Updating Phospholipase A2 Biology

Abstract

The phospholipase A₂ (PLA₂) superfamily contains more than 50 enzymes in mammals that are subdivided into several distinct families on a structural and biochemical basis. In principle, PLA₂ has the capacity to hydrolyze the sn-2 position of glycerophospholipids to release fatty acids and lysophospholipids, yet several enzymes in this superfamily catalyze other reactions rather than or in addition to the PLA₂ reaction. PLA₂ enzymes play crucial roles in not only the production of lipid mediators, but also membrane remodeling, bioenergetics, and body surface barrier, thereby participating in a number of biological events. Accordingly, disturbance of PLA₂-regulated lipid metabolism is often associated with various diseases. This review updates the current state of understanding of the classification, enzymatic properties, and biological functions of various enzymes belonging to the PLA₂ superfamily, focusing particularly on the novel roles of PLA₂s in vivo.

Keywords: fatty acid; knockout mouse; lipid mediator; lipidomics; lysophospholipid; membrane; phospholipase A2; phospholipid.

Figure 1

The roles of sPLA₂-IIA in anti-bacterial defense by degrading bacterial membrane and in sterile inflammation by releasing pro-inflammatory eicosanoids from extracellular microvesicles (EVs) derived from inflammatory cells.

Figure 2

The role of sPLA₂-IID expressed in M2 macrophages in adipocyte browning and adaptive thermogenesis. sPLA₂-IID releases ω3 PUFAs, which then act on GPR120 to drive the thermogenic and anti-inflammatory programs toward metabolic health. Impairment of this sPLA₂-IID-driven lipid pathway leads to impaired thermogenesis and exacerbated diet-induced obesity.

Figure 3

The role of endothelial sPLA₂-V in aortic stability. sPLA₂-V is a major sPLA₂ isoform expressed in aortic endothelial cells (ECs) and is largely retained on the luminal surface of the aortic endothelium likely through binding to heparin sulfate proteoglycans. Endothelial sPLA₂-V acts on membrane phospholipids of AT-II-activated ECs to mobilize oleic acid (OA) and linoleic acid (LA), which in turn promote AT-II-induced upregulation of lysyl oxidase (LOX) that facilitates ECM crosslinking, thereby stabilizing the aortic wall. Impairment of this sPLA₂-V-driven lipid pathway leads to increased susceptibility to aortic dissection.

Figure 4

Examples of PLA₂ enzymes that have unique enzymatic activity. (A) cPLA₂ε catalyzes an N-acyltransferase reaction, transferring the sn-1 fatty acid of PC to the amino group of PE to produce NAPE, which is then converted to NAE by NAPE-PLD. (B) PNPLA1 acts as a unique transacylase, transferring LA from triglyceride to ω-hydroxyceramide to give rise to ω-O-acylceramide, which is essential for skin barrier function.

Figure 5

The role of PAF-AH2 in mast cell activation by producing ω3 epoxides. PAF-AH2 constitutively hydrolyzes ω3 epoxide-esterified phospholipids in cell membranes to liberate ω3 epoxides. These unique ω3 PUFA metabolites attenuate PPARγ signaling and downregulate Srcin1, which blocks activation of the Src family kinases Fyn and Lyn, thereby augmenting FcεRI signaling.