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Diabetes Publish Ahead of Print published online ahead of print March 14, 2007
DOI: 10.2337/db06-1177
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Original Research

PPAR{alpha} Agonists suppress Osteopontin Expression in Macrophages and decrease Plasma Levels in Patients with Type 2 Diabetes

Takafumi Nakamachi1, Takashi Nomiyama1, Florence Gizard1, Elizabeth B. Heywood1, Karrie L. Jones1, Yue Zhao1, Lucia Fuentes2,3,4, Kohzo Takebayashi5, Yoshimasa Aso5, Bart Staels2,3,4, Toshihiko Inukai5, and Dennis Bruemmer1

1Division of Endocrinology and Molecular Medicine, University of Kentucky College of Medicine, Lexington, KY-40536, USA
2Institut Pasteur de Lille, Departement d'Atherosclerose, Lille, F-59019, France
3Inserm, U545, Lille, F-59019, France
4Universite de Lille 2, Lille, F-59006 France
5Department of Medicine, Koshigaya Hospital, Dokkyo University School of Medicine, Koshigaya 343-8555, Japan

Correspondence: Dennis.Bruemmer{at}uky.edu

Osteopontin (OPN) is a proinflammatory cytokine implicated in the chemoattraction of monocytes and the development of atherosclerosis. 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 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 AP-1 consensus site conferred this repression. Overexpression of c-Fos and c-Jun reversed the inhibitory effect of PPAR{alpha} 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 PPAR{alpha} 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 PPAR{alpha} ligands may impact macrophage inflammatory responses and decrease early proinflammatory markers for cardiovascular disease.


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