Nitrolinoleic acid: An endogenous peroxisome proliferator-activated receptor γ ligand

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Abstract
Nitroalkene derivatives of linoleic acid (nitrolinoleic acid, LNO 2 ) are formed via nitric oxide-dependent oxidative inflammatory reactions and are found at concentrations of ≈500 nM in the blood of healthy individuals. We report that LNO 2 is a potent endogenous ligand for peroxisome proliferator-activated receptor γ (PPARγ; K i ≈133 nM) that acts within physiological concentration ranges. This nuclear hormone receptor (PPARγ) regulates glucose homeostasis, lipid metabolism, and inflammation. PPARγ ligand activity is specific for LNO 2 and not mediated by LNO 2 decay products, NO donors, linoleic acid (LA), or oxidized LA. LNO 2 is a significantly more robust PPARγ ligand than other reported endogenous PPARγ ligands, including lysophosphatidic acid (16:0 and 18:1), 15-deoxy-Δ 12,14 -PGJ 2 , conjugated LA and azelaoyl-phosphocholine. LNO 2 activation of PPARγ via CV-1 cell luciferase reporter gene expression analysis revealed a ligand activity that rivals or exceeds synthetic PPARγ agonists such as rosiglitazone and ciglitazone, is coactivated by 9 cis -retinoic acid and is inhibited by the PPARγ antagonist GW9662. LNO 2 induces PPARγ-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.