CD36-mediated cholesterol efflux is associated with PPARgamma activation via a MAPK-dependent COX-2 pathway in macrophages.
OBJECTIVE
Growth hormone-releasing peptides (GHRPs) as CD36 selective ligands feature potent anti-atherosclerotic activity that is associated with an upregulation of the peroxisome proliferator-activated receptor gamma (PPARgamma)-liver X receptor alpha (LXRalpha)-ATP-binding cassette (ABC) transporter pathway. However, the mechanism involved in PPARgamma activation in response to CD36 signalling has yet to be determined. Therefore, the present study aims to elucidate the upstream molecular mechanisms through which EP 80317, a selective CD36 ligand, promotes lipid efflux from macrophages through PPARgamma activation.


RESULTS
[3H]-Cholesterol- and [3H]-methylcholine chloride-labelled murine macrophages treated with EP 80317 showed a significant increase in cholesterol and phospholipid efflux to both apolipoprotein A-I and high-density lipoprotein in a CD36-dependent manner. Lipid efflux was associated with enhanced activation of PPARgamma. The signalling pathway by which this CD36 ligand promoted lipid efflux involved an increase in intracellular 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2) levels induced by extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent cyclooxygenase-2 (COX-2) expression, leading to PPARgamma activation. In agreement, EP 80317-mediated cholesterol efflux was abrogated by inhibitors of PPARgamma, ERK1/2, and COX-2 as well as ABC transporter inhibitors, whereas a p38 mitogen-activated protein kinase inhibitor had no effect.


CONCLUSIONS
These findings suggest a central role for the prostanoid 15d-PGJ2 in PPARgamma activation and the upregulation of the ABC transporter pathway in response to CD36 activation by synthetic GHRPs analogues. The resulting enhanced cholesterol efflux might explain, at least in part, the atheroprotective effect of selective CD36 ligands.
Bujold
Kim
K
Université de Montréal, PO Box 6128, Station Centre-Ville, Montréal, Québec H3C 3J7, Canada.
Rhainds
David
D
Jossart
Christian
C
Febbraio
Maria
M
Marleau
Sylvie
S
Ong
Huy
H
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000276:immunology / Q000517:prevention & control; D001692:Biological Transport; D018955:CD36 Antigens / Q000187:drug effects / Q000378:metabolism*; D002317:Cardiovascular Agents / Q000494:pharmacology; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D008074:Lipoproteins / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D047495:PPAR gamma / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
C477819:15-deoxyprostaglandin J2; C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D018955:CD36 Antigens; D002317:Cardiovascular Agents; C468852:EP80317; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D009842:Oligopeptides; D047495:PPAR gamma; D010743:Phospholipids; D002784:Cholesterol; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D015230:Prostaglandin D2