Peroxisome proliferator-activated receptor α controls cellular cholesterol trafficking in macrophages

Abstract

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 (Ox-LDL) 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.

Cholesterol-lowering effect of bezafibrate is independent of peroxisome proliferator-activated receptor activation in mice

“…Previous reports have established a prominent role for hepatic ABCA1 in the regulation of plasma high-density lipoprotein cholesterol levels [46,47]. In addition, NPC1 has been shown to transport free cholesterol from lysosomes to the plasma membrane, contributing to cholesterol efflux through the ABCA1 pathway [48]. Therefore, these changes may be partly related to bezafibrate enhancement of high-density lipoprotein cholesterol in humans.…”

Congenic Analysis of the NKT Cell Control Gene Nkt2 Implicates the Peroxisomal Protein Pxmp4

“…PPAR␣ activation also leads to up-regulation of Npc1 and Npc2, the genes that are mutated in Niemann-Pick type C disease (NPC) (43). Although NPC belongs to the group of lysosomal storage diseases characterized by an accumulation of cholesterol and sphingomyelin in lysosomes, studies of BALB/cNctr-Npc1 m1N /J mice, a spontaneous mutant mouse model of Npc1 deficiency, suggest additional effects on peroxisome function.…”

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

“…However, a synthetic PPARδ agonist has little effect on atherosclerosis in mice (Li et al, 2004), suggesting that PPARs may have diverse effects on the atherogenic processes. In macrophages, PPARα also induces the expression of NPC1 and NPC2, which control the transport of free cholesterol from the lysosome to the plasma membrane (Chinetti-Gbaguidi et al, 2005), thus leading to increased cholesterol efflux. In a similar pathway, PPARα and γ induce ABCA1 expression (Chinetti et al, 2001), which also aids cholesterol efflux from macrophages and cholesterol reverse transport.…”