Nitro-Fatty Acid Logistics: Formation, Biodistribution, Signaling, and Pharmacology

• Published in: Trends in endocrinology and metabolism Vol. 30; no. 8; pp. 505 - 519
• Main Authors: Schopfer, Francisco J., Khoo, Nicholas K.H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.08.2019
• Subjects: endogenous formation; inflammation; nitro-fatty acid; signaling; systemic distribution; nitro-fatty acid; signaling; endogenous formation; inflammation; systemic distribution
• ISSN: 1043-2760; 1879-3061
• DOI: 10.1016/j.tem.2019.04.009

In addition to supporting cellular energetic demands and providing building blocks for lipid synthesis, fatty acids (FAs) are precursors of potent signaling molecules. In particular, the presence of conjugated double bonds on the fatty-acyl chain provides a preferential target for nitration generating nitro-FAs (NO2-FAs). The formation of NO2-FAs is a nonenzymatic process that requires reactive nitrogen species and occurs locally at the site of inflammation or during gastric acidification. NO2-FAs are electrophilic and display pleiotropic signaling actions through reversible protein alkylation. This review focuses on the endogenously formed NO2-FAs' mechanism of absorption, systemic distribution, signaling, and preclinical models. Understanding the dynamics of these processes will facilitate targeted dietary interventions and further the current pharmacological development aimed at low-grade inflammatory diseases. Nitro-fatty acids (NO2-FAs) are endogenously formed through nonenzymatic mechanisms that require conjugated fatty acids (FAs) and nitrogen dioxide (•NO2), a reactive oxidation product of nitrite and nitric oxide (•NO). NO2-FAs are formed in the gastric compartment, at sites of inflammation and during ischemia-reperfusion.Nitro-conjugated linoleic acid (NO2-CLA) is the most abundant endogenously-formed NO2-FA and nitro oleic acid (NO2-OA) is a synthetic NO2-FA being developed as a drug.NO2-FAs exert cell signaling responses through their electrophilic reactivity by reversibly modifying cysteine residues. NO2-FAs regulate signaling activities, mainly through the activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heat shock response, and inhibition of NF-κB signaling.NO2-FAs are distributed to tissues and esterified to triglycerides.Endothelium is both protected by NO2-FAs and provides the necessary mechanism and regulation to transport NO2-FAs to surrounding tissues.NO2-FAs have been shown to be effective in a large range of preclinical animal models.