Activation of Peroxisome Proliferator-activated Receptor (PPARγ) and CD36 Protein Expression THE DUAL PATHOPHYSIOLOGICAL ROLES OF PROGESTERONE

Progesterone or its analog, one of components of hormone replacement therapy, may attenuate the cardioprotective effects of estrogen. However, the underlying mechanisms have not been fully elucidated. Expression of CD36, a receptor for oxidized LDL (oxLDL) that enhances macrophage/foam cell formation, is activated by the transcription factor peroxisome proliferator-activated receptor gamma (PPARy). CD36 also functions as a fatty acid transporter to influence fatty acid metabolism and the pathophysiological status of several diseases. In this study, we determined that progesterone induced macrophage CD36 expression, which is related to progesterone receptor (PR) activity. Progesterone enhanced cellular oxLDL uptake in a CD36dependent manner. Mechanistically, progesterone increased PPARy expression and PPARy promoter activity in a PR dependent manner and the binding of PR with the progesterone response element in the PPARy promoter. Specific deletion of macrophage PPARy (MOPPARy KO) expression in mice abolished progesterone -induced macrophage CD36 expression and cellular oxLDL accumulation. We also determined that, associated with gestation and increased serum progesterone levels, CD36 and PPARy expression in mouse adipose tissue, skeletal muscle, and peritoneal macrophages were substantially activated. Taken together, our study demonstrates that progesterone can play dual pathophysiological roles by activating PPARy expression, in which progesterone increases macrophage CD36 expression and oxLDL accumulation, a negative effect on atherosclerosis, and enhances the PPAR gamma-CD36 pathway in adipose tissue and skeletal muscle, a protective effect on pregnancy.