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- Title
CD36-mediated cholesterol efflux is associated with PPAR{gamma} activation via a MAPK-dependent COX-2 pathway in macrophages.
- Authors
Kim Bujold; David Rhainds; Christian Jossart; Maria Febbraio; Sylvie Marleau; Huy Ong
- Abstract
: Aims 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 γ (PPARγ)–liver X receptor α (LXRα)–ATP-binding cassette (ABC) transporter pathway. However, the mechanism involved in PPARγ 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 PPARγ activation. : Methods and 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 PPARγ. The signalling pathway by which this CD36 ligand promoted lipid efflux involved an increase in intracellular 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) levels induced by extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent cyclooxygenase-2 (COX-2) expression, leading to PPARγ activation. In agreement, EP 80317-mediated cholesterol efflux was abrogated by inhibitors of PPARγ, ERK1/2, and COX-2 as well as ABC transporter inhibitors, whereas a p38 mitogen-activated protein kinase inhibitor had no effect. : Conclusion These findings suggest a central role for the prostanoid 15d-PGJ2 in PPARγ 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.
- Subjects
NUCLEAR receptors (Biochemistry); ENZYME regulation; MITOGEN-activated protein kinases; MACROPHAGES; MOLECULAR dynamics; GROWTH hormone releasing factor; LIGANDS (Biochemistry); ATHEROSCLEROSIS treatment
- Publication
Cardiovascular Research, 2009, Vol 83, Issue 3, p457
- ISSN
0008-6363
- Publication type
Article
- DOI
10.1093/cvr/cvp118