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Cited by 428Peroxisome Proliferator-Activated ReceptorsFatty Acid Research and HealthParaoxonase enzyme and polymorphisms

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

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Schopfer, Francisco J., Lin, Yiming, Baker, Paul R. S., Cui, Taixing, Garcia-Barrio, Minerva, Zhang, Jifeng, Chen, Kai, Chen, Yuqing E. +1 more·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0408384102PMC PMC548962
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Abstract

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.

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  • NO2-FA are orders of magnitude more potent than native fatty acids in modulating similar transcriptional regulatory mechanisms of anti-inflammatory signaling.

    “Considering that nitroalkene fatty acid derivatives are readily generated from CLA and that NO 2 -FA are orders of magnitude more potent than native fatty acids in modulating similar transcriptional regulatory mechanisms of anti-inflammatory signaling (2,24), Fig. 6 reveals that nitroalkenes can mediate the transduction of many of the salutary signaling actions noted for both NO 2 Ϫ and CLA.”

    From Conjugated linoleic acid is a preferential substrate for fatty acid nitration (2012) · cites this paper as [24]

  • OA-NO2 activates PPARγ.

    “For instance, nitro derivatives of linoleic and oleic (OA-NO2) acids are activators of peroxisome proliferator-activated receptor-γ (PPARγ)14, 15”

    From Nitro-oleic acid inhibits angiotensin II-induced hypertension (2010) · cites this paper as [14]

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Authors
Schopfer, F. J., Lin, Y., Baker, P. R. S., Cui, T., Garcia-Barrio, M., Zhang, J., Chen, K., Chen, Y. E., & Freeman, B. A.
Affiliations
  • University of Alabama at Birmingham (US)
  • Department of Anesthesiology and Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294; and Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, GA 30310
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2005-02-08
Volume
102
Issue
7
Pages
2340-2345
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0408384102
PMC
PMC548962
OpenAlex
W2109692501
Cited by
428
References
41
Citations by year
2026: 6 · 2025: 9 · 2024: 13 · 2023: 4 · 2022: 6 · 2021: 10 · 2020: 10 · 2019: 15 · 2018: 10 · 2017: 11 · 2016: 10 · 2015: 18 · 2014: 22 · 2013: 24 · 2012: 18
FWCI
15.95
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5s06gm008248-23)
  • National Heart, Lung, and Blood Institute (HL 64937, R01HL064937, HL 58115, HL 075397, R25HL003676, HL-03676, HL-068878, R37HL058115, R01HL058115, R01HL068878, UH1HL003676, R01HL075397, T32HL007457)
  • National Institute of General Medical Sciences (S06 GM 08248, S06 GM-008248)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
Keywords
PPARγ, endogenous ligands, nitric oxide, nitroalkenes, linoleic acid, nuclear receptors, adipogenesis, glucose uptake, inflammation, thiazolidinediones
MeSH terms
Animals, Binding, Competitive, Cell Differentiation, Cell Line, Humans, Ligands, Linoleic Acids, Recombinant Fusion Proteins, Signal Transduction, Adipocytes, 3T3-L1 Cells, PPAR gamma, Mice

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