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  • On the opposite side sPLA X has

    2019-07-11

    On the opposite side, sPLA2-X has also been implicated in the pathology of cancer [167,168]. Human sPLA2-X induces lipid droplet formation in Ras-driven MDA-MB-231 triple-negative breast cancer BI-7273 and promotes their survival during nutrient stress. It acts through the products of its enzymatic activity, most likely by providing mono- and polyunsaturated free fatty acids from cell membrane phospholipids for triacylglycerol synthesis that favor lipid droplet formation and reduces the requirement for de novo lipogenesis, protecting the cell against lipotoxicity and nutrient deprivation [167,168].
    Oxidized phospholipids are formed from unsaturated acyl residues under oxidative stress in lipid membranes [169,170]. Oxidized phospholipids are frequently found in vascular tissues and lipoproteins, and usually contain an oxovaleroyl or glutaroyl residue at the sn-2 position, which result from the truncation and oxidation of an AA or EPA residue at C5. Traditionally, two PLA2 enzymes were thought to hydrolyze truncated phopholipids, namely PAF acetylhydrolase I (group VIIA PLA2), which is associated to liproproteins, and PAF acetylhydrolase II (group VIIB PLA2), which acts intracellularly. Recent work has demonstrated that a third PLA2, the lysosomal PLA2 (group XV PLA2) is also able to cleave oxidized phospholipids, thus uncovering a new catabolic pathway for the clearance of these molecules [171]. Recent work by Shimanaka et al. [172] has unveiled a novel and unexpected role for PAF acetylhydrolase II in regulating the production of a novel class of omega-3 epoxides in mast cells with key roles in mast cell activation and anaphylaxis. These epoxy omega-3 fatty acids are stored as esterified forms in membrane choline glycerophospholipids. Using bone marrow-derived mast cells from Pafah2−/− mice, it was demonstrated that PAF acetylhydrolase II is the specific enzyme that excises the epoxides away from the membrane. This way, PAF acetylhydrolase II initiates a novel signaling cascade mediated by epoxy omega-3 mediators that optimizes FcεRI-dependent mast cell activation [172]. Novel functions for other sPLA2s have been described based on the lipid that they generate. sPLA2-IIE acts preferentially on minor lipoprotein phospholipids, phosphatidylserine (PS) and PE [150]. sPLA2-IID has been found to release DHA from PE in lymph node membranes, suggesting that this enzyme may also constitute another “resolving sPLA2” that ameliorates inflammation through mobilizing DHA-derived pro-resolving lipid mediators [173]. Conversely, sPLA2-IIA has recently been described to BI-7273 target phospholipids in extracellular mitochondria that are released from activated platelets or leukocytes to accumulate at inflamed sites, thereby amplifying inflammation [174].
    CoA-independent transacylation reactions The most common forms of membrane glycerophospholipids contain two acyl chains attached to the sn-1 and sn-2 positions of the glycerol backbone by ester bonds. However, there are glycerophospholipids that possess an sn-1 ether bond instead of an ester bond. Additionally, some of these ether-containing phospholipids also possess a cis double bond that is conjugated with the ether oxygen, i.e. forming a vinyl ether (Fig. 4). These phospholipids are called plasmalogens. In humans, plasmalogens constitute about 20% of total phospholipid content [175], but their biological roles are still to be fully recognized. Because of the lack of a carbonyl group at the sn-1 position, plasmalogens allow for a tighter packing of phospholipids in the membrane, which results in decreased membrane fluidity, and favor the formation and stabilization of membrane lipid raft domains with key roles in cellular signaling. Plasmalogens are also thought to act as endogenous antioxidants [175,176]. Only two major kinds of plasmalogens are found in mammalian cells, i.e. those containing either choline or ethanolamine as headgroups [177,178]. Inositol-containing plasmalogens have also been described but their levels are exceedingly low [179]. While heart contains relatively high amounts of choline plasmalogens, ethanolamine plasmalogens are particularly abundant in innate immune cells such as monocytes and macrophages. Notably, in these cells, practically only polyunsaturated fatty acids of both the omega-6 and omega-3 series are to be found at the sn-2 position of ethanolamine plasmalogens, with AA being the most prevalent one (Fig. 4). Owing to such fatty acid composition, the importance of this class of lipids to PLA2-regulated pathways leading to generation of lipid mediators has long been recognized.