A growth hormone-releasing peptide that binds scavenger receptor CD36 and ghrelin receptor up-regulates sterol transporters and cholesterol efflux in macrophages through a peroxisome proliferator-activated receptor gamma-dependent pathway.
Macrophages play a central role in the pathogenesis of atherosclerosis by accumulating cholesterol through increased uptake of oxidized low-density lipoproteins by scavenger receptor CD36, leading to foam cell formation. Here we demonstrate the ability of hexarelin, a GH-releasing peptide, to enhance the expression of ATP-binding cassette A1 and G1 transporters and cholesterol efflux in macrophages. These effects were associated with a transcriptional activation of nuclear receptor peroxisome proliferator-activated receptor (PPAR)gamma in response to binding of hexarelin to CD36 and GH secretagogue-receptor 1a, the receptor for ghrelin. The hormone binding domain was not required to mediate PPARgamma activation by hexarelin, and phosphorylation of PPARgamma was increased in THP-1 macrophages treated with hexarelin, suggesting that the response to hexarelin may involve PPARgamma activation function-1 activity. However, the activation of PPARgamma by hexarelin did not lead to an increase in CD36 expression, as opposed to liver X receptor (LXR)alpha, suggesting a differential regulation of PPARgamma-targeted genes in response to hexarelin. Chromatin immunoprecipitation assays showed that, in contrast to a PPARgamma agonist, the occupancy of the CD36 promoter by PPARgamma was not increased in THP-1 macrophages treated with hexarelin, whereas the LXRalpha promoter was strongly occupied by PPARgamma in the same conditions. Treatment of apolipoprotein E-null mice maintained on a lipid-rich diet with hexarelin resulted in a significant reduction in atherosclerotic lesions, concomitant with an enhanced expression of PPARgamma and LXRalpha target genes in peritoneal macrophages. The response was strongly impaired in PPARgamma(+/-) macrophages, indicating that PPARgamma was required to mediate the effect of hexarelin. These findings provide a novel mechanism by which the beneficial regulation of PPARgamma and cholesterol metabolism in macrophages could be regulated by CD36 and ghrelin receptor downstream effects.
Avallone
Roberta
R
Faculty of Pharmacy, Pavillon Jean-Coutu, and Research Center, Ste-Justine Hospital, University of Montreal, Montréal, Québec, Canada.
Demers
Annie
A
Rodrigue-Way
Amélie
A
Bujold
Kim
K
Harb
Diala
D
Anghel
Silvia
S
Wahli
Walter
W
Marleau
Sylvie
S
Ong
Huy
H
Tremblay
André
A
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000517:prevention & control; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism*; D000071518:Liver X Receptors; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology*; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D054440:Receptors, Ghrelin; D014158:Transcription, Genetic; D015854:Up-Regulation
C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D018955:CD36 Antigens; D004268:DNA-Binding Proteins; D008074:Lipoproteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D009842:Oligopeptides; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; C420120:gamma-aminobutyryl-2-methyltryptophyl-2-methyltryptophyl-2-methyltryptophyl-lysinamide; C086184:hexarelin; D002784:Cholesterol