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

  1. Takafumi Nakamachi1,
  2. Takashi Nomiyama1,
  3. Florence Gizard1,
  4. Elizabeth B. Heywood1,
  5. Karrie L. Jones1,
  6. Yue Zhao1,
  7. Lucia Fuentes234,
  8. Kohzo Takebayashi5,
  9. Yoshimasa Aso5,
  10. Bart Staels234,
  11. Toshihiko Inukai5 and
  12. Dennis Bruemmer1
  1. 1Division of Endocrinology and Molecular Medicine, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky
  2. 2Department of Atherosclerosis, Institut Pasteur de Lille, Lille, France
  3. 3INSERM, U545, Lille, France
  4. 4Faculte de Pharmacie et Faculte de Medecine, Universite de Lille 2, Lille, France
  5. 5Department of Medicine, Koshigaya Hospital, Dokkyo University School of Medicine, Koshigaya, Japan
  1. 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

Abstract

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

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 14 March 2007. DOI: 10.2337/db06-1177.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted February 27, 2007.
    • Received August 21, 2006.
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  1. Published online before print March 14, 2007, doi: 10.2337/db06-1177 Diabetes June 2007 vol. 56 no. 6 1662-1670
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