PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL.
The formation of foam cells from macrophages in the arterial wall is characterized by dramatic changes in lipid metabolism, including increased expression of scavenger receptors and the uptake of oxidized low-density lipoprotein (oxLDL). We demonstrate here that the nuclear receptor PPARgamma is induced in human monocytes following exposure to oxLDL and is expressed at high levels in the foam cells of atherosclerotic lesions. Ligand activation of the PPARgamma:RXRalpha heterodimer in myelomonocytic cell lines induces changes characteristic of monocytic differentiation and promotes uptake of oxLDL through transcriptional induction of the scavenger receptor CD36. These results reveal a novel signaling pathway controlling differentiation and lipid metabolism in monocytic cells, and suggest that endogenous PPARgamma ligands may be important regulators of gene expression during atherogenesis.
Tontonoz
P
P
The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Nagy
L
L
Alvarez
J G
JG
Thomazy
V A
VA
Evans
R M
RM
D000077556:Alitretinoin; D000818:Animals; D001161:Arteriosclerosis / Q000473:pathology; D018955:CD36 Antigens / Q000032:analysis / Q000235:genetics; D002454:Cell Differentiation; D019281:Dimerization; D005487:Foam Cells / Q000737:chemistry; D018922:HL-60 Cells; D006801:Humans; D008024:Ligands; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D011971:Receptors, Immunologic / Q000235:genetics; D018110:Receptors, Lipoprotein; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000378:metabolism; D051116:Receptors, Scavenger; D047488:Retinoid X Receptors; D000077154:Rosiglitazone; D051122:Scavenger Receptors, Class B; D015398:Signal Transduction / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000032:analysis / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D018955:CD36 Antigens; D008024:Ligands; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D018168:Receptors, Retinoic Acid; D051116:Receptors, Scavenger; D047488:Retinoid X Receptors; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C099252:oxidized low density lipoprotein; D000077154:Rosiglitazone; D000077556:Alitretinoin; D014212:Tretinoin; D015230:Prostaglandin D2