Schopfer Francisco J, Lin Yiming, Baker Paul R S, Cui Taixing, Garcia-Barrio Minerva, Zhang Jifeng, Chen Kai, Chen Yuqing E, Freeman Bruce A
Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2340-5. doi: 10.1073/pnas.0408384102. Epub 2005 Feb 8.
Nitroalkene derivatives of linoleic acid (nitrolinoleic acid, LNO2) are formed via nitric oxide-dependent oxidative inflammatory reactions and are found at concentrations of approximately 500 nM in the blood of healthy individuals. We report that LNO2 is a potent endogenous ligand for peroxisome proliferator-activated receptor gamma (PPARgamma; Ki approximately 133 nM) that acts within physiological concentration ranges. This nuclear hormone receptor (PPARgamma) regulates glucose homeostasis, lipid metabolism, and inflammation. PPARgamma ligand activity is specific for LNO2)and not mediated by LNO2 decay products, NO donors, linoleic acid (LA), or oxidized LA. LNO2 is a significantly more robust PPARgamma ligand than other reported endogenous PPARgamma ligands, including lysophosphatidic acid (16:0 and 18:1), 15-deoxy-Delta12,14-PGJ2, conjugated LA and azelaoyl-phosphocholine. LNO2 activation of PPARgamma via CV-1 cell luciferase reporter gene expression analysis revealed a ligand activity that rivals or exceeds synthetic PPARgamma agonists such as rosiglitazone and ciglitazone, is coactivated by 9 cis-retinoic acid and is inhibited by the PPARgamma antagonist GW9662. LNO2 induces PPARgamma-dependent macrophage CD-36 expression, adipocyte differentiation, and glucose uptake also at a potency rivaling thiazolidinediones. These observations reveal that NO-mediated cell signaling reactions can be transduced by fatty acid nitration products and PPAR-dependent gene expression.
亚油酸的硝基烯烃衍生物（硝基亚油酸，LNO2）通过一氧化氮依赖性氧化炎症反应形成，在健康个体血液中的浓度约为500 nM。我们报告称，LNO2是过氧化物酶体增殖物激活受体γ（PPARγ；Ki约为133 nM）的强效内源性配体，在生理浓度范围内发挥作用。这种核激素受体（PPARγ）调节葡萄糖稳态、脂质代谢和炎症。PPARγ配体活性对LNO2具有特异性，并非由LNO2降解产物、NO供体、亚油酸（LA）或氧化型LA介导。与其他已报道的内源性PPARγ配体相比，包括溶血磷脂酸（16:0和18:1）、15-脱氧-Δ12,14-前列腺素J2、共轭LA和壬二酰磷酰胆碱，LNO2是一种更强大的PPARγ配体。通过CV-1细胞荧光素酶报告基因表达分析，LNO2对PPARγ的激活显示出一种配体活性，可与或超过罗格列酮和环格列酮等合成PPARγ激动剂，可被9-顺式视黄酸共激活，并被PPARγ拮抗剂GW9662抑制。LNO2诱导PPARγ依赖性巨噬细胞CD-36表达、脂肪细胞分化和葡萄糖摄取，其效力也可与噻唑烷二酮类药物相媲美。这些观察结果表明，NO介导的细胞信号反应可由脂肪酸硝化产物和PPAR依赖性基因表达转导。
