RT Journal Article
SR Electronic
T1 PPARα Agonists Suppress Osteopontin Expression in Macrophages and Decrease Plasma Levels in Patients With Type 2 Diabetes
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 1662
OP 1670
DO 10.2337/db06-1177
VO 56
IS 6
A1 Nakamachi, Takafumi
A1 Nomiyama, Takashi
A1 Gizard, Florence
A1 Heywood, Elizabeth B.
A1 Jones, Karrie L.
A1 Zhao, Yue
A1 Fuentes, Lucia
A1 Takebayashi, Kohzo
A1 Aso, Yoshimasa
A1 Staels, Bart
A1 Inukai, Toshihiko
A1 Bruemmer, Dennis
YR 2007
UL http://diabetes.diabetesjournals.org/content/56/6/1662.abstract
AB 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.