PPARalpha agonists suppress osteopontin expression in macrophages and decrease plasma levels in patients with type 2 diabetes.
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.
Nakamachi
Takafumi
T
Division of Endocrinology and Molecular Medicine, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0200, USA.
Nomiyama
Takashi
T
Gizard
Florence
F
Heywood
Elizabeth B
EB
Jones
Karrie L
KL
Zhao
Yue
Y
Fuentes
Lucia
L
Takebayashi
Kohzo
K
Aso
Yoshimasa
Y
Staels
Bart
B
Inukai
Toshihiko
T
Bruemmer
Dennis
D
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
D000960:Hypolipidemic Agents; D008024:Ligands; D047493:PPAR alpha; D011743:Pyrimidines; D053495:Osteopontin; C006253:pirinixic acid; D001629:Bezafibrate