Abstract
In eukaryotes, the C20:4 polyunsaturated fatty acid arachidonic acid (AA) plays important roles as a phospholipid component, signaling molecule and precursor of the endocannabinoid-prostanoid axis. Accordingly, the absence of AA causes detrimental effects. Here, compensatory mechanisms involved in AA deficiency in Caenorhabditis elegans were investigated. We show that the ω-3 C20:4 polyunsaturated fatty acid juniperonic acid (JuA) is generated in the C. elegans fat-3(wa22) mutant, which lacks Δ6 desaturase activity and cannot generate AA and ω-3 AA. JuA partially rescued the loss of function of AA in growth and development. Additionally, we observed that supplementation of AA and ω-3 AA modulates lifespan of fat-3(wa22) mutants. We described a feasible biosynthetic pathway that leads to the generation of JuA from α-linoleic acid (ALA) via elongases ELO-1/2 and Δ5 desaturase which is rate-limiting. Employing liquid chromatography mass spectrometry (LC-MS/MS), we identified endocannabinoid-like ethanolamine and glycerol derivatives of JuA and ω-3 AA. Like classical endocannabinoids, these lipids exhibited binding interactions with NPR-32, a G protein coupled receptor (GPCR) shown to act as endocannabinoid receptor in C. elegans. Our study suggests that the eicosatetraenoic acids AA, ω-3 AA and JuA share similar biological functions. This biosynthetic plasticity of eicosatetraenoic acids observed in C. elegans uncovers a possible biological role of JuA and associated ω-3 endocannabinoids in Δ6 desaturase deficiencies, highlighting the importance of ALA.
Highlights
Fatty acids (FAs) are endogenous and dietary constituents that have far-reaching biological roles in the animal kingdom
While the classical ECs have already been reported in N2 (WT) C. elegans (i.e., 1/2-AG and AEA), we identified for the first time the ECs derived from ω-3 arachidonic acid (AA), namely ω-3 1/2-AG and ω-3 N-arachidonoyl ethanolamine (ω-3 AEA)
A deficiency in AA biosynthesis caused by mutations in the rate limiting enzyme ∆6 desaturase (FADS2) leads to significant immune response impairment in mice [46]
Summary
Fatty acids (FAs) are endogenous and dietary constituents that have far-reaching biological roles in the animal kingdom. FAs containing two or more double bonds in the acyl chain (i.e., polyunsaturated fatty acids, PUFAs) are bioavailable and can reach cells via diet. The ω-6 and ω-3 eicosatetraenoic acids (C20:4), the ω-3 eicosapentaenoic acid (C20:5) and the ω-3 docosahexaenoic acid (C22:6) constitute the main biologically important PUFAs [1]. In eukaryotes, they are both conserved and play distinct roles as constituents of membrane phospholipids, signaling molecules or substrates for oxygenases [2]. One of the most abundant and biologically relevant PUFA is the ω-6
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