Nitroalkene fatty acids mediate activation of Nrf2/ARE-dependent and PPARγ-dependent transcription by distinct signaling pathways and with significantly different potencies
Open accessAbstract
Naturally occurring nitroalkene fatty acids (NAs) derived from oleic (NO(2)-OA) and linoleic (NO(2)-LA) acids mediate a variety of cellular responses. We examined the signaling pathways involved in NA activation of Nrf2/ARE-dependent versus PPARγ/PPRE-dependent transcription in human MCF7 breast cancer cells. Additionally, we compared the relative potencies of NO(2)-OA and NO(2)-LA in activating these two transcriptional programs. Here it is demonstrated that, in addition to the direct adduct formation of NA with the Nrf2 inhibitory protein, Keap1, shown by others, NA activation of Nrf2/ARE-mediated transcription results from increased nuclear Nrf2 levels and depends upon activation of the PI3K/AKT and PKC, but not ERK and JNK MAPK, signaling pathways. Examination of the relationship between NA stimulation of the Nrf2/ARE versus PPARγ/PPRE transcriptional programs revealed concentration-dependent activation of distinct signaling pathways that were readily distinguished by selective attenuation of Nrf2/ARE-dependent, but not PPARγ-dependent, transcription by inhibitors of PI3K and PKC. Moreover, measurable, statistically significant activation of PPARγ/PPRE-dependent transcription occurred at nanomolar concentrations of NAs-the 12-NO(2) isomer of NO(2)-LA showing the most potent activity-whereas significant activation of Nrf2/ARE-dependent transcription occurred at much higher NA concentrations (≥3 μM) with the NO(2)-OA isomers the most potent. These findings have implications for the physiological roles of NAs, suggesting that, at concentrations likely to be encountered in vivo, their direct activation of PPARγ transcription will dominate over their electrophilic activation of Nrf2 antioxidant/protective responses.
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Electrophilic derivatives of unsaturated fatty acids (nitroalkene and α,β-unsaturated carbonyl species) are critical proximal mediators of signaling actions, because electrophilic fatty acids are orders of magnitude more potent than native unsaturated fatty acids in modulating tissue-protective and adaptive signaling mechanisms.
“Notably, electrophilic derivatives of these unsaturated fatty acids (i.e.nitroalkene and ␣,-unsaturated carbonyl species) are critical proximal mediators of these signaling actions, because electrophilic fatty acids are orders of magnitude more potent than native unsaturated fatty acids in modulating these and other key tissue-protective and adaptive signaling mechanisms (2,3,11).”
From Conjugated linoleic acid is a preferential substrate for fatty acid nitration (2012) · cites this paper as [11]
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Conjugated linoleic acid is a preferential substrate for fatty acid nitration
Bonacci, G., Baker, P. R. S., Salvatore, S. R., Shores, D., Khoo, N. K. H., Koenitzer, J. R., Vitturi, D. A., Woodcock, S. R., Golin-Bisello, F., Cole, M. P., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.401356 · Cited by 147 · see citing works
- Authors
- Bates, D. J. P., Smitherman, P. K., Townsend, A. J., King, S. B., & Morrow, C. S.
- Affiliations
- Wake Forest University Health Sciences (US)
- Corresponding author
- Morrow, Charles S.
- ORCID
- King, S. Bruce
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-08-17
- Volume
- 50
- Issue
- 36
- Pages
- 7765-7773
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- PMC
- PMC3168690
- OpenAlex
- W1982552985
- Cited by
- 15
- References
- 49
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2022: 1 · 2019: 2 · 2017: 2 · 2015: 1 · 2013: 1 · 2012: 3
- FWCI
- 0.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA70338, R01CA070338)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Keywords
- Keap1, PI3K/Akt signaling, PKC signaling, MCF-7 cells, electrophilic activation, antioxidant response
- MeSH terms
- Alkenes, Humans, Linoleic Acids, Oleic Acids, Transcription, Genetic, Signal Transduction, Response Elements, Cell Line, Tumor, PPAR gamma, MAP Kinase Kinase 4, NF-E2-Related Factor 2
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