PPARα agonists suppress osteopontin expression in macrophages and decrease plasma levels in patients with type 2 diabetes
PPARα agonists suppress osteopontin expression in macrophages and decrease plasma levels in patients with type 2 diabetes
复制标题
DOI：
10.2337/db06-1177
复制
发表时间：
2007-06-01
期刊：
影响因子：
7.7
通讯作者：
Bruemmer, Dennis
中科院分区：
文献类型：
--
作者：
Nakamachi, Takafumi;Nomiyama, Takashi;Bruemmer, Dennis
骨桥蛋白（OPN）是一种促炎细胞因子，与单核细胞的化学吸引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）a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，贝特类药物经常用于治疗心血管疾病高危的2型糖尿病患者的血脂异常。在本研究中，我们检测了巨噬细胞中PPAR α激动剂对OPN的调节，并确定了贝特治疗对2型糖尿病患者血浆中OPN水平的影响。用PPAR α配体贝扎贝特或WY14643处理人巨噬细胞可抑制OPN的表达。PPAR α配体抑制OPN启动子活性，激活蛋白(AP)-1共识位点赋予这种抑制作用。过表达的c-Fos和c-Jun逆转了PPARa配体对OPN转录的抑制作用，并且，在染色质免疫沉淀试验中，PPAR α配体抑制了c-Fos和磷酸化-c-Jun与OPN启动子的结合。此外，PPAR α激动剂抑制了c-Fos和phospho-c-Jun蛋白的表达，这表明PPAR α配体通过与ap -1依赖性OPN启动子的反激活负互扰抑制OPN的表达。在PPAR α缺失的巨噬细胞中，PPA-R α配体对OPN表达的抑制作用不存在，这提示了受体介导的OPN抑制机制。最后，治疗2型糖尿病患者贝扎布特显著降低OPN血浆水平。这些结果证明了PPAR α配体可能影响巨噬细胞炎症反应并降低心血管疾病早期促炎标志物的新机制。
Osteopontin (OPN) is a proinflammatory cytoldne implicated in the chemoattraction of monocytes and the development of atherosclerosis. Peroxisome proliferator-activated receptor (PPAR)a, 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 activator protein (AP)-1 consensus site conferred this repression. Overexpression of c-Fos and c-Jun reversed the inhibitory effect of PPARa 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 PPA-R alpha ligands on OPN expression was absent in PPAR alpha-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.