Abstract
The endocannabinoids 2-arachidonoyl-glycerol and N-arachidonoyl-ethanolamine are lipids regulating many physiological processes, notably inflammation. Endocannabinoid hydrolysis inhibitors are now being investigated as potential anti-inflammatory agents. In addition to 2-arachidonoyl-glycerol and N-arachidonoyl-ethanolamine, the endocannabinoidome also includes other monoacylglycerols and N-acyl-ethanolamines such as 1-linoleoyl-glycerol (1-LG) and N-linoleoyl-ethanolamine (LEA). By increasing monoacylglycerols and/or N-acyl-ethanolamine levels, endocannabinoid hydrolysis inhibitors will likely increase the levels of their metabolites. Herein, we investigated whether 1-LG and LEA were substrates for the 15-lipoxygenase pathway, given that both possess a 1Z,4Z-pentadiene motif, near their omega end. We thus assessed how human eosinophils and neutrophils biosynthesized the 15-lipoxygenase metabolites of 1-LG and LEA. Linoleic acid (LA), a well-documented substrate of 15-lipoxygenases, was used as positive control. N-13-hydroxy-octodecadienoyl-ethanolamine (13-HODE-EA) and 13-hydroxy-octodecadienoyl-glycerol (13-HODE-G), the 15-lipoxygenase metabolites of LEA and 1-LG, were synthesized using Novozym 435 and soybean lipoxygenase. Eosinophils, which express the 15-lipoxygenase-1, metabolized LA, 1-LG, and LEA into their 13-hydroxy derivatives. This was almost complete after five minutes. Substrate preference of eosinophils was LA > LEA > 1-LG in presence of 13-HODE-G hydrolysis inhibition with methyl-arachidonoyl-fluorophosphonate. Human neutrophils also metabolized LA, 1-LG, and LEA into their 13-hydroxy derivatives. This was maximal after 15–30 s. Substrate preference was LA ≫ 1-LG > LEA. Importantly, 13-HODE-G was found in humans and mouse tissue samples. In conclusion, our data show that human eosinophils and neutrophils metabolize 1-LG and LEA into the novel endogenous 15-lipoxygenase metabolites 13-HODE-G and 13-HODE-EA. The full biological importance of 13-HODE-G and 13-HODE-EA remains to be explored.
Highlights
IntroductionBioactive lipids mediatingtheir theireffects effectsmostly mostlyby byactivating activatingthe thecannabinoid canna(AEA)
The endocannabinoids2-arachidonoyl-glycerol (2-AG)(2-AG)and andN-arachidonoyl-ethanoN-arachidonoyl-ethanolamine lamine (AEA)bioactive lipids mediatingtheir theireffects effectsmostly mostlyby byactivating activatingthe thecannabinoid canna(AEA)areare bioactive lipids mediating binoid receptorsCB CBAs they modulate several physiological responses, receptors andAs such, modulate several physiological responses, the the most mostrecognized recognizedones onesbeing being nociception, nociception, appetite, appetite, adipogenesis, adipogenesis, and inflammation [1,2]. [1,2]
Methyl-arachidonoyl-fluorophosphonate (MAFP), linoleic acid, linoleoylglycerol, and linoleoyl-ethanolamine were purchased from Cayman Chemicals (Ann Arbor, MI, USA)
Summary
Bioactive lipids mediatingtheir theireffects effectsmostly mostlyby byactivating activatingthe thecannabinoid canna(AEA). Areare bioactive lipids mediating binoid receptorsCB CB. As they modulate several physiological responses, receptors and. Modulate several physiological responses, the the most mostrecognized recognizedones onesbeing being nociception, nociception, appetite, appetite, adipogenesis, adipogenesis, and inflammation [1,2]. 2-AG is hydrolyzed into into of 2-AG
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