Michel Lagarde, Nathalie Bernoud-Hubac, Catherine Calzada, Evelyne Véricel, Michel Guichardant, Université de Lyon, UMR 1060 Inserm (CarMeN), IMBL, INSA-Lyon, Villeurbanne, France.
Polyunsaturated fatty acids (PUFA) in mammals all derive from the essential/indispensable ones, linoleic (18:2n-6) and linolenic (18:3n-3) acids. Most of them are esterified in membrane phospholipids (PLs) from which they can be directly mobilized by various phospholipases A2 or through phospholipases C and D, and cleavage of the resulting diacylglycerols and phosphatidates, respectively. Once released from PLs, they may be oxygenated by several dioxygenases (Cox and Lox) and monooxygenases into very potent derivatives that are promptly metabolized to arrest the biological responses. The main bioactive metabolites are hydroxy-octadecadienoic (HODEs) and hydroxy-octadecatrienoic (HOTEs/diHOTES) acids from 18:2n-6 and 18:3n-3, respectively, prostanoids from 20:3n-6, 20:4n-6, 20:5n-3 and 22:4n-6, leukotrienes from 20:3n-9, 20:4n-6 and 20:5n-3, as well as protectins and resolvins from 20:5n-3 and 22:6n-3. In addition, cytochrome P450-dependent monooxygenases produce PUFA epoxides and hydroxylated derivatives. Different locations of the metabolism, and kinetics in their production, must be taken into consideration as well as kinetics in their degradation, if we intend to approach the phenotypes of the biological systems related to those bioactive molecules. Some precursor PUFA such as 20:4n-6 and 22:6n-3 may also be transformed into ethanolamides and other amide derivatives that exhibit endocannabinoid activities, and may be further oxygenated by Cox and Lox to provide other bioactive derivatives such as prostamides. A lipidomic analysis of these precursors and metabolites should be completed with the measurement of non-enzyme-dependent peroxidation products for an overall metabolism. Ideally, this myriad of compounds should be all measured in function of time. All included, there are hundreds of precursors, bioactive oxygenated metabolites and degradation products to take into account in a fluxolipidomics approach.