Peroxisome proliferator-activated receptorcontrols cellular cholesterol trafficking in macrophages

The mobilization of cholesterol from intracellu- lar pools to the plasma membrane is a determinant that gov- erns its availability for efflux to extracellular acceptors. NPC1 and NPC2 are proteins localized in the late endo- some 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 (Ox- LDL) in human macrophages. Because OxLDLs contain natural activators of peroxisome proliferator-activated re- ceptor � (PPAR � ), a fatty acid-activated nuclear receptor, the regulation of NPC1 and NPC2 by PPARand the conse- quences on cholesterol trafficking were further studied. NPC1 and NPC2 expression is induced by synthetic PPAR � ligands in human macrophages. Furthermore, PPARacti- vation 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 PPARactivators. These observations identify a novel regulatory role for PPARin the control of cholesterol availability for efflux that, associated with its ability to in- hibit cholesterol esterification and to stimulate ABCA1 and scavenger receptor class B type I expression, may contrib- ute to the stimulation of reverse cholesterol transport. — Chinetti-Gbaguidi, G., E. Rigamonti, L. Helin, A. L. Mutka, M. Lepore, J. C. Fruchart, V. Clavey, E. Ikonen, S. Lestavel, and B. Staels. Peroxisome proliferator-activated receptor � controls cellular cholesterol trafficking in macrophages. J. Lipid Res. 2005. 46: 2717-2725.