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Review
. 2014:76:79-105.
doi: 10.1146/annurev-physiol-021113-170341. Epub 2013 Oct 16.

Redox-dependent anti-inflammatory signaling actions of unsaturated fatty acids

Meghan Delmastro-Greenwood  1 , Bruce A Freeman, Stacy Gelhaus Wendell
Affiliations
Review

Redox-dependent anti-inflammatory signaling actions of unsaturated fatty acids

Meghan Delmastro-Greenwood et al. Annu Rev Physiol. 2014.

Abstract

Unsaturated fatty acids are metabolized to reactive products that can act as pro- or anti-inflammatory signaling mediators. Electrophilic fatty acid species, including nitro- and oxo-containing fatty acids, display salutary anti-inflammatory and metabolic actions. Electrophilicity can be conferred by both enzymatic and oxidative reactions, via the homolytic addition of nitrogen dioxide to a double bond or via the formation of α,β-unsaturated carbonyl and epoxide substituents. The endogenous formation of electrophilic fatty acids is significant and influenced by diet, metabolic, and inflammatory reactions. Transcriptional regulatory proteins and enzymes can sense the redox status of the surrounding environment upon electrophilic fatty acid adduction of functionally significant, nucleophilic cysteines. Through this covalent and often reversible posttranslational modification, gene expression and metabolic responses are induced. At low concentrations, the pleiotropic signaling actions that are regulated by these protein targets suggest that some classes of electrophilic lipids may be useful for treating metabolic and inflammatory diseases.

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Figures

Figure 1
Figure 1
Endogenously detected electrophilic fatty acids. Two examples of electrophilic fatty acids that have been endogenously detected are (a) nitro-conjugated linoleic acid (NO2-cLA) and (b) 13-oxo-docosahexaenoic acid (13-oxoDHA). An asterisk indicates an electrophilic carbon.
Figure 2
Figure 2
Dietary sources of electrophilic fatty acid precursors. (a) Leafy vegetables and cured meats are high in nitrate (NO3−) and nitrite (NO2−). NO3− can be reduced by bacteria in the saliva to NO2−. NO2− in the stomach can form nitrous acid, HNO2, which decomposes to nitrogen dioxide (•NO2). •NO2 is able to form an adduct with free fatty acids. (b) This addition reaction happens preferentially with conjugated linoleic acid (cLA) to form the electrophilic fatty acid NO2-cLA. Meat and dairy products are rich sources of cLA. Additionally, bacteria can convert vaccenic acid, an isomer of oleic acid, to cLA. (c) The essential Ω-3 and Ω-6 fatty acids, α-linolenic acid (18:3n-3) and linoleic acid (18:2n-6), are also obtained through dietary sources, including various seeds and oils. These essential fatty acids are the precursors to the most-studied fatty acids, arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). Because humans are not very efficient at making DHA and EPA from α-linolenic acid, dietary sources of these Ω-3 fatty acids, such as fish, are also very important.
Figure 3
Figure 3
(a) Reactive nitrogen and oxygen species formation of electrophilic fatty acids. Nitrate (NO3−) and nitrite (NO2−) are dietary sources of nitrogen dioxide (NO2•). NO3− is reduced to NO2− by enterosalivary bacteria. NO2−, combined with the low pH of the stomach, favors •NO2 formation via nitrous acid (HNO2) generation. Various oxides of nitrogen can form from the decomposition of HNO2 in the gut, including •NO2. •NO2 reacts with the π electrons of alkenes via an addition reaction, and a reaction with a second •NO2 results in double-bond reformation. In inflammation, •NO2 can arise from the protonation of NO2− to HNO2 or from NO2− oxidation by heme peroxidases. Another significant mechanism of •NO2 formation involves peroxynitrite (ONOO−) and peroxynitrous acid (ONOOH). These species mediate unsaturated fatty acid nitration and oxidation via homolysis of ONOOH to •NO2 and •OH. ONOO− also reacts with CO2 to form nitrosoperoxocarbonate (ONOOCO2), and like HNO2, this compound can undergo homolytic scission to form •NO2. Nonenzymatic formation of keto-fatty acids begins with initiation by free radical–mediated hydrogen atom abstraction. During the propagation reactions, molecular oxygen adds to a carbon-centered radical to form a peroxyl radical (COO•). This peroxyl radical is unstable and abstracts a hydrogen from another polyunsaturated fatty acid to form a peroxide. A peroxidase then converts the hydroperoxide to an hydroxyl group, which can be oxidized by a dehydrogenase to an α,β-unsaturated ketone. (b) Enzymatic electrophilic fatty acid formation. Ω-3 and Ω-6 fatty acids are oxidized by cyclooxygenase-2 (COX-2) or lipoxygenases (LOs) to hydroxylated lipid species. Therefore, LO or COX-2 hydroxylation at an olefinic carbon is the first step in the formation of an α,β-unsaturated carbonyl. Once the hydroxylated species is formed, one of a number of dehydrogenases can further oxidize the hydroxyl group to a ketone. COX-2 also metabolizes arachidonic acid (AA) to prostaglandin (PG)H2. A variety of PG synthases then form other PGs and thromboxane. PG synthases form PGD2 and PGE2, of which the two primary cyclopentenone prostaglandins, PGJ2 and PGA2, are metabolites, respectively. CYP450s also have epoxygenase abilities, and the CYP2C and CYP2J isoforms are primarily responsible for the formation of Ω-6-derived epoxides epoxyeicosatrienoic acids and Ω-3-derived epoxides. Although epoxides are electrophiles, they are not considered to be Michael acceptors. Asterisks indicate electrophilic carbons. Other abbreviations: cLA, conjugated linoleic acid; NO2-cLA, nitro-conjugated linoleic acid; NO2-OA, nitro-oleic acid; OA, oleic acid.
Figure 4
Figure 4
Transcriptional regulators as targets of electrophilic fatty acid modification. The endogenous production and exogenous administration of electrophilic fatty acids target multiple redox-sensing transcriptional regulators. In the cytoplasm, nitroalkenes (a) putatively bind HSF-1, releasing HSP70 and driving HSF-1-dependent gene transcription, and (b) covalently adduct Keap1, causing dissociation from and translocation of Nrf2 to induce ARE gene transcription. (c) The cyPG 15d-PGJ2 modifies the p65 subunit of NF-κB, sustaining inhibition by IκB and blocking p50/p65-dependent gene transcription. In the nucleus, (d) α,β-unsaturated electrophilic fatty acids covalently bind and act as partial PPARγ agonists, stimulating gene transcription. Abbreviations: 15d-PGJ2, 15-deoxy-prostaglandin J2; ARE, antioxidant-response element; cyPG, cyclopentenone prostaglandin; HSF-1, heat shock factor 1; HSP70, heat shock protein 70; IκB, inhibitor of κB; Keap1, kelch-like ECH-associated protein 1; NF-κB, nuclear factor-κB; Nrf2, nuclear factor (erythroid-derived 2)-like 2; PPARγ, peroxisome proliferator–activated receptor γ.
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