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 γ-Dependent Pathway

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 20; no. 12; pp. 3165 - 3178
• Main Authors: Avallone, Roberta, Demers, Annie, Rodrigue-Way, Amélie, Bujold, Kim, Harb, Diala, Anghel, Silvia, Wahli, Walter, Marleau, Sylvie, Ong, Huy, Tremblay, André
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01-12-2006; Oxford University Press
• Subjects: Animals; Apolipoproteins E - genetics; Atherosclerosis - genetics; Atherosclerosis - prevention & control; ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Sub-Family G, Member 1; ATP-Binding Cassette Transporters - metabolism; CD36 Antigens - genetics; CD36 Antigens - metabolism; Cells, Cultured; Cholesterol - metabolism; DNA-Binding Proteins - genetics; Humans; Lipoproteins - metabolism; Liver X Receptors; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - metabolism; Mice; Mice, Knockout; Oligopeptides - pharmacology; Orphan Nuclear Receptors; Phosphorylation; PPAR gamma - metabolism; Promoter Regions, Genetic; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, G-Protein-Coupled - genetics; Receptors, Ghrelin; Transcription, Genetic; Up-Regulation
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2006-0146

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