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Journal of Lipid Research, Vol. 48, 299-306, February 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Increased lipid rafts and accelerated lipopolysaccharide-induced tumor necrosis factor- secretion in Abca1-deficient macrophages

Masahiro Koseki^1,*, Ken-ichi Hirano^*,, Daisaku Masuda^*, Chiaki Ikegami^*, Masaki Tanaka, Akemi Ota^*, Jose C. Sandoval, Yumiko Nakagawa-Toyama^*, Satoshi B. Sato^**, Toshihide Kobayashi, Yukiko Shimada, Yoshiko Ohno-Iwashita, Fumihiko Matsuura^*,, Iichiro Shimomura^* and Shizuya Yamashita^*,

^* Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Department of Medicine and Pathology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
^** Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan
RIKEN, Wako, Saitama, Japan
Biomembrane Research Group, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, Japan

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of figures.

Published, JLR Papers in Press, November 7, 2006.

¹ To whom correspondence should be addressed. e-mail: koseki{at}imed2.med.osaka-u.ac.jp

Lipid rafts on the cell surface are believed to be very important as platforms for various cellular functions. The aim of this study was to know whether defective lipid efflux may influence lipid rafts on the cell surface and their related cellular functions. We investigated macrophages with defective lipid efflux from ATP binding cassette transporter A1-deficient (Abca1-KO) mice. Lipid rafts were evaluated by the following two novel probes: a biotinylated and protease (subtilisin Carlsberg)-nicked derivative of -toxin and a fluorescein ester of polyethylene glycol-derived cholesterol. Lipid rafts in Abca1-KO macrophages were increased, as demonstrated by both probes. Moreover, activities of nuclear factor B, mRNA and intracellular distribution, and secretion of tumor necrosis factor- (TNF-) were examined after stimulation by lipopolysaccharides (LPSs). LPS-induced responses of the activation of nuclear factor B and TNF- were more prompt and accelerated in the Abca1-KO macrophages compared with wild-type macrophages. Modification of lipid rafts by cyclodextrin and nystatin corrected the abnormal response, suggesting an association between the increased lipid rafts and abnormal TNF- secretion. We report here that Abca1-KO macrophages with defective lipid efflux exhibited increased lipid rafts on the cell surface and accelerated TNF- secretion.

Supplementary key words ATP binding cassette transporter A1 • biotinylated and protease (subtilisin Carlsberg)-nicked derivative of -toxin • cholesterol efflux • lipid rafts • polyethylene glycol-derived cholesterol • tumor necrosis factor-

Abbreviations: Abca1-KO, ATP binding cassette transporter A1-deficient; apoA-I, apolipoprotein A-I; BC, biotinylated and protease (subtilisin Carlsberg)-nicked derivative of -toxin; fPEG-chol, fluorescent polyethylene glycol cholesteryl ether; LPS, lipopolysaccharide; NF-B, nuclear factor-B; 2OHpßCD, 2-hydroxypropyl-ß-cyclodextrin; RCT, reverse cholesterol transport; TD, Tangier disease; TNF-, tumor necrosis factor-; WT, wild-type

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