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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 -Dependent Pathway

Faculty of Pharmacy (R.A., A.D., K.B., D.H., S.M., H.O.), Pavillon Jean-Coutu, University of Montreal, Montréal, Québec, H3C 3J7 Canada; Research Center, Ste-Justine Hospital (R.A., A.D., A.R.-W., A.T.), and Departments of Biochemistry (A.R.-W., A.T.), and Obstetrics and Gynecology (A.T.), Faculty of Medicine, University of Montreal, Montreal, Québec, H3T 1C5 Canada; and Center for Integrative Genomics and National Center of Competence in Research Frontiers in Genetics (S.A., W.W.), University of Lausanne, CH-1015 Lausanne, Switzerland

Address all correspondence and requests for reprints to: André Tremblay, Research Center, Ste-Justine Hospital, 3175 Côte Ste-Catherine, Montréal (Québec), Canada H3T 1C5. E-mail: andre.tremblay{at}recherche-ste-justine.qc.ca; or Huy Ong, Pavillon Jean-Coutu, University of Montreal, Montréal (Québec), Canada H3C 3J7. E-mail: huy.ong{at}umontreal.ca.

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) 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 PPAR activation by hexarelin, and phosphorylation of PPAR was increased in THP-1 macrophages treated with hexarelin, suggesting that the response to hexarelin may involve PPAR activation function-1 activity. However, the activation of PPAR by hexarelin did not lead to an increase in CD36 expression, as opposed to liver X receptor (LXR), suggesting a differential regulation of PPAR-targeted genes in response to hexarelin. Chromatin immunoprecipitation assays showed that, in contrast to a PPAR agonist, the occupancy of the CD36 promoter by PPAR was not increased in THP-1 macrophages treated with hexarelin, whereas the LXR promoter was strongly occupied by PPAR 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 PPAR and LXR target genes in peritoneal macrophages. The response was strongly impaired in PPAR^+/– macrophages, indicating that PPAR was required to mediate the effect of hexarelin. These findings provide a novel mechanism by which the beneficial regulation of PPAR and cholesterol metabolism in macrophages could be regulated by CD36 and ghrelin receptor downstream effects.

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARα  |  PPARδ  |  PPARγ  |  LXRβ  |  LXRα  |  RXRα

Ligands:   22α-Hydroxycholesterol  |  GW 9662  |  Pirinixic acid

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