A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis.
Previous work has implicated PPAR gamma in the regulation of CD36 expression and macrophage uptake of oxidized LDL (oxLDL). We provide evidence here that in addition to lipid uptake, PPAR gamma regulates a pathway of cholesterol efflux. PPAR gamma induces ABCA1 expression and cholesterol removal from macrophages through a transcriptional cascade mediated by the nuclear receptor LXR alpha. Ligand activation of PPAR gamma leads to primary induction of LXR alpha and to coupled induction of ABCA1. Transplantation of PPAR gamma null bone marrow into LDLR -/- mice results in a significant increase in atherosclerosis, consistent with the hypothesis that regulation of LXR alpha and ABCA1 expression is protective in vivo. Thus, we propose that PPAR gamma coordinates a complex physiologic response to oxLDL that involves particle uptake, processing, and cholesterol removal through ABCA1.
Chawla
A
A
Salk Institute for Biological Studies, Howard Hughes Medical Institute, La Jolla, CA 92037, USA.
Boisvert
W A
WA
Lee
C H
CH
Laffitte
B A
BA
Barak
Y
Y
Joseph
S B
SB
Liao
D
D
Nagy
L
L
Edwards
P A
PA
Curtiss
L K
LK
Evans
R M
RM
Tontonoz
P
P
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D008078:Cholesterol, LDL / Q000378:metabolism*; D004268:DNA-Binding Proteins; D008077:Lipoproteins, LDL / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008078:Cholesterol, LDL; D004268:DNA-Binding Proteins; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C099252:oxidized low density lipoprotein