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  • Another interesting finding regarding substrate selectivity

    2019-10-22

    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 plk1 inhibitor 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 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. Another important new result that has expanded the range of functions of iPLA2-VIA in physiology and pathophysiology is its implication in macrophage polarization under stimulation conditions. Ashley et al. [129] described in peritoneal macrophages from Pla2g6−/− mice that the absence of iPLA2-VIA facilitates macrophage polarization towards an anti-inflammatory M2 state, and modulates the expression of several enzymes involved in the synthesis of eicosanoid and reactive oxygen species. Conversely, the activation of genes involved in polarization to a pro-inflammatory M1 state is blunted in Pla2g6−/− macrophages. Overall, these results support a scenario where macrophage polarization may be dependent on signaling lipid molecules generated by PLA2s [129]. Regarding novel roles for iPLA2-IVA in metabolism, Deng et al. [130] recently demonstrated in Pla2g6−/− mice that the lack of the enzyme protects genetic obese mice from obesity and hepatic steatosis. The data support the notion that iPLA2-VIA has a pathophysiological function via phospholipid remodeling which ultimately results in the depletion of polyunsaturated fatty acids from PC and PE, especially those molecular species that carry palmitic or stearic acids at the sn-1 position. Inactivation of iPLA2-VIA reverses remodeling and establishes the return to normal homeostasis [130].
    An abundant body of work dating back from the 90\'s has documented the involvement of sPLA2-V in AA mobilization and attendant eicosanoid production [131]. In general terms, sPLA2-V acts by amplifying the action of cPLA2α, which is the key enzyme in the process, via activity-dependent or -independent mechanisms. sPLA2-V shows no clear fatty acid preference [24], and is able to release other fatty acids from cells, e.g. oleic acid or linoleic acid [[132], [133], [134]], with regulatory features that are strikingly similar to those of AA release. From these results it can be inferred that sPLA2-V may also be implicated in lipid metabolic pathways distinct from canonical AA signaling to exert its biological actions in vivo.