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  • A major open question in the field of lipid mediators


    A major open question in the field of lipid mediators is the molecular nature of the PLA2 enzyme involved in the release of DHA and related omega-3 fatty acids from phospholipids as a first committed step for the generation of SPMs. Although by analogy with AA it is often assumed that cPLA2α may serve this role, currently there is no direct evidence for this and, as discussed in the previous section, the in vitro specificity data are not revealing in this regard. Importantly, several recent studies provide evidence to suggest that iPLA2-VIA may fulfill this role in brain. DHA is found at high concentrations in the sn-2 position of brain membrane phospholipids and is critical for maintaining normal brain structure, function and metabolism, participating in signal transduction, gene transcription, and membrane stability [110]. It has been shown that Pla2g6−/− mice exhibit disturbances in brain lipid composition and metabolism, which are associated with reduced incorporation of unesterified DHA from plasma into brain lipids and reduced esterified DHA concentrations in lipid classes [[111], [112], [113]]. Because DHA is the precursor of anti-inflammatory SPMs, the reduced brain DHA metabolism in the Pla2g6−/− mice may increase their vulnerability to neuroinflammation [[114], [115], [116], [117]]. An unexpected result regarding the substrate selectivity of iPLA2-VIA in cells has come from studies in mouse peritoneal macrophages [57]. Using pharmacological approaches and lipidomic strategies, evidence was obtained that cPLA2α and iPLA2-VIA act on different phospholipid pools. While the former regulates AA release and eicosanoid production, the later acts on phospholipids that do not contain AA. iPLA2-VIA appears to selectively hydrolyze choline glycerophospholipids with palmitic A 779 at the sn-1 position, resulting in the production of palmitate-containing lysoPC, a lysophospholipid species with defined biological roles [85,118] (Fig. 3). Thus, iPLA2-VIA also takes part in signaling cascades leading to the generation of lipid mediators. Interestingly, this selectivity of iPLA2-VIA for PC containing palmitic acid at the sn-1 position had also been appreciated in a prior study utilizing iPLA2-VIA-overexpressing HEK293 cells [119]. These two studies suggest more selectivity at the cellular level than observed for the in vitro selectivity of the pure recombinant human iPLA2-VIA for the sn-1 fatty acid or phospholipid headgroup [24], pointing out the intriguing possibility that, in a physiological environment, iPLA2-VIA could be compartmentalized in specific membranes enriched in palmitic acid-containing lipids. Another interesting finding regarding substrate selectivity of iPLA2-VIA in whole cellular systems stems from the observation that some of the major species hydrolyzed by the enzyme contain a 16:1 fatty acid at the sn-2 position [57,119], raising the possibility that iPLA2-VIA may constitute a major pathway for the mobilization of this fatty acid from membrane phospholipids. The most abundant 16:1 fatty acid of mammalian cells is palmitoleic acid (16:1n-7), and there is strong evidence that this free fatty acid possesses anti-inflammatory activity, and suppresses hepatic steatosis and improves insulin sensitivity in murine models of metabolic disease [120,121]. Two isomers of palmitoleic acid, namely cis-7-hexadecenoic acid (16:1n-9) and sapienic acid (16:1n-10), were later identified in monocytes and macrophages [122,123] and, at least the first one displays strong anti-inflammatory activity as well. Differences in the distribution of the three 16:1 isomers among membrane phospholipids were detected [122], suggesting that not all of them may be mobilized in a similar manner during activation and that the multiplicity of effects initially attributed to palmitoleic acid may reflect the overlapping actions of several 16:1 isomers acting in concert at the same locations. It is also notorious the discovery of a novel family of anti-inflammatory lipids that results from the esterification of the hydroxyl group of a hydroxy fatty acid with A 779 another fatty acid (collectively termed “branched fatty acid esters of hydroxy fatty acids”, FAHFAs) [[124], [125], [126], [127], [128]]. The hydroxyfatty acids forming FAHFAs possess 16 or 18 carbon atoms. Little is yet known of their biosynthesis, but it has been shown that they are produced endogenously, thus it is tempting to speculate that the 16‑carbon containing ones could derive from hydration of different isomers of 16:1 fatty acids.