15-Lipoxygenase metabolites of α-linolenic acid, [13-(S)-HPOTrE and 13-(S)-HOTrE], mediate anti-inflammatory effects by inactivating NLRP3 inflammasome

Abstract

The ratio of ω-6 to ω-3 polyunsaturated fatty acids (PUFAs) appears to be critical in the regulation of various pathophysiological processes and to maintain cellular homeostasis. While a high proportion of dietary intake of ω-6 PUFAs is associated with various inflammatory disorders, higher intake of ω-3 PUFAs is known to offer protection. It is now well established that beneficial effects of ω-3 PUFAs are mediated in part by their oxygenated metabolites mainly via the lipoxygenase (LOX) and cyclooxygenase (COX) pathways. However, the down-stream signaling pathways that are involved in these anti-inflammatory effects of ω-3 PUFAs have not been elucidated. The present study evaluates the effects of 15-LOX metabolites of α-linolenic acid (ALA, ω-3 PUFA) on lipopolysaccharide (LPS) induced inflammation in RAW 264.7 cells and peritoneal macrophages. Further, the effect of these metabolites on the survival of BALB/c mice in LPS mediated septic shock and also polymicrobial sepsis in Cecal Ligation and Puncture (CLP) mouse model was studied. These studies reveal the anti-inflammatory effects of 13-(S)-hydroperoxyoctadecatrienoic acid [13-(S)-HPOTrE] and 13-(S)-hydroxyoctadecatrienoic acid [13-(S)-HOTrE] by inactivating NLRP3 inflammasome complex through the PPAR-γ pathway. Additionally, both metabolites also deactivated autophagy and induced apoptosis. In mediating all these effects 13-(S)-HPOTrE was more potent than 13-(S)-HOTrE.

Postprandial effect to decrease soluble epoxide hydrolase activity: roles of insulin and gut microbiota

“…Numerous oxylipins derived from LA or ALA were significantly increased after the clamp, whereas many oxylipins derived from DHA or EPA decreased (Table 3). In particular, we noted that the clamp marked increased 9-HODE and 13-HODE, oxidative stress markers derived from LA [14, 15], and 9-HOTrE and 13- HOTrE, derived from ALA and known to exert anti-inflammatory effects [18, 19] ( P < 0.001; see Discussion). These precursor FFA-dependent changes in oxylipins might be related to differential changes in precursor FFA levels during the clamp; plasma levels of EPA or DHA levels might decrease as a result of inhibition of lipolysis in adipocytes by insulin, whereas plasma levels of LA or ALA might increase as a result of lipolysis of Intralipid infused during the clamp that provides LA and ALA (see Discussion).…”

“…In addition, insulin dramatically increased 9- and 13-HOTrE (23- and 18-fold, respectively) derived from ALA. Again, these increases may indicate more than mass action effects arising from increases in plasma ALA levels, as other ALA-derived oxylipins also increased but not as much as 9- or 13-HOTrE (Table 3). HOTrEs are known to exert anti-inflammatory effects [18, 19], and our data suggest that these effects of insulin to increase 9- or 13-HOTrE may contribute to its well-known anti-inflammatory effects [20]. …”

Twelve-Month Studies on Perilla Oil Intake in Japanese Adults—Possible Supplement for Mental Health

“…We consider that all these possibilities may coexist. The basis of these speculations are: (i) animals fed LNA-only diets might have brain DHA levels similar to DHA-fed animals [39]; (ii) dietary LNA is sufficiently converted to DHA to increase bioactive lipids derived from DHA in rats [40]; (iii) LNA metabolites can mediate cellular anti-inflammatory effects [41]; (iv) PO-fed rats [40] or cells directly treated with LNA [42] exhibit enhanced β-oxidation, signifying that LNA is a utilizable energy source; (v) long chain ω-3 PUFAs, including EPA and DHA, are formed from LNA via a series of desaturation and elongation reactions [43]; (vi) vegans and vegetarians, who consume negligible DHA, as it primarily originates from plankton-fed fish and marine animals, depend on LNA to provide adequate DHA to their brains [44][45][46]; and finally, (vii) the liver maintains the desaturase and elongase enzymes at their highest concentrations as compared to those in the brain [47,48]. DHA synthesis in the liver occurs at >30-fold higher rates than that in the brain [49].…”

Negative regulators and their mechanisms in NLRP3 inflammasome activation and signaling

“…Although this report did not interpret the inhibitory effects of PPAR‐δ agonist on the inflammasome complex assembly, PPAR‐δ agonist might function as a potential treatment of non‐alcoholic fatty liver diseases 70 . In addition, α‐linolenic acid (ω‐3 polyunsaturated fatty acid) inhibits the inflammatory responses in vitro and in vivo through inactivation of the NLRP3 inflammasome complex and the PPAR‐γ pathway 71 …”