Lysophospholipases cooperate to mediate lipid homeostasis and lysophospholipid signaling

Abstract

This article is available online at http://www.jlr.org ture, shape, and fluidity of cell membranes (1)(2)(3). Each LysoPL comprises one nonpolar acyl chain, varying in length and degree of unsaturation, and a polar glycerophosphate headgroup. Based on the structure of the headgroup, LysoPLs belong primarily to one of six classes, including lysophosphatidic acids (LPAs), lysophosphatidylcholines (LPCs), lysophosphatidylethanolamines (LPEs), lysophosphatidylglycerols (LPGs), lysophosphatidylinositols (LPIs), and lysophosphatidylserines (LPSs), each with distinct biological functions dependent on physiological location and availability of their respective cellular receptors.LysoPLs have been shown to elicit a wide range of biological effects, including cell proliferation, intracellular calcium mobilization, metabolic activity, inflammatory and antiinflammatory processes, and neuritogenesis (4-20). These effects are generally evoked through ligand-receptor interactions, but this is not always the case. For example, high physiological concentrations of LPCs (200 µM in human plasma) call into question a receptor agonist role in some circumstances, and accruing evidence supports the hypothesis that they can elicit effects by altering membrane properties or interacting directly with proteins in ways other than saturable binding to a specific site (21-24). Abstract Lysophospholipids (LysoPLs) are bioactive lipid species involved in cellular signaling processes and the regulation of cell membrane structure. LysoPLs are metabolized through the action of lysophospholipases, including lysophospholipase A1 (LYPLA1) and lysophospholipase A2 (LYPLA2).A new X-ray crystal structure of LYPLA2 compared with a previously published structure of LYPLA1 demonstrated nearidentical folding of the two enzymes; however, LYPLA1 and LYPLA2 have displayed distinct substrate specificities in recombinant enzyme assays. To determine how these in vitro substrate preferences translate into a relevant cellular setting and better understand the enzymes' role in LysoPL metabolism, CRISPR-Cas9 technology was utilized to generate stable KOs of Lypla1 and/or Lypla2 in Neuro2a cells. Using these cellular models in combination with a targeted lipidomics approach, LysoPL levels were quantified and compared between cell lines to determine the effect of losing lysophospholipase activity on lipid metabolism. This work suggests that LYPLA1 and LYPLA2 are each able to account for the loss of the other to maintain lipid homeostasis in cells; however, when both are deleted, LysoPL levels are dramatically increased, causing phenotypic and morphological changes to the cells.-Wepy, pholipases cooperate to mediate lipid homeostasis and lysophospholipid signaling. J. Lipid Res. 2019. 60: 360-374.Supplementary key words brain lipids • eicosanoids • prostaglandins • fatty acid • protein kinases/MAP kinase • lipidomics • mass spectrometry • fluorescence microscopy • neurons • X-ray crystallography Lysophospholipids (LysoPLs) are detergent-like lipid species that play a c...

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