title: PPARalpha agonists suppress osteopontin expression in macrophages and decrease plasma levels in patients with type 2 diabetes.
abstract: Osteopontin (OPN) is a proinflammatory cytokine implicated in the chemoattraction of monocytes and the development of atherosclerosis. Peroxisome proliferator-activated receptor (PPAR)alpha, 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 PPARalpha 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 PPARalpha ligands bezafibrate or WY14643 inhibited OPN expression. PPARalpha 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 PPARalpha ligands on OPN transcription, and, in chromatin immunoprecipitation assays, PPARalpha 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 PPARalpha agonists, indicating that PPARalpha ligands suppress OPN expression through negative cross talk with AP-1-dependent transactivation of the OPN promoter. This inhibitory effect of PPARalpha ligands on OPN expression was absent in PPARalpha-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 PPARalpha ligands may impact macrophage inflammatory responses and decrease early proinflammatory markers for cardiovascular disease.
authors.affiliation: Division of Endocrinology and Molecular Medicine, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0200, USA.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Nakamachi
authors.forename: Takashi
authors.initials: T
authors.lastname: Nomiyama
authors.forename: Florence
authors.initials: F
authors.lastname: Gizard
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Heywood
authors.forename: Karrie L
authors.initials: KL
authors.lastname: Jones
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Lucia
authors.initials: L
authors.lastname: Fuentes
authors.forename: Kohzo
authors.initials: K
authors.lastname: Takebayashi
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Aso
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Inukai
authors.forename: Dennis
authors.initials: D
authors.lastname: Bruemmer
mesh_terms: D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology*; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008024:Ligands; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D009000:Monocytes / Q000502:physiology; D053495:Osteopontin / Q000097:blood / Q000235:genetics*; D047493:PPAR alpha / Q000819:agonists*; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000494:pharmacology; D014162:Transfection
chemical_list: D000960:Hypolipidemic Agents; D008024:Ligands; D047493:PPAR alpha; D011743:Pyrimidines; D053495:Osteopontin; C006253:pirinixic acid; D001629:Bezafibrate