PLAAT5 as an N-acyltransferase responsible for the generation of anti-inflammatory N-acylethanolamines in testis

N-Acylethanolamines (NAEs) are a class of lipid mediators that exhibit anti-inflammatory and appetite-suppressive activities. Among them, palmitoylethanolamide (PEA) and arachidonoylethanolamide (AEA) bind to peroxisomal proliferator-activated receptor (PPAR) α and cannabinoid receptor CB1, respectively. N-Acyl-phosphatidylethanolamine (NAPE) as a precursor of NAEs is biosynthesized from membrane phospholipids by N-acyltransferases, which consist of group IVE cytosolic phospholipase A₂ε (cPLA₂ε) and PLAAT (phospholipase A and acyltransferase) family enzymes. While cPLA₂ε is responsible for the production of NAEs not only in specific tissues, including muscle, skin, and the stomach, but also under pathological conditions, such as psoriasis and brain ischemia, the involvement of the PLAAT family in vivo remains unclear. Considering the specific expression of PLAAT5 in testes, we investigated the potential role of PLAAT5 in the formation of NAEs in testes using PLAAT5-deficient (Plaat5^-/-) mice. High-performance liquid chromatography coupled with tandem mass spectrometry showed that PLAAT5 deficiency decreased the total level of NAEs by 61 %, with PEA and AEA being reduced by 64 % and 87 %, respectively. Following a treatment with cadmium chloride, an environmental toxin that induces testicular inflammation, the expression of inflammatory genes (Il6, Tnf, and Nos2) in testes was markedly higher in Plaat5^-/- mice than in Plaat5^+/+ mice, and their expression was attenuated by the administration of PEA and AEA. Furthermore, these anti-inflammatory effects were canceled by a co-treatment with the antagonists of PPARα or CB1. These results suggest that PLAAT5 is responsible for the biosynthesis of anti-inflammatory NAEs in testes.