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Journal of Lipid Research, Vol. 46, 2717-2725, December 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Peroxisome proliferator-activated receptor controls cellular cholesterol trafficking in macrophages

G. Chinetti-Gbaguidi^1,*, E. Rigamonti^1,*, L. Helin^*, A. L. Mutka, M. Lepore^*, J. C. Fruchart^*, V. Clavey^*, E. Ikonen, S. Lestavel^* and B. Staels^2,*

^* UR 545 Inserm, Institut Pasteur de Lille and Université de Lille 2, Lille, France
Institute of Biotechnology, University of Helsinki, Helsinki, Finland

Published, JLR Papers in Press, September 14, 2005. DOI 10.1194/jlr.M500326-JLR200

¹ G. Chinetti-Gbaguidi and E. Rigamonti contributed equally to this work.

² To whom correspondence should be addressed. e-mail: bart.staels{at}pasteur-lille.fr

The mobilization of cholesterol from intracellular pools to the plasma membrane is a determinant that governs its availability for efflux to extracellular acceptors. NPC1 and NPC2 are proteins localized in the late endosome and control cholesterol transport from the lysosome to the plasma membrane. Here, we report that NPC1 and NPC2 gene expression is induced by oxidized LDL (OxLDL) in human macrophages. Because OxLDLs contain natural activators of peroxisome proliferator-activated receptor (PPAR), a fatty acid-activated nuclear receptor, the regulation of NPC1 and NPC2 by PPAR and the consequences on cholesterol trafficking were further studied. NPC1 and NPC2 expression is induced by synthetic PPAR ligands in human macrophages. Furthermore, PPAR activation leads to an enrichment of cholesterol in the plasma membrane. By contrast, incubation with progesterone, which blocks postlysosomal cholesterol trafficking, as well as NPC1 and NPC2 mRNA depletion using small interfering RNA, abolished ABCA1-dependent cholesterol efflux induced by PPAR activators.

These observations identify a novel regulatory role for PPAR in the control of cholesterol availability for efflux that, associated with its ability to inhibit cholesterol esterification and to stimulate ABCA1 and scavenger receptor class B type I expression, may contribute to the stimulation of reverse cholesterol transport.

Abbreviations: apoA-I, apolipoprotein A-I; CE, cholesteryl ester; FC, free cholesterol; NPC, Niemann Pick type C; OxLDL, oxidized LDL; PPAR, peroxisome proliferator-activated receptor ; RCT, reverse cholesterol transport; siRNA, small interfering RNA; SR-BI, scavenger receptor class B type I

Supplementary key words nuclear receptors • gene regulation • atherosclerosis • cholesterol homeostasis

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