for chylomicron remnants. Chol markedly increased the apolipoprotein E (apoE) binding maximum of emulsions without changing the binding affinity and thereby promoted emulsion uptake by J774 macrophages. Fluorescence measurements showed that Chol increased acyl chain order and head group hydration of the surface phospholipid (PL) layer of emulsions. The binding maximum of apoE was closely correlated with the hydration and the increase in the PL head group separation at the emulsion surface. From experiments using inhibitors for lipoprotein receptors, heparan sulfate proteoglycans and low density lipoprotein receptor-related protein were found to be the major contributors to the uptake of Chol-containing emulsions. Trypan blue dye exclusion revealed that the uptake of Chol-containing emulsions induced cytotoxicity to J774 macrophages.

This study proposes a mechanism of atherosclerosis induced by chylomicron remnants.

Abbreviations: apoE, apolipoprotein E; Chol, cholesterol; dansyl-PE, N-(5-dimethylaminonaphthalene-1-sulfonyl)dipalmitoylphosphatidylethanolamine; DPH-PC, 1-palmitoyl-2-[3-(diphenylhexatrienyl)propionyl]-sn-3-phosphatidylcholine; HSPG, heparan sulfate proteoglycan; LRP, low density lipoprotein receptor-related protein; PC, phosphatidylcholine; PL, phospholipid; PMC-oleate, 1-pyrenemethyl 3ß-(cis-9-octadecenoyloxy)-22,23-bisnor-5-cholenate; SM, sphingomyelin; TO, triolein

Supplementary key words apolipoprotein E • J774 macrophages • phosphatidylcholine head group separation

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