Peroxisome proliferator-activated receptor alpha controls cellular cholesterol trafficking in macrophages.
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 alpha (PPARalpha), a fatty acid-activated nuclear receptor, the regulation of NPC1 and NPC2 by PPARalpha and the consequences on cholesterol trafficking were further studied. NPC1 and NPC2 expression is induced by synthetic PPARalpha ligands in human macrophages. Furthermore, PPARalpha 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 PPARalpha activators. These observations identify a novel regulatory role for PPARalpha 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.
Chinetti-Gbaguidi
G
G
UR 545 Inserm, Institut Pasteur de Lille and Université de Lille 2, Lille, France.
Rigamonti
E
E
Helin
L
L
Mutka
A L
AL
Lepore
M
M
Fruchart
J C
JC
Clavey
V
V
Ikonen
E
E
Lestavel
S
S
Staels
B
B
D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics; D002454:Cell Differentiation; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics; D000077296:Niemann-Pick C1 Protein; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D033921:Vesicular Transport Proteins
D002352:Carrier Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; C104585:NPC2 protein, human; D000077296:Niemann-Pick C1 Protein; D047493:PPAR alpha; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D033921:Vesicular Transport Proteins; C099252:oxidized low density lipoprotein; D011374:Progesterone; D002784:Cholesterol