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.