Nitration of PPARγ inhibits ligand‐dependent translocation into the nucleus in a macrophage‐like cell line, RAW 264

Abstract

Nitration of tyrosine residues in proteins has been observed in many in£ammatory tissues of arthritis, ulcerative colitis, septic shock and ischemia-reperfusion injury. Although several studies have been carried out, it is still unclear what type of protein is nitrated and whether tyrosine nitration interferes with protein function. Peroxisome proliferator-activated receptor gamma (PPARQ Q) is a nuclear receptor whose activation is linked to several physiological pathways including regulation of insulin sensitivity and control of in£ammation. PPARQ Q possesses several tyrosine residues, which might be potential targets for nitration by peroxynitrite during in£ammatory responses. Here we have investigated whether PPARQ Q is nitrated in macrophagelike RAW 264 cells and the e¡ect of nitration on the translocation of PPARQ Q into the nucleus. Western blot analysis showed that tumor necrosis factor-K K, lipopolysaccharide or peroxynitrite treatment signi¢cantly increases the nitration of PPARQ Q. Cell fractionation analysis and immuno£uorescence coupled with confocal laser microscopy revealed that nitration of PPARQ Q inhibits its ligand-dependent translocation from the cytosol into the nucleus. Together, these results indicate that nitration of PPARQ Q during in£ammation may be involved in a reduction in the control of in£ammatory responses and also in the development of resistance to PPARQ Q ligand-based therapies against in£ammation. ß

Cerium oxide nanoparticles protect against Aβ-induced mitochondrial fragmentation and neuronal cell death

“…44 For example, peroxisome proliferator-activated receptor gamma expression protects neurons from Abmediated toxicity; 45 however, its nitration prevents its translocation to the nucleus, thereby preventing mitochondrial biogenesis. 46 We also found that nanoceria blocked Ab-mediated mitochondrial fragmentation via a mechanism that involved reduction of DRP1 S616 hyperphosphorylation (Figure 5b). Although it is unlikely that nitrosative stress mediates mitochondrial fragmentation and neuronal cell death only by phosphorylation of a single protein target, such as DRP1, our data describe one possible pathway by which nanoceria can attenuate the downstream effects of RNS/ROS.…”

COX-2 and PPAR-γ Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells

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Polyunsaturated fatty acids: From diet to binding to ppars and other nuclear receptors

“…The impact of phosphorylation on the activity of PPARs depends on the residue being phosphorylated, and the kinase cascade that has been activated ; nitration of tyrosine residues in PPARγ inhibits the translocation from the cytosol to the nucleus (Shibuya et al, 2002). Ligand binding to PPARγ induces ubiquitilation (Hauser et al, 2000), and therefore receptor degradation, while ligand binding to PPARα stabilizes the receptor by decreasing its rate of ubiquitilation (Blanquart et al, 2002).…”