Nitro-fatty acids: mechanisms of action, roles in metabolic diseases, and therapeutics

Nitro-fatty acids (NO₂-FAs) are a class of bioactive lipids that mediate metabolic, anti-oxidative stress, anti-inflammatory, and other signaling actions. Endogenously, NO₂-FAs are derived from the non-enzymatic reactions of unsaturated fatty acids with reactive nitrogen species. The electrophilic properties of the nitro group results in NO₂-FAs being able to undergo rapid and reversible reactions with biological nucleophiles, such as cysteine and histidine, thus supporting post-translational modifications of proteins. The reactions of NO₂-FAs with biological nucleophiles regulate a range of key signaling pathways involved in gene expression responses, enzyme activity, and cellular processes. In disease animal models, NO₂-FAs are produced under conditions of inflammation and oxidative stress and play a protective role in a variety of metabolic diseases, which have been associated with anti-atherosclerosis, blood-pressure lowering, and are involved in the regulation of glycolipid metabolism and insulin resistance. Based on these, more clinical studies might find a correlation between NO₂-FAs levels and pathophysiology in patients with metabolic diseases. Importantly, NO₂-FAs therapeutics are effective in clinical trials. In addition, dietary supplementation with nitrates and unsaturated fatty acids can endogenously increase NO₂-FAs levels in mice and humans. These findings support dietary approaches that increase the endogenous levels of NO₂-FAs might potentially reduce the risk of metabolic diseases. To identify the specific mechanism of action and therapeutic potential of NO₂-FAs, we have summarized the main mechanisms of action of NO₂-FAs in metabolic disease progression to provide insights for the development of new therapeutics for metabolic diseases.