N-Arachidonoyl-ethanolamine (AEA) is an endocannabinoid (eCB) and endogenous lipid mimicking many of the effects of Δ9-tetrahydrocannabinol, notably on brain functions, appetite, pain and inflammation. The eCBs and eCB-like compounds contain fatty acids, the main classes being the monoacylglycerols and the N-acyl-ethanolamines (NAEs). Thus, each long chain fatty acid likely exists under the form of a monoacylglycerol and NAE, as it is the case for arachidonic acid (AA) and linoleic acid (LA). Following their biosynthesis, AA and AEA can be further metabolized into additional eicosanoids, notably by the 15-lipoxygenase pathway. Thus, we postulated that NAEs possessing a 1Z,4Z-pentadiene motif, near their omega end, would be transformed into their 15-lipoxygenase metabolites. As a proof of concept, we investigated N-linoleoyl-ethanolamine (LAE). We successfully synthesized LEA and LEA-d4 as well as their 15-lipoxygenase-derived derivatives, namely 13-hydroxy-9Z,11E-octadecadienoyl-N-ethanolamine (13-HODE-EA) and 13-HODE-EA-d4, using Novozyme 435 immobilized on acrylic resin and soybean lipoxygenase respectively. We also show that both human 15-lipoxygenase-1 and -2 can biosynthesize 13-HODE-EA. Co-incubation of LEA and LA with either human 15-lipoxygenase led to the biosynthesis of 13-HODE-EA and 13-HODE in a ratio equal to or greater than 3:1, indicating that LEA is preferred to LA by these enzymes. Finally, we show that 13-HODE-EA is found in human saliva and skin and is a weak although selective TRPV1 agonist. The full biological importance of 13-HODE-EA remains to be explored.
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Date of publication: August 2021; Biochimica et Biophysica Acta (BBA) – Molecular and Cell Biology of Lipids, Volume 1866, Issue 8, 2021, 158954
Author Information: Francesco Tinto (1,5), Anne-Sophie Archambault (1,5), Élizabeth Dumais (1,5), Volatiana Rakotoarivelo (1,5), Magdalena Kostrzew (1,2), Cyril Martin (1,5), Pier-Luc Plante (3), Yves Desjardins (3), Mélissa Simard (6), Roxane Pouliot (6), Luciano De Petrocellis (2), Alessia Ligresti (2), Vincenzo Di Marzo abcde, Nicolas Flamand (1,5)
(1) Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Faculté de médecine, Université Laval, Québec City, QC G1V 4G5, Canada
(2) Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche (CNR), Pozzuoli, Italy
(3) Institut sur la Nutrition et les Aliments Fonctionnels, Centre NUTRISS, École de nutrition, Faculté des sciences de l’agriculture et de l’alimentation, Université Laval, Québec City, Canada
(4) Joint International Unit between the CNR of Italy and Université Laval on Chemical and Biomolecular Research on the Microbiome and its Impact on Metabolic Health and Nutrition (UMI-MicroMeNu), Italy
(5) Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec City, Canada
(6) Faculté de pharmacie de l’Université Laval, Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Axe médecine régénératrice, Centre de recherche du CHU de Québec-Université Laval, Québec City, Canada