PPARα agonists suppress osteopontin expression in macrophages and decrease plasma levels in patients with type 2 diabetes

Osteopontin (OPN) is a proinflammatory cytoldne implicated in the chemoattraction of monocytes and the development of atherosclerosis. Peroxisome proliferator-activated receptor (PPAR)a, a ligand-activated transcription factor with pleiotropic anti-inflammatory effects in macrophages, is the molecular target for fibrates, which are frequently used to treat dyslipidemia in patients with type 2 diabetes at high risk for cardiovascular disease. In the present study, we examined the regulation of OPN by PPAR alpha agonists in macrophages and determined the effect of fibrate treatment on OPN plasma levels in patients with type 2 diabetes. Treatment of human macrophages with the PPAR alpha ligands bezafibrate or WY14643 inhibited OPN expression. PPAR alpha ligands suppressed OPN promoter activity, and an activator protein (AP)-1 consensus site conferred this repression. Overexpression of c-Fos and c-Jun reversed the inhibitory effect of PPARa ligands on OPN transcription, and, in chromatin immunoprecipitation assays, PPAR alpha ligands inhibited c-Fos and phospho-c-Jun binding to the OPN promoter. Moreover, c-Fos and phospho-c-Jun protein expression was inhibited by PPAR alpha agonists, indicating that PPAR alpha ligands suppress OPN expression through negative cross talk with AP-1-dependent transactivation of the OPN promoter. This inhibitory effect of PPA-R alpha ligands on OPN expression was absent in PPAR alpha-deficient macrophages, suggesting a receptor-mediated mechanism of OPN suppression. Finally, treatment of type 2 diabetic patients with bezafibrate significantly decreased OPN plasma levels. These results demonstrate a novel mechanism whereby PPAR alpha ligands may impact macrophage inflammatory responses and decrease early proinflammatory markers for cardiovascular disease.