Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2011 Oct 12;111(10):5997-6021.
doi: 10.1021/cr200131e. Epub 2011 Sep 20.

Formation and signaling actions of electrophilic lipids

Francisco J Schopfer  1 , Chiara Cipollina, Bruce A Freeman
Affiliations
Review

Formation and signaling actions of electrophilic lipids

Francisco J Schopfer et al. Chem Rev. .
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1
Reaction scheme of lipid derived electrophiles. (A) Bifunctional electrophiles, a hallmark of lipid breakdown products, react with cellular nucleophiles through Michael addition (α-β-unsaturated carbonyl) and Schiff’s base adduct formation (aldehyde). (B) Conjugated nitro-fatty acids react with thiolates at carbons β and δ to form two positional isomers. The adduction at the δ-carbon allows for a subsequent reaction with a nucleophile, allowing cross-linking reactions.
Figure 2
Figure 2
Structure of α-β-unsaturated ketones and nitroalkenes. (A) Enzymatic and nonenzymatic oxidation of polyunsaturated fatty acids results in the formation of α-β-, γ-δ-unsaturated ketones. Both carbons β and δ are electron poor (shown with an *) and are reactive toward nucleophiles. (B) Nitroalkene structures show a similar conjugation as α-β-unsaturated ketones, and C′β and C′δ are electrophilic. In both cases, the electrophilicity is not lost after an initial reaction with C′δ, allowing for a second nucleophile to react at C′β, permitting cross-linking reactions.
Figure 3
Figure 3
Different lipid-derived electrophilic groups. (A) Electrophiles containing carbonyl groups. (B) Electrophiles containing nitro groups.
Figure 4
Figure 4
Nitration of conjugated linoleic acid. The nitration of conjugated linoleic acid proceeds through an initial addition of nitrogen dioxide to the double bond, forming a resonance-stabilized radical. Under low oxygen conditions, a second nitrogen dioxide molecule reacts with the carbon-centered radical, generating an unstable nitrito intermediate that decomposes to form a conjugated nitro-linoleic acid and nitrous acid. In the presence of oxygen, a peroxyl radical is initially formed, that after reduction forms a nitro-hydroperoxy derivative. The peroxyl radical can be reduced to hydroxyl radical, followed by reduction to a nitro-hydroxy derivative or an oxidation to nitro-keto derivative. Although both the presence and absence of oxygen lead to electrophilic products, the final electrophilic groups are different, a nitroalkene formed in the absence of oxygen and an α-β-unsaturated keto in the presence of oxygen.
Figure 5
Figure 5
Keap1-dependent regulation of Nrf2 activity by electrophiles. (A) Functional domains of Keap1. (B) Under normal conditions, Keap1 binds to Nrf2 in the cytosol through the Kelch domain, promoting cullin 3-dependent Nrf2 ubiquitination. The ubiquitinated Nrf2 is degraded by the proteasome. In the presence of electrophiles, reaction with target cysteines in Keap1 occurs, destabilizing the interaction between Keap1 and Nrf2 and switching the ubiquitination reaction from Nrf2 to Keap1. Nrf2 accumulates in the nucleus, activating the expression of phase II gene. Ubiquitinated Keap1 is further degraded.
Figure 6
Figure 6
Dual pathway for the activation of HSF1 by electrophiles. HSPs, specifically HSP90 and HSP72, are basally bound to HSF1. The primary pathway through which electrophiles promote activation of HSF1 involves the electrophilic adduction of nucleophilic residues in HSP90 and HSP72. This destabilizes the interaction of HSP72 and HSP90 with HSF1. Free HSF1 becomes activated in a three-step process involving phosphorylation, trimerization, and nuclear translocation. The HSF1 homotrimer binds to specific heat shock elements (HSEs) to induce the expression of heat shock response genes, which include several HSP chaperones. A secondary pathway through which electrophiles may activate HSF1 is based on the hypothesis that protein electrophilic modifications increase superficial hydrophobicity, attracting HSPs and releasing HSF1.
Figure 7
Figure 7
NF-κB activation by pro-inflammatory stimuli and inhibition by electrophiles. Under basal conditions, IKKβ phosphorylates IκB, releasing the heterodimer p50/p65. Upon nuclear translocation, p65 activates the transcription of a variety of cytokine and inflammatory enzyme-coding genes. Adduction of IKKβ by electrophiles results in its inhibition, impairing NF-κB activation. Moreover, direct adduction of p65 inhibits its nuclear localization by most likely interfering with the dimerization that leads to NfkB dependent gene expression.
Figure 8
Figure 8
Regulation of insulin sensitivity by electrophiles through adduction and inhibition of PTP1B. Phosphatases play a critical role in maintaining cellular homeostasis by regulating and limiting phosphorylation and downstream signaling. In particular, the insulin receptor and its signaling pathway are tightly regulated by phosphorylation and dephosphorylation reactions. Activation of the insulin receptor leads to its phosphorylation and triggers the phosphorylation of the IRS protein family, resulting in downstream activation of kinases and modulation of metabolic enzymes and pathways. PTP1B exerts a tight control of these phosphorylation events. Adduction of PTP1B by electrophiles at the catalytic cysteine results in catalytic inhibition, prolonging the effects and intensity of regulated pathways, thus impacting glucose homeostasis and insulin sensitivity. Electrophiles modulate this pathway both directly (through covalent binding to PTP1B) and indirectly (through activation of the general metabolic regulator PPARγ).
See this image and copyright information in PMC

References

    1. Chattaraj PK, Sarkar U, Roy DR. Chem Rev. 2006;106:2065. - PubMed
    1. Makosza M, Wojciechowski K. Chem. Rev. 2004;104:2631. - PubMed
    1. Schultz TW, Carlson RE, Cronin MTD, Hermens JLM, Johnson R, O’Brien PJ, Roberts DW, Siraki A, Wallace KB, Veith GD. SAR QSAR Environ. Res. 2006;17:413. - PubMed
    1. LoPachin RM, Barber DS, Gavin T. Toxicol. Sci. 2008;104:235. - PMC - PubMed
    1. Enoch SJ, Cronin MTD. Crit. Rev. Toxicol. 40:728. - PubMed

Publication types