Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids SELECTIVE LIGAND ACTIVITY AND ANTI-DIABETIC SIGNALING ACTIONS
Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids SELECTIVE LIGAND ACTIVITY AND ANTI-DIABETIC SIGNALING ACTIONS
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DOI：
10.1074/jbc.m109.091512
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发表时间：
2010-04-16
影响因子：
4.8
通讯作者：
Freeman, Bruce A.
中科院分区：
文献类型：
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作者：
Schopfer, Francisco J.;Cole, Marsha P.;Freeman, Bruce A.
过氧化物酶体增殖物激活受体-γ(PPAR-Gamma)与多种配体结合，在转录上调节新陈代谢和炎症。PPARγ的激活剂包括脂质和降血糖药物，如噻唑烷二酮(TZDS)。最近，TZD在与外周水肿、体重增加和不良心血管事件的风险增加有关后，引起了人们的关注。已报道的大多数内源性PPARγ配体是脂代谢和氧化的中间产物，以非常低的亲和力结合PPARγ。相反，不饱和脂肪酸的硝基衍生物(NO2-FA)是一氧化氮((NO)-N-中心点)和亚硝酸盐(NO2-)介导的氧化还原反应的内源产物，这些反应在纳摩尔浓度下激活PPARγ。我们报道了NO2-FA作为PPAR-γ的部分激动剂，通过Michael加成与PPAR-γ在Cys-285上共价结合。NO2-FA通过诱导辅调节蛋白相互作用、关键靶基因的PPARγ依赖性表达和脂质积累与TZD罗格列酮诱导的反应明显不同，显示出选择性的PPAR伽玛调节剂特性。给ob/ob小鼠服用这类信号媒介表明，NO2-FA降低了胰岛素和血糖水平，而不会引起不良副作用，如TZDS导致的体重增加。
The peroxisome proliferator-activated receptor-gamma (PPAR gamma) binds diverse ligands to transcriptionally regulate metabolism and inflammation. Activators of PPAR gamma include lipids and anti-hyperglycemic drugs such as thiazolidinediones (TZDs). Recently, TZDs have raised concern after being linked with increased risk of peripheral edema, weight gain, and adverse cardiovascular events. Most reported endogenous PPAR gamma ligands are intermediates of lipid metabolism and oxidation that bind PPAR gamma with very low affinity. In contrast, nitro derivatives of unsaturated fatty acids (NO2-FA) are endogenous products of nitric oxide ((NO)-N-center dot) and nitrite (NO2-)-mediated redox reactions that activate PPAR gamma at nanomolar concentrations. We report that NO2-FA act as partial agonists of PPAR gamma and covalently bind PPAR gamma at Cys-285 via Michael addition. NO2-FA show selective PPAR gamma modulator characteristics by inducing coregulator protein interactions, PPAR gamma-dependent expression of key target genes, and lipid accumulation is distinctively different from responses induced by the TZD rosiglitazone. Administration of this class of signaling mediators to ob/ob mice revealed that NO2-FA lower insulin and glucose levels without inducing adverse side effects such as the increased weight gain induced by TZDs.