Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids
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The peroxisome proliferator-activated receptor-gamma (PPARgamma) binds diverse ligands to transcriptionally regulate metabolism and inflammation. Activators of PPARgamma 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 PPARgamma ligands are intermediates of lipid metabolism and oxidation that bind PPARgamma with very low affinity. In contrast, nitro derivatives of unsaturated fatty acids (NO(2)-FA) are endogenous products of nitric oxide ((*)NO) and nitrite (NO(2)(-))-mediated redox reactions that activate PPARgamma at nanomolar concentrations. We report that NO(2)-FA act as partial agonists of PPARgamma and covalently bind PPARgamma at Cys-285 via Michael addition. NO(2)-FA show selective PPARgamma modulator characteristics by inducing coregulator protein interactions, PPARgamma-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 NO(2)-FA lower insulin and glucose levels without inducing adverse side effects such as the increased weight gain induced by TZDs.
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In murine models of metabolic syndrome, fatty acid nitroalkene administration at nanomolar concentrations limits weight gain and loss of insulin sensitivity.
“Thus, in murine models of metabolic and inflammatory injury, fatty acid nitroalkene administration at nanomolar concentrations prevents restenosis after vessel injury (49), limits weight gain and loss of insulin sensitivity in murine models of metabolic syndrome (14), protects against ischemia-reperfusion injury (17,47,50), reduces plaque formation in a rodent model of atherosclerosis (51), and in”
From Conjugated linoleic acid is a preferential substrate for fatty acid nitration (2012) · cites this paper as [14]
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Self-citation
- Authors
- Schopfer, F. J., Cole, M. P., Groeger, A. L., Chen, C.-S., Khoo, N. K. H., Woodcock, S. R., Golin-Bisello, F., Motanya, U. N., Li, Y., Zhang, J., Garcia-Barrio, M. T., Rudolph, T. K., Rudolph, V., Bonacci, G., Baker, P. R. S., Xu, H. E., Batthyany, C. I., Chen, Y. E., Hallis, T. M., & Freeman, B. A.
- Affiliations
- University of Pittsburgh (US)
- Van Andel Institute (US)
- University of Michigan (US)
- Morehouse School of Medicine (US)
- Universität Hamburg (DE)
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-04
- Volume
- 285
- Issue
- 16
- Pages
- 12321-12333
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2852971
- OpenAlex
- W2010571219
- Cited by
- 171
- References
- 44
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 8 · 2023: 3 · 2022: 2 · 2021: 8 · 2020: 12 · 2019: 15 · 2018: 13 · 2017: 9 · 2016: 11 · 2015: 18 · 2014: 12 · 2013: 15 · 2012: 10
- FWCI
- 6.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p30dk046204-15)
- National Heart, Lung, and Blood Institute (R01HL64937, R01HL064937, R01HL089544, R01HL089301, R37HL058115, R01HL058115, HL68878, R01HL068878, K99HL095769, R01-HL-58115, R01HL075397, HL089544, HL089301, HL-75397)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK066202, P30 DK 046204-15, DK066202, DK071662, R01DK071662, T32DK007052, P30-DK046204)
- 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, nitro-fatty acids, Michael addition, thiazolidinediones, rosiglitazone, PPARγ partial agonists, nitric oxide, nitrite, lipid accumulation, ob/ob mice, weight gain
- MeSH terms
- Rosiglitazone, Amino Acid Sequence, Animals, Base Sequence, Blood Glucose, Cell Line, Diabetes Mellitus, Fatty Acids, Unsaturated, Humans, Hypoglycemic Agents, Insulin, Ligands, Male, Mice, Inbred C57BL, Mice, Obese, Molecular Sequence Data, Nitro Compounds, Protein Binding, Protein Processing, Post-Translational, Recombinant Proteins, Signal Transduction, Mutagenesis, Site-Directed, Protein Structure, Tertiary, DNA Primers, Oleic Acid, Amino Acid Substitution, 3T3-L1 Cells, Thiazolidinediones, PPAR gamma, Lipid Metabolism, Mice, Tandem Mass Spectrometry, In Vitro Techniques
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