Molecular recognition of nitrated fatty acids by PPARγ
Open accessAbstract
Peroxisome proliferator activated receptor-gamma (PPAR gamma) regulates metabolic homeostasis and adipocyte differentiation, and it is activated by oxidized and nitrated fatty acids. Here we report the crystal structure of the PPAR gamma ligand binding domain bound to nitrated linoleic acid, a potent endogenous ligand of PPAR gamma. Structural and functional studies of receptor-ligand interactions reveal the molecular basis of PPAR gamma discrimination of various naturally occurring fatty acid derivatives.
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NO2-FA signalling pathways are mediated through S-alkylation of nuclear factor κB (resulting in inhibition of macrophage cytokine and iNOS expression) and peroxisome proliferator-activated receptor-γ (PPAR-γ).
“Signalling pathways are mediated through S-alkylation of, for example, nuclear factor k B (resulting in inhibition of macrophage cytokine and iNOS expression) [194] and peroxisome proliferator-activated receptor-g (PPAR-g) [195].”
From Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway (2013) · cites this paper as [194]
The paper reports that nitrated linoleic acid binds and activates PPARγ, supporting PPARγ as a signalling target. Its receptor-binding passage describes hydrogen bonds with PPARγ residues, not S-alkylation of PPARγ; the NF-κB and macrophage effects are attached to a different citation in the citing sentence. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIncreased NOX1 promotes tumor angiogenesis and growth.
“For instance, knockdown of NOX1 can decrease angiogenesis (343), whereas increased NOX1 promotes tumor angiogenesis and growth (582).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [582]
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 [15]
Nitroalkene derivatives of fatty acids (NO2-FA) are partial agonists of peroxisome proliferator-activated receptor-γ (PPARγ), which they activate via hydrogen bonding interactions and covalent adduction of the ligand binding domain Cys285.
“NO2-FA are also partial agonists of peroxisome proliferator-activated receptor-γ (PPARγ), which NO2-FA activate via hydrogen bonding interactions and covalent adduction of the ligand binding domain Cys285 [19].”
From Olives and olive oil are sources of electrophilic fatty acid nitroalkenes (2014) · cites this paper as [19]
Nitroalkene derivatives of fatty acids (NO2-FA) instigate adaptive anti-inflammatory gene expression and metabolic responses.
“Since NO2-FA instigate adaptive anti-inflammatory gene expression and metabolic responses, these redox-derived metabolites may contribute to the cardiovascular benefits associated with the Mediterranean diet.”
From Olives and olive oil are sources of electrophilic fatty acid nitroalkenes (2014) · cites this paper as [19]
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- Authors
- Li, Y., Zhang, J., Schopfer, F. J., Martynowski, D., Garcia-Barrio, M. T., Kovach, A., Suino-Powell, K., Baker, P. R. S., Freeman, B. A., Chen, Y. E., & Xu, H. E.
- Affiliations
- Van Andel Institute (US)
- University of Michigan (US)
- University of Pittsburgh (US)
- Morehouse School of Medicine (US)
- Corresponding author
- Li, Yong
- Xu, H Eric
- Venue
- Nature Structural & Molecular Biology
- Published
- 2008-07-06
- Volume
- 15
- Issue
- 8
- Pages
- 865-867
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC2538624
- OpenAlex
- W1622211725
- Cited by
- 168
- References
- 16
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 5 · 2022: 4 · 2021: 7 · 2020: 4 · 2019: 11 · 2018: 14 · 2017: 9 · 2016: 5 · 2015: 11 · 2014: 10 · 2013: 10 · 2012: 20
- FWCI
- 7.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 64937, R01HL064937, HL 58115, R01HL089544, R01HL089301, R37HL058115, R01HL058115, HL68878, R01HL068878, R01HL075397, HL089544, HL089301, HL-75397)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK066202, DK066202, DK071662, R01DK071662)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- PPARγ, nitrated fatty acids, ligand-binding domain, crystal structure, nuclear receptor activation, oxidized fatty acids, ligand-receptor interactions, endogenous ligands, adipogenesis, metabolic homeostasis
- MeSH terms
- Cell Differentiation, Fatty Acids, Humans, Ligands, Models, Molecular, Molecular Conformation, Nitrogen, Oxygen, Protein Structure, Tertiary, Adipocytes, Crystallography, X-Ray, Linoleic Acid, PPAR gamma
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