Nakamachi Takafumi, Nomiyama Takashi, Gizard Florence, Heywood Elizabeth B, Jones Karrie L, Zhao Yue, Fuentes Lucia, Takebayashi Kohzo, Aso Yoshimasa, Staels Bart, Inukai Toshihiko, Bruemmer Dennis
Division of Endocrinology and Molecular Medicine, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0200, USA.
Diabetes. 2007 Jun;56(6):1662-70. doi: 10.2337/db06-1177. Epub 2007 Mar 14.
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.
骨桥蛋白（OPN）是一种促炎细胞因子，与单核细胞的趋化作用和动脉粥样硬化的发展有关。过氧化物酶体增殖物激活受体（PPAR）α是一种在巨噬细胞中具有多效抗炎作用的配体激活转录因子，是贝特类药物的分子靶点，贝特类药物常用于治疗有心血管疾病高风险的2型糖尿病患者的血脂异常。在本研究中，我们检测了PPARα激动剂对巨噬细胞中OPN的调节作用，并确定了贝特类药物治疗对2型糖尿病患者血浆OPN水平的影响。用PPARα配体苯扎贝特或WY14643处理人巨噬细胞可抑制OPN表达。PPARα配体抑制OPN启动子活性，且一个激活蛋白（AP）-1共有位点介导了这种抑制作用。c-Fos和c-Jun的过表达逆转了PPARα配体对OPN转录的抑制作用，并且在染色质免疫沉淀试验中，PPARα配体抑制c-Fos和磷酸化c-Jun与OPN启动子的结合。此外，PPARα激动剂抑制c-Fos和磷酸化c-Jun蛋白表达，表明PPARα配体通过与OPN启动子的AP-1依赖性反式激活的负性相互作用来抑制OPN表达。PPARα配体对OPN表达的这种抑制作用在PPARα缺陷的巨噬细胞中不存在，提示存在一种受体介导的OPN抑制机制。最后，用苯扎贝特治疗2型糖尿病患者可显著降低血浆OPN水平。这些结果证明了一种新机制，通过该机制PPARα配体可能影响巨噬细胞炎症反应并降低心血管疾病的早期促炎标志物。
