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PPAR Agonists Suppress Osteopontin Expression in Macrophages and Decrease Plasma Levels in Patients With Type 2 Diabetes

¹ Division of Endocrinology and Molecular Medicine, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky
² Department of Atherosclerosis, Institut Pasteur de Lille, Lille, France
³ INSERM, U545, Lille, France
⁴ Faculte de Pharmacie et Faculte de Medecine, Universite de Lille 2, Lille, France
⁵ Department of Medicine, Koshigaya Hospital, Dokkyo University School of Medicine, Koshigaya, Japan

Address correspondence and reprint requests to Dennis Bruemmer, MD, University of Kentucky College of Medicine, Department of Internal Medicine, Division of Endocrinology and Molecular Medicine, Wethington Health Sciences Building, Room 575, 900 South Limestone St., Lexington, KY 40536-0200. E-mail: dennis.bruemmer{at}uky.edu

Abbreviations: AP, activator protein; ChIP, Chromatin immunoprecipitation; FBS, fetal bovine serum; IL, interleukin; OPN, osteopontin; PMA, phorbol myristic acid; PPAR, peroxisome proliferator–activated receptor; TNF, tumor necrosis factor

Osteopontin (OPN) is a proinflammatory cytokine implicated in the chemoattraction of monocytes and the development of atherosclerosis. Peroxisome proliferator–activated receptor (PPAR), 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 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 ligands bezafibrate or WY14643 inhibited OPN expression. PPAR 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 PPAR ligands on OPN transcription, and, in chromatin immunoprecipitation assays, PPAR 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 agonists, indicating that PPAR ligands suppress OPN expression through negative cross talk with AP-1–dependent transactivation of the OPN promoter. This inhibitory effect of PPAR ligands on OPN expression was absent in PPAR-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 ligands may impact macrophage inflammatory responses and decrease early proinflammatory markers for cardiovascular disease.

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