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

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