Diversity and function of membrane glycerophospholipids generated by the remodeling pathway in mammalian cells

  • Daisuke Hishikawa
    Affiliations
    Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
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  • Tomomi Hashidate
    Affiliations
    Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
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  • Takao Shimizu
    Affiliations
    Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan

    Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan
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  • Hideo Shindou
    Correspondence
    To whom correspondence should be addressed
    Affiliations
    Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan

    Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
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      Cellular membranes are composed of numerous kinds of glycerophospholipids with different combinations of polar heads at the sn-3 position and acyl moieties at the sn-1 and sn-2 positions, respectively. The glycerophospholipid compositions of different cell types, organelles, and inner/outer plasma membrane leaflets are quite diverse. The acyl moieties of glycerophospholipids synthesized in the de novo pathway are subsequently remodeled by the action of phospholipases and lysophospholipid acyltransferases. This remodeling cycle contributes to the generation of membrane glycerophospholipid diversity and the production of lipid mediators such as fatty acid derivatives and lysophospholipids. Furthermore, specific glycerophospholipid transporters are also important to organize a unique glycerophospholipid composition in each organelle. Recent progress in this field contributes to understanding how and why membrane glycerophospholipid diversity is organized and maintained.
      One of the major components of cellular membranes is a class of molecules known as glycerophospholipids, which are synthesized from glycerol-3-phosphate (G3P) in a de novo pathway that initially produces phosphatidic acid (PA) and diacylglycerol (DAG) or cytidine diphosphate-DAG (CDP-DAG) (
      • Kennedy E.P.
      The synthesis of cytidine diphosphate choline, cytidine diphosphate ethanolamine, and related compounds.
      ,
      • Kennedy E.P.
      The biological synthesis of phospholipids.
      ,
      • Holub B.J.
      • Kuksis A.
      Metabolism of molecular species of diacylglycerophospholipids.
      ). Via the de novo pathway, various types of glycerophospholipids with different polar heads at the sn-3 position in the glycerol backbone, such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), and cardiolipin (CL) are generated (
      • van Meer G.
      • Voelker D.R.
      • Feigenson G.W.
      Membrane lipids: where they are and how they behave.
      ,
      • Yamashita A.
      • Hayashi Y.
      • Nemoto-Sasaki Y.
      • Ito M.
      • Oka S.
      • Tanikawa T.
      • Waku K.
      • Sugiura T.
      Acyltransferases and transacylases that determine the fatty acid composition of glycerolipids and the metabolism of bioactive lipid mediators in mammalian cells and model organisms.
      ). Subsequently, glycerophospholipid acyl chains are remodeled by the orchestrated reactions of phospholipase As (PLAs), acyl-CoA synthases, transacylases, and lysophospholipid acyltransferases (LPLATs) (
      • Yamashita A.
      • Hayashi Y.
      • Nemoto-Sasaki Y.
      • Ito M.
      • Oka S.
      • Tanikawa T.
      • Waku K.
      • Sugiura T.
      Acyltransferases and transacylases that determine the fatty acid composition of glycerolipids and the metabolism of bioactive lipid mediators in mammalian cells and model organisms.
      ,
      • Murakami M.
      • Taketomi Y.
      • Miki Y.
      • Sato H.
      • Hirabayashi T.
      • Yamamoto K.
      Recent progress in phospholipase A(2) research: from cells to animals to humans.
      ,
      • Kita Y.
      • Ohto T.
      • Uozumi N.
      • Shimizu T.
      Biochemical properties and pathophysiological roles of cytosolic phospholipase A2s.
      ,
      • Shimizu T.
      Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation.
      ,
      • Shindou H.
      • Hishikawa D.
      • Harayama T.
      • Yuki K.
      • Shimizu T.
      Recent progress on acyl CoA: lysophospholipid acyltransferase research.
      ). This glycerophospholipid remodeling (also called Lands' cycle) was originally described in 1958 and is involved in the generation of a large variety of cellular glycerophospholipids (Fig. 1) (
      • Lands W.E.
      Metabolism of glycerolipides; a comparison of lecithin and triglyceride synthesis.
      ,
      • Yamashita A.
      • Sugiura T.
      • Waku K.
      Acyltransferases and transacylases involved in fatty acid remodeling of phospholipids and metabolism of bioactive lipids in mammalian cells.
      ). Thus far, investigations of glycerophospholipid remodeling have mainly focused on PLAs, especially in the production of lipid mediators (
      • Murakami M.
      • Taketomi Y.
      • Miki Y.
      • Sato H.
      • Hirabayashi T.
      • Yamamoto K.
      Recent progress in phospholipase A(2) research: from cells to animals to humans.
      ,
      • Kita Y.
      • Ohto T.
      • Uozumi N.
      • Shimizu T.
      Biochemical properties and pathophysiological roles of cytosolic phospholipase A2s.
      ,
      • Shimizu T.
      Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation.
      ). However, in recent years, various LPLATs have been identified from the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) and membrane bound O-acyltransferase (MBOAT) families (Table 1). Although studies with tissue homogenates initially suggested that each LPLAT recognizes a specific substrate, isolated LPLATs have shown promiscuous substrate specificities (
      • Yamashita A.
      • Hayashi Y.
      • Nemoto-Sasaki Y.
      • Ito M.
      • Oka S.
      • Tanikawa T.
      • Waku K.
      • Sugiura T.
      Acyltransferases and transacylases that determine the fatty acid composition of glycerolipids and the metabolism of bioactive lipid mediators in mammalian cells and model organisms.
      ,
      • Shindou H.
      • Hishikawa D.
      • Harayama T.
      • Yuki K.
      • Shimizu T.
      Recent progress on acyl CoA: lysophospholipid acyltransferase research.
      ,
      • Shindou H.
      • Hishikawa D.
      • Harayama T.
      • Eto M.
      • Shimizu T.
      Generation of membrane diversity by lysophospholipid acyltransferases.
      ). Because the acyl composition of membrane glycerophospholipids is known to affect not only the production of lipid mediators but also membrane properties, characterizing these LPLATs will reveal the biological importance of membrane glycerophospholipid diversity.
      Figure thumbnail gr1
      Fig. 1Biosynthetic pathways of glycerophospholipids. Upper panel shows the de novo synthesis (green lines) and the fatty acid remodeling (magenta lines) of glycerophospholipids. LPLATs involved in each reacylation of the lysophospholipids are indicated. Lower panel shows an example of the fatty acid remodeling of PC. In this reaction, PLA2s release fatty acid (arachidonic acid) from the sn-2 position of PC, while LPCATs catalyze the reacylation at the sn-2 position of LPC using acyl-CoA (arachidonoyl-CoA). The details are discussed in the text. PGP, phosphatidylglycerolphosphate.
      TABLE 1.Summary of characteristics of LPLATs
      Substrate In Vitro
      NameOther NamesLysophospholipidAcyl-CoAExpressionPhenotypes of KO, Knockdown, and Mutations In VivoReferences
      LPAAT1
      AGPAT family member.
      AGPAT1, LPAATαLPAUbiquitous(
      • West J.
      • Tompkins C.K.
      • Balantac N.
      • Nudelman E.
      • Meengs B.
      • White T.
      • Bursten S.
      • Coleman J.
      • Kumar A.
      • Singer J.W.
      • et al.
      Cloning and expression of two human lysophosphatidic acid acyltransferase cDNAs that enhance cytokine-induced signaling responses in cells.
      • Kume K.
      • Shimizu T.
      cDNA cloning and expression of murine 1-acyl-sn-glycerol-3-phosphate acyltransferase.
      )
      LPAAT2
      AGPAT family member.
      AGPAT2, LPAATβLPA, LPIAdipose, liver, pancreas, heartLipodystrophy, diabetes(
      • West J.
      • Tompkins C.K.
      • Balantac N.
      • Nudelman E.
      • Meengs B.
      • White T.
      • Bursten S.
      • Coleman J.
      • Kumar A.
      • Singer J.W.
      • et al.
      Cloning and expression of two human lysophosphatidic acid acyltransferase cDNAs that enhance cytokine-induced signaling responses in cells.
      ,
      • Eberhardt C.
      • Gray P.W.
      • Tjoelker L.W.
      Human lysophosphatidic acid acyltransferase. cDNA cloning, expression, and localization to chromosome 9q34.3.
      • Cortés V.A.
      • Curtis D.E.
      • Sukumaran S.
      • Shao X.
      • Parameswara V.
      • Rashid S.
      • Smith A.R.
      • Ren J.
      • Esser V.
      • Hammer R.E.
      • et al.
      Molecular mechanisms of hepatic steatosis and insulin resistance in the AGPAT2-deficient mouse model of congenital generalized lipodystrophy.
      )
      LPAAT3
      AGPAT family member.
      AGPAT3, LPAATγLPA, LPG, LPC, LPE, lyso-PAFPUFA-CoATestis, adipose, liver, kidney(
      • Yuki K.
      • Shindou H.
      • Hishikawa D.
      • Shimizu T.
      Characterization of mouse lysophosphatidic acid acyltransferase 3: an enzyme with dual functions in the testis.
      ,
      • Vergnes L.
      • Beigneux A.P.
      • Davis R.
      • Watkins S.M.
      • Young S.G.
      • Reue K.
      Agpat6 deficiency causes subdermal lipodystrophy and resistance to obesity.
      ,
      • Prasad S.S.
      • Garg A.
      • Agarwal A.K.
      Enzymatic activities of the human AGPAT isoform 3 and isoform 5: localization of AGPAT5 to mitochondria.
      )
      LPCAT1
      AGPAT family member.
      AGPAT9, Aytl2LPC, lyso-PAF, LPESaturated species, acetyl-CoAATII cells in lung, retinaReduction of DPPC in pulmonary surfactant, retinal degeneration(
      • Harayama T.
      • Shindou H.
      • Ogasawara R.
      • Suwabe A.
      • Shimizu T.
      Identification of a novel noninflammatory biosynthetic pathway of platelet-activating factor.
      ,
      • Nakanishi H.
      • Shindou H.
      • Hishikawa D.
      • Harayama T.
      • Ogasawara R.
      • Suwabe A.
      • Taguchi R.
      • Shimizu T.
      Cloning and characterization of mouse lung-type acyl-CoA:lysophosphatidylcholine acyltransferase 1 (LPCAT1). Expression in alveolar type II cells and possible involvement in surfactant production.
      • Bridges J.P.
      • Ikegami M.
      • Brilli L.L.
      • Chen X.
      • Mason R.J.
      • Shannon J.M.
      LPCAT1 regulates surfactant phospholipid synthesis and is required for transitioning to air breathing in mice.
      ,
      • Friedman J.S.
      • Chang B.
      • Krauth D.S.
      • Lopez I.
      • Waseem N.H.
      • Hurd R.E.
      • Feathers K.L.
      • Branham K.E.
      • Shaw M.
      • Thomas G.E.
      • et al.
      Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice.
      ,
      • Soupene E.
      • Fyrst H.
      • Kuypers F.A.
      Mammalian acyl-CoA:lysophosphatidylcholine acyltransferase enzymes.
      ,
      • Cheng L.
      • Han X.
      • Shi Y.
      A regulatory role of LPCAT1 in the synthesis of inflammatory lipids, PAF and LPC, in the retina of diabetic mice.
      )
      LPCAT2
      AGPAT family member.
      AGPAT11, Aytl1LPC, LPS, LPEPUFA-CoA, acetyl-CoASpleen, macrophage, neutrophil(
      • Shindou H.
      • Hishikawa D.
      • Nakanishi H.
      • Harayama T.
      • Ishii S.
      • Taguchi R.
      • Shimizu T.
      A single enzyme catalyzes both platelet-activating factor production and membrane biogenesis of inflammatory cells. Cloning and characterization of acetyl-CoA:LYSO-PAF acetyltransferase.
      ,
      • Soupene E.
      • Fyrst H.
      • Kuypers F.A.
      Mammalian acyl-CoA:lysophosphatidylcholine acyltransferase enzymes.
      )
      LPCAT3
      MBOAT family member.
      MBOAT5LPC, LPEPUFA-CoATestis, liver, kidneyHepatic inflammation in ob/ob mouse(
      • Hishikawa D.
      • Shindou H.
      • Kobayashi S.
      • Nakanishi H.
      • Taguchi R.
      • Shimizu T.
      Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity.
      ,
      • Zhao Y.
      • Chen Y.Q.
      • Bonacci T.M.
      • Bredt D.S.
      • Li S.
      • Bensch W.R.
      • Moller D.E.
      • Kowala M.
      • Konrad R.J.
      • Cao G.
      Identification and characterization of a major liver lysophosphatidylcholine acyltransferase.
      ,
      • Gijón M.A.
      • Riekhof W.R.
      • Zarini S.
      • Murphy R.C.
      • Voelker D.R.
      Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils.
      ,
      • Rong X.
      • Albert C.J.
      • Hong C.
      • Duerr M.A.
      • Chamberlain B.T.
      • Tarling E.J.
      • Ito A.
      • Gao J.
      • Wang B.
      • Edwards P.A.
      • et al.
      LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition.
      ,
      • Matsuda S.
      • Inoue T.
      • Lee H.C.
      • Kono N.
      • Tanaka F.
      • Gengyo-Ando K.
      • Mitani S.
      • Arai H.
      Member of the membrane-bound O-acyltransferase (MBOAT) family encodes a lysophospholipid acyltransferase with broad substrate specificity.
      )
      LPCAT4
      MBOAT family member.
      MBOAT2LPE, LPSOleoyl-CoATestis, epididymis, ovary, brain(
      • Hishikawa D.
      • Shindou H.
      • Kobayashi S.
      • Nakanishi H.
      • Taguchi R.
      • Shimizu T.
      Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity.
      ,
      • Gijón M.A.
      • Riekhof W.R.
      • Zarini S.
      • Murphy R.C.
      • Voelker D.R.
      Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils.
      )
      LPEAT1
      MBOAT family member.
      MBOAT1LPEOleoyl-CoATestis, epididymis, ovary, brainBrachydactyly-syndactyly syndrome(
      • Hishikawa D.
      • Shindou H.
      • Kobayashi S.
      • Nakanishi H.
      • Taguchi R.
      • Shimizu T.
      Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity.
      ,
      • Gijón M.A.
      • Riekhof W.R.
      • Zarini S.
      • Murphy R.C.
      • Voelker D.R.
      Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils.
      )
      LPEAT2
      AGPAT family member.
      AGPAT7, Aytl3, LPCAT4LPIBrain(
      • Cao J.
      • Shan D.
      • Revett T.
      • Li D.
      • Wu L.
      • Liu W.
      • Tobin J.F.
      • Gimeno R.E.
      Molecular identification of a novel mammalian brain isoform of acyl-CoA:lysophospholipid acyltransferase with prominent ethanolamine lysophospholipid acylating activity, LPEAT2.
      )
      LPIAT1
      MBOAT family member.
      MBOAT7, MBOA7LPIPUFA-CoAUbiquitousPostnatal lethal, atrophy of the cerebral cortex and hippocampus, altered fatty acid composition of PI and PIPs(
      • Lee H.C.
      • Inoue T.
      • Imae R.
      • Kono N.
      • Shirae S.
      • Matsuda S.
      • Gengyo-Ando K.
      • Mitani S.
      • Arai H.
      Caenorhabditis elegans mboa-7, a member of the MBOAT family, is required for selective incorporation of polyunsaturated fatty acids into phosphatidylinositol.
      ,
      • Yuki K.
      • Shindou H.
      • Hishikawa D.
      • Shimizu T.
      Characterization of mouse lysophosphatidic acid acyltransferase 3: an enzyme with dual functions in the testis.
      ,
      • Anderson K.E.
      • Kielkowska A.
      • Durrant T.N.
      • Juvin V.
      • Clark J.
      • Stephens L.R.
      • Hawkins P.T.
      Lysophosphatidylinositol-acyltransferase-1 (LPIAT1) is required to maintain physiological levels of PtdIns and PtdInsP(2) in the mouse.
      ,
      • Lee H.C.
      • Inoue T.
      • Sasaki J.
      • Kubo T.
      • Matsuda S.
      • Nakasaki Y.
      • Hattori M.
      • Tanaka F.
      • Udagawa O.
      • Kono N.
      • et al.
      LPIAT1 regulates arachidonic acid content in phosphatidylinositol and is required for cortical lamination in mice.
      )
      LPGAT1
      AGPAT family member.
      LPGLiver, heart, small intestine, kidney(
      • Yang Y.
      • Cao J.
      • Shi Y.
      Identification and characterization of a gene encoding human LPGAT1, an endoplasmic reticulum-associated lysophosphatidylglycerol acyltransferase.
      )
      LCLAT1
      AGPAT family member.
      AGPAT8, ALCAT1, LYCAT1LCL, LPG, LPA, LPI (2-acyl and 1-acyl)Liver, heart, pancreas, kidneyProtected from obesity and insulin resistance, prevent of T4-induced cardiomyopathy, altered fatty acid composition of PI and PIPs(
      • Yamashita A.
      • Hayashi Y.
      • Nemoto-Sasaki Y.
      • Ito M.
      • Oka S.
      • Tanikawa T.
      • Waku K.
      • Sugiura T.
      Acyltransferases and transacylases that determine the fatty acid composition of glycerolipids and the metabolism of bioactive lipid mediators in mammalian cells and model organisms.
      ,
      • Li J.
      • Romestaing C.
      • Han X.
      • Li Y.
      • Hao X.
      • Wu Y.
      • Sun C.
      • Liu X.
      • Jefferson L.S.
      • Xiong J.
      • et al.
      Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity.
      • Imae R.
      • Inoue T.
      • Nakasaki Y.
      • Uchida Y.
      • Ohba Y.
      • Kono N.
      • Nakanishi H.
      • Sasaki T.
      • Mitani S.
      • Arai H.
      LYCAT, a homologue of C. elegans acl-8, acl-9, and acl-10, determines the fatty acid composition of phosphatidylinositol in mice.
      )
      TAZ
      AGPAT family member.
      G4.5LCLTransacylationHeart, skeletal muscleBarth syndrome, accumulation of MLCL and altered CL composition, cardiac abnormalities, impaired oxygen consumption rates during an exercise(
      • Xu Y.
      • Kelley R.I.
      • Blanck T.J.
      • Schlame M.
      Remodeling of cardiolipin by phospholipid transacylation.
      ,
      • Bione S.
      • D'Adamo P.
      • Maestrini E.
      • Gedeon A.K.
      • Bolhuis P.A.
      • Toniolo D.
      A novel X-linked gene, G4.5. is responsible for Barth syndrome.
      ,
      • Soustek M.S.
      • Falk D.J.
      • Mah C.S.
      • Toth M.J.
      • Schlame M.
      • Lewin A.S.
      • Byrne B.J.
      Characterization of a transgenic short hairpin RNA-induced murine model of Tafazzin deficiency.
      ,
      • Xu Y.
      • Zhang S.
      • Malhotra A.
      • Edelman-Novemsky I.
      • Ma J.
      • Kruppa A.
      • Cernicica C.
      • Blais S.
      • Neubert T.A.
      • Ren M.
      • et al.
      Characterization of tafazzin splice variants from humans and fruit flies.
      • Powers C.
      • Huang Y.
      • Strauss A.
      • Khuchua Z.
      Diminished Exercise Capacity and Mitochondrial bc1 Complex Deficiency in Tafazzin-Knockdown Mice.
      )
      Gene names, families, substrates preferences, mRNA expression patterns, and in vivo functions of LPLATs are summarized. Please note that there are several inconsistent reports about the enzymatic substrates in vitro.
      a AGPAT family member.
      b MBOAT family member.
      In mammalian cells, glycerophospholipid composition differs among cell types, organelles, and inner/outer membranes, and these differences are known to play important roles in various cellular functions including signal transduction, vesicle trafficking, and membrane fluidity (
      • van Meer G.
      • Voelker D.R.
      • Feigenson G.W.
      Membrane lipids: where they are and how they behave.
      ). Recently, several molecules involved in phospholipid transport between membranes and in phospholipid scrambling in plasma membranes have been identified. These factors are also important for constructing the specific composition of local membranes.
      In this review, we summarize and discuss the biological importance of the variety of membrane glycerophospholipids generated via glycerophospholipid remodeling by LPLATs.

      GENERATION OF PUFA-CONTAINING GLYCEROPHOSPHOLIPIDS

      Glycerophospholipid remodeling by the concerted action of PLAs and LPLATs is important for the production of PUFA-containing glycerophospholipids (
      • Shimizu T.
      Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation.
      ). Glycerophospholipids containing PUFAs, such as arachidonic acid, linoleic acid, EPA, and DHA, are known as major sources of fatty acid-derived lipid mediators and endocannabinoids (
      • Shimizu T.
      Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation.
      ,
      • Serhan C.N.
      • Chiang N.
      • Van Dyke T.E.
      Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.
      ,
      • Vangaveti V.
      • Baune B.T.
      • Kennedy R.L.
      Hydroxyoctadecadienoic acids: novel regulators of macrophage differentiation and atherogenesis.
      ,
      • Piomelli D.
      • Sasso O.
      Peripheral gating of pain signals by endogenous lipid mediators.
      ). Although numerous studies have shown the importance of PLAs in producing lipid mediators, the involvement of LPLATs in lipid mediator production is poorly understood (
      • Murakami M.
      • Taketomi Y.
      • Miki Y.
      • Sato H.
      • Hirabayashi T.
      • Yamamoto K.
      Recent progress in phospholipase A(2) research: from cells to animals to humans.
      ,
      • Kita Y.
      • Ohto T.
      • Uozumi N.
      • Shimizu T.
      Biochemical properties and pathophysiological roles of cytosolic phospholipase A2s.
      ).
      At present, lyso-PC (LPC) acyltransferase (LPCAT)2, LPCAT3, lyso-PI (LPI) acyltransferase (LPIAT)1, and lyso-PA (LPA) acyltransferase (LPAAT)3 are reported to incorporate PUFAs into lysophospholipids with different acceptor preferences (
      • Shindou H.
      • Hishikawa D.
      • Nakanishi H.
      • Harayama T.
      • Ishii S.
      • Taguchi R.
      • Shimizu T.
      A single enzyme catalyzes both platelet-activating factor production and membrane biogenesis of inflammatory cells. Cloning and characterization of acetyl-CoA:LYSO-PAF acetyltransferase.
      ,
      • Hishikawa D.
      • Shindou H.
      • Kobayashi S.
      • Nakanishi H.
      • Taguchi R.
      • Shimizu T.
      Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity.
      ,
      • Zhao Y.
      • Chen Y.Q.
      • Bonacci T.M.
      • Bredt D.S.
      • Li S.
      • Bensch W.R.
      • Moller D.E.
      • Kowala M.
      • Konrad R.J.
      • Cao G.
      Identification and characterization of a major liver lysophosphatidylcholine acyltransferase.
      ,
      • Lee H.C.
      • Inoue T.
      • Imae R.
      • Kono N.
      • Shirae S.
      • Matsuda S.
      • Gengyo-Ando K.
      • Mitani S.
      • Arai H.
      Caenorhabditis elegans mboa-7, a member of the MBOAT family, is required for selective incorporation of polyunsaturated fatty acids into phosphatidylinositol.
      ,
      • Yuki K.
      • Shindou H.
      • Hishikawa D.
      • Shimizu T.
      Characterization of mouse lysophosphatidic acid acyltransferase 3: an enzyme with dual functions in the testis.
      ). LPCAT3 is ubiquitously expressed, especially in liver, testis, kidney, pancreas, and adipose tissue (
      • Hishikawa D.
      • Shindou H.
      • Kobayashi S.
      • Nakanishi H.
      • Taguchi R.
      • Shimizu T.
      Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity.
      ,
      • Zhao Y.
      • Chen Y.Q.
      • Bonacci T.M.
      • Bredt D.S.
      • Li S.
      • Bensch W.R.
      • Moller D.E.
      • Kowala M.
      • Konrad R.J.
      • Cao G.
      Identification and characterization of a major liver lysophosphatidylcholine acyltransferase.
      ). Expression of LPCAT3 mRNA is controlled by PPARα and liver X receptors, and is induced during adipogenesis (
      • Demeure O.
      • Lecerf F.
      • Duby C.
      • Desert C.
      • Ducheix S.
      • Guillou H.
      • Lagarrigue S.
      Regulation of LPCAT3 by LXR.
      ,
      • Eto M.
      • Shindou H.
      • Koeberle A.
      • Harayama T.
      • Yanagida K.
      • Shimizu T.
      Lysophosphatidylcholine acyltransferase 3 is the key enzyme for incorporating arachidonic acid into glycerophospholipids during adipocyte differentiation.
      ). Knockdown of LPCAT3 by siRNA reduces arachidonic acid incorporation into PC and production of eicosanoids (
      • Ishibashi M.
      • Varin A.
      • Filomenko R.
      • Lopez T.
      • Athias A.
      • Gambert P.
      • Blache D.
      • Thomas C.
      • Gautier T.
      • Lagrost L.
      • et al.
      Liver X receptor regulates arachidonic acid distribution and eicosanoid release in human macrophages: a key role for lysophosphatidylcholine acyltransferase 3.
      ). Similar results were obtained from the treatment of thimerosal, a LPLAT inhibitor, and triacsin C, an acyl-CoA synthetase inhibitor (
      • Goppelt-Struebe M.
      • Koerner C.F.
      • Hausmann G.
      • Gemsa D.
      • Resch K.
      Control of prostanoid synthesis: role of reincorporation of released precursor fatty acids.
      ,
      • Kaever V.
      • Goppelt-Strube M.
      • Resch K.
      Enhancement of eicosanoid synthesis in mouse peritoneal macrophages by the organic mercury compound thimerosal.
      ,
      • Gijón M.A.
      • Riekhof W.R.
      • Zarini S.
      • Murphy R.C.
      • Voelker D.R.
      Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils.
      ,
      • Hartman E.J.
      • Omura S.
      • Laposata M.
      Triacsin C: a differential inhibitor of arachidonoyl-CoA synthetase and nonspecific long chain acyl-CoA synthetase.
      ,
      • Kuwata H.
      • Yoshimura M.
      • Sasaki Y.
      • Yoda E.
      • Nakatani Y.
      • Kudo I.
      • Hara S.
      Role of long-chain acyl-coenzyme A synthetases in the regulation of arachidonic acid metabolism in interleukin 1β-stimulated rat fibroblasts.
      ). These reports suggested that the control of arachidonic acid pools in membrane glycerophospholipids is important for the eicosanoid production. Furthermore, it has been reported that induction of LPCAT3 ameliorates saturated free fatty acid-induced endoplasmic reticulum (ER) stress in vitro (
      • Rong X.
      • Albert C.J.
      • Hong C.
      • Duerr M.A.
      • Chamberlain B.T.
      • Tarling E.J.
      • Ito A.
      • Gao J.
      • Wang B.
      • Edwards P.A.
      • et al.
      LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition.
      ). Using liver-specific LPCAT3 overexpression and knockdown mice, the study demonstrated that LPCAT3 regulates hepatic inflammatory cytokine levels and inflammation. Although the exact mechanism is unclear, the authors suggest that LPCAT3 may control inflammation by altering the fatty acid composition of PC.
      Although LPCAT2 and LPCAT3 can produce arachidonic acid-containing PC, the substrate preference and expression pattern for each differs. While LPCAT3 prefers 1-acyl LPC as an acyl acceptor, LPCAT2 utilizes both 1-acyl LPC and 1-alkyl LPC (
      • Shindou H.
      • Hishikawa D.
      • Nakanishi H.
      • Harayama T.
      • Ishii S.
      • Taguchi R.
      • Shimizu T.
      A single enzyme catalyzes both platelet-activating factor production and membrane biogenesis of inflammatory cells. Cloning and characterization of acetyl-CoA:LYSO-PAF acetyltransferase.
      ,
      • Hishikawa D.
      • Shindou H.
      • Kobayashi S.
      • Nakanishi H.
      • Taguchi R.
      • Shimizu T.
      Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity.
      ,
      • Zhao Y.
      • Chen Y.Q.
      • Bonacci T.M.
      • Bredt D.S.
      • Li S.
      • Bensch W.R.
      • Moller D.E.
      • Kowala M.
      • Konrad R.J.
      • Cao G.
      Identification and characterization of a major liver lysophosphatidylcholine acyltransferase.
      ). LPCAT2 is highly expressed in inflammatory cells such as macrophages and neutrophils, which contain ether-phospholipids, and LPCAT2 is believed to contribute to the production of lipid mediators in these cells (
      • Shindou H.
      • Hishikawa D.
      • Nakanishi H.
      • Harayama T.
      • Ishii S.
      • Taguchi R.
      • Shimizu T.
      A single enzyme catalyzes both platelet-activating factor production and membrane biogenesis of inflammatory cells. Cloning and characterization of acetyl-CoA:LYSO-PAF acetyltransferase.
      ). Induction of LPCAT2 has been observed in three scenarios: i) in macrophages by lipopolysaccharide and CpG oligodeoxynucleotide 1826 stimulation; ii) in the spinal cords of mice with experimental allergic encephalomyelitis; and iii) in mice with peripheral nerve injury (
      • Shindou H.
      • Hishikawa D.
      • Nakanishi H.
      • Harayama T.
      • Ishii S.
      • Taguchi R.
      • Shimizu T.
      A single enzyme catalyzes both platelet-activating factor production and membrane biogenesis of inflammatory cells. Cloning and characterization of acetyl-CoA:LYSO-PAF acetyltransferase.
      ,
      • Kihara Y.
      • Yanagida K.
      • Masago K.
      • Kita Y.
      • Hishikawa D.
      • Shindou H.
      • Ishii S.
      • Shimizu T.
      Platelet-activating factor production in the spinal cord of experimental allergic encephalomyelitis mice via the group IVA cytosolic phospholipase A2-lyso-PAFAT axis.
      ,
      • Okubo M.
      • Yamanaka H.
      • Kobayashi K.
      • Kanda H.
      • Dai Y.
      • Noguchi K.
      Up-regulation of platelet-activating factor synthases and its receptor in spinal cord contribute to development of neuropathic pain following peripheral nerve injury.
      ). These observations support the hypothesis that LPCAT2 may be involved in lipid mediator production under inflammatory conditions. In addition to LPCAT activity, LPCAT2 and LPCAT1 also possess lyso-platelet-activating factor (PAF) acetyltransferase (lysoPAFAT) activity for the production of PAF (
      • Shindou H.
      • Hishikawa D.
      • Nakanishi H.
      • Harayama T.
      • Ishii S.
      • Taguchi R.
      • Shimizu T.
      A single enzyme catalyzes both platelet-activating factor production and membrane biogenesis of inflammatory cells. Cloning and characterization of acetyl-CoA:LYSO-PAF acetyltransferase.
      ,
      • Harayama T.
      • Shindou H.
      • Ogasawara R.
      • Suwabe A.
      • Shimizu T.
      Identification of a novel noninflammatory biosynthetic pathway of platelet-activating factor.
      ). It has been reported that LPCAT2, but not LPCAT1, is activated by phosphorylation at Ser34 by lipopolysaccharide stimulation for 30 min (
      • Morimoto R.
      • Shindou H.
      • Oda Y.
      • Shimizu T.
      Phosphorylation of lysophosphatidylcholine acyltransferase 2 at Ser34 enhances platelet-activating factor production in endotoxin-stimulated macrophages.
      ). The biological importance of the dual activities in PAF and PAF-precursor glycerophospholipid production remains to be elucidated.
      In general, it is thought that PUFAs are mainly incorporated into glycerophospholipids in the remodeling pathway. However, DHA-containing glycerophospholipids are synthesized in the remodeling pathway as well as in the de novo pathway, because CDP-ethanolamine:DAG ethanolamine transferase and PE-N-methyltransferase prefer DHA-containing DAG and PE, respectively, in rat liver microsomes (
      • Kanoh H.
      Biosynthesis of molecular species of phosphatidyl choline and phosphatidyl ethanolamine from radioactive precursors in rat liver slices.
      ,
      • Kanoh H.
      • Ohno K.
      Substrate-selectivity of rat liver microsomal 1,2-diacylglycerol: CDP-choline(ethanolamine) choline(ethanolamine)phosphotransferase in utilizing endogenous substrates.
      ,
      • Holub B.J.
      Differential utilization of 1-palmitoyl and 1-stearoyl homologues of various unsaturated 1,2-diacyl-sn-glycerols for phosphatidylcholine and phosphatidylethanolamine synthesis in rat liver microsomes.
      ). In fact, LPAAT3 can produce DHA-containing PA, and LPAAT3 may contribute to the production of DHA-containing glycerophospholipids in the de novo pathway. Overexpression of LPAAT3 in HeLa cells inhibits Golgi tubule formation and protein trafficking (
      • Schmidt J.A.
      • Brown W.J.
      Lysophosphatidic acid acyltransferase 3 regulates Golgi complex structure and function.
      ). Although the mechanism underlying this is unclear, it is possible that the products of LPAAT3 (PUFA-containing PAs) may affect membrane properties. Because PUFAs are reported to increase membrane fluidity, these enzymes may be important not only for lipid mediator production, but also for cellular functions, such as signal transduction and stabilization of proteins, by controlling the biophysical properties of the membrane (
      • Yang X.
      • Sheng W.
      • Sun G.Y.
      • Lee J.C.
      Effects of fatty acid unsaturation numbers on membrane fluidity and alpha-secretase-dependent amyloid precursor protein processing.
      ).

      FUNCTIONS OF DISATURATED GLYCEROPHOSPHOLIPIDS

      Pulmonary surfactant is produced in alveolar type II (ATII) cells and is secreted into the alveolar space to prevent collapse (
      • Whitsett J.A.
      • Wert S.E.
      • Weaver T.E.
      Alveolar surfactant homeostasis and the pathogenesis of pulmonary disease.
      ). Pulmonary surfactant is composed of lipids (∼90%), mainly dipalmitoyl-PC (DPPC), and associated proteins (∼10%) (
      • Whitsett J.A.
      • Wert S.E.
      • Weaver T.E.
      Alveolar surfactant homeostasis and the pathogenesis of pulmonary disease.
      ,
      • Goerke J.
      Pulmonary surfactant: functions and molecular composition.
      ). The microsomal fraction from ATII cells exhibits high LPCAT activity with palmitoyl-CoA, indicating that surfactant DPPC is produced in the remodeling pathway (
      • Batenburg J.J.
      • Longmore W.J.
      • Klazinga W.
      • van Golde L.M.
      Lysolecithin acyltransferase and lysolecithin: lysolecithin acyltransferase in adult rat lung alveolar type II epithelial cells.
      ). Indeed, LPCAT1, which is highly expressed in ATII cells, shows a preference for palmitoyl-CoA as an acyl donor (
      • Nakanishi H.
      • Shindou H.
      • Hishikawa D.
      • Harayama T.
      • Ogasawara R.
      • Suwabe A.
      • Taguchi R.
      • Shimizu T.
      Cloning and characterization of mouse lung-type acyl-CoA:lysophosphatidylcholine acyltransferase 1 (LPCAT1). Expression in alveolar type II cells and possible involvement in surfactant production.
      ,
      • Chen X.
      • Hyatt B.A.
      • Mucenski M.L.
      • Mason R.J.
      • Shannon J.M.
      Identification and characterization of a lysophosphatidylcholine acyltransferase in alveolar type II cells.
      ). Recently, LPCAT1 gene-trapped mice were reported to have reduced LPCAT activity, disaturated PC content in the lung, and a low survival rate (
      • Bridges J.P.
      • Ikegami M.
      • Brilli L.L.
      • Chen X.
      • Mason R.J.
      • Shannon J.M.
      LPCAT1 regulates surfactant phospholipid synthesis and is required for transitioning to air breathing in mice.
      ). Pulmonary surfactant collected from dead LPCAT1 gene-trapped mice was less able to reduce surface tension than that of wild-type mice. This report indicated that LPCAT1 was important for pulmonary surfactant phospholipid production in vivo (
      • Bridges J.P.
      • Ikegami M.
      • Brilli L.L.
      • Chen X.
      • Mason R.J.
      • Shannon J.M.
      LPCAT1 regulates surfactant phospholipid synthesis and is required for transitioning to air breathing in mice.
      ). PG is a second-order glycerophospholipid (∼10% of surfactant phospholipid) in pulmonary surfactant. In the remodeling pathway, both lyso-PG (LPG) acyltransferase (LPGAT)1 and LPCAT1 are reported to have LPGAT activities in vitro (
      • Nakanishi H.
      • Shindou H.
      • Hishikawa D.
      • Harayama T.
      • Ogasawara R.
      • Suwabe A.
      • Taguchi R.
      • Shimizu T.
      Cloning and characterization of mouse lung-type acyl-CoA:lysophosphatidylcholine acyltransferase 1 (LPCAT1). Expression in alveolar type II cells and possible involvement in surfactant production.
      ,
      • Yang Y.
      • Cao J.
      • Shi Y.
      Identification and characterization of a gene encoding human LPGAT1, an endoplasmic reticulum-associated lysophosphatidylglycerol acyltransferase.
      ). Further studies are needed to clarify the mechanisms underlying high-level PG production in the lung.
      Linkage analysis in mice has shown that LPCAT1 is mutated in rd11 (one nucleotide insertion) and B6-JR2845 (seven nucleotide deletion) mice, which exhibit retinal degeneration (
      • Friedman J.S.
      • Chang B.
      • Krauth D.S.
      • Lopez I.
      • Waseem N.H.
      • Hurd R.E.
      • Feathers K.L.
      • Branham K.E.
      • Shaw M.
      • Thomas G.E.
      • et al.
      Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice.
      ). Because disaturated PC is abundant in disk membranes of rod outer segments (
      • Miljanich G.P.
      • Sklar L.A.
      • White D.L.
      • Dratz E.A.
      Disaturated and dipolyunsaturated phospholipids in the bovine retinal rod outer segment disk membrane.
      ), LPCAT1 may have important roles for function of the disk membrane.
      Membrane fatty acid saturation of glycerophospholipids by stearoyl-CoA desaturase 1 knockdown and palmitic acid treatment were reported to induce the ER stress (
      • Ariyama H.
      • Kono N.
      • Matsuda S.
      • Inoue T.
      • Arai H.
      Decrease in membrane phospholipid unsaturation induces unfolded protein response.
      ,
      • Kitai Y.
      • Ariyama H.
      • Kono N.
      • Oikawa D.
      • Iwawaki T.
      • Arai H.
      Membrane lipid saturation activates IRE1α without inducing clustering.
      ,
      • Volmer R.
      • van der Ploeg K.
      • Ron D.
      Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains.
      ,
      • Holzer R.G.
      • Park E.J.
      • Li N.
      • Tran H.
      • Chen M.
      • Choi C.
      • Solinas G.
      • Karin M.
      Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation.
      ). Although it is unclear whether glycerophospholipid remodeling is involved in this cellular response, LPCAT1 may also contribute to regulate the level of saturated fatty acid in glycerophospholipids.
      Moreover, recent studies suggest a correlation between LPCAT1 expression and cancer progression (
      • Mansilla F.
      • da Costa K.A.
      • Wang S.
      • Kruhoffer M.
      • Lewin T.M.
      • Orntoft T.F.
      • Coleman R.A.
      • Birkenkamp-Demtroder K.
      Lysophosphatidylcholine acyltransferase 1 (LPCAT1) overexpression in human colorectal cancer.
      ,
      • Zhou X.
      • Lawrence T.J.
      • He Z.
      • Pound C.R.
      • Mao J.
      • Bigler S.A.
      The expression level of lysophosphatidylcholine acyltransferase 1 (LPCAT1) correlates to the progression of prostate cancer.
      ,
      • Grupp K.
      • Sanader S.
      • Sirma H.
      • Simon R.
      • Koop C.
      • Prien K.
      • Hube-Magg C.
      • Salomon G.
      • Graefen M.
      • Heinzer H.
      • et al.
      High lysophosphatidylcholine acyltransferase 1 expression independently predicts high risk for biochemical recurrence in prostate cancers.
      ). Because LPCAT1 has both LPLAT and lysoPAFAT activities, further studies are needed to determine which LPCAT1 products, disaturated glycerophospholipids or PAF, are involved in cancer progression.

      GLYCEROPHOSPHOLIPIDS AS SIGNALING MOLECULES

      Of the cellular membrane glycerophospholipids, PS and PI phosphates (PIPs) act as signaling molecules via interactions with specific proteins (
      • Stace C.L.
      • Ktistakis N.T.
      Phosphatidic acid- and phosphatidylserine-binding proteins.
      ,
      • Vicinanza M.
      • D'Angelo G.
      • Di Campli A.
      • De Matteis M.A.
      Function and dysfunction of the PI system in membrane trafficking.
      ). Thus, although their percentage of total cellular glycerophospholipids is low, PS and PIPs play important roles in various cellular functions. PIPs can be recognized by various binding domains, such as the pleckstrin homology, Fab1/YOTB/Vac1/EEA1, phox homology, and epsin N-terminal homology domains (
      • Vicinanza M.
      • D'Angelo G.
      • Di Campli A.
      • De Matteis M.A.
      Function and dysfunction of the PI system in membrane trafficking.
      ,
      • Lemmon M.A.
      Membrane recognition by phospholipid-binding domains.
      ,
      • Itoh T.
      • Takenawa T.
      Phosphoinositide-binding domains: functional units for temporal and spatial regulation of intracellular signalling.
      ). On the other hand, γ-carboxyglutamic acid, protein kinase C C2, discoidin C2, and kinase associated-1 are reported to be PS-recognizing domains (
      • Lemmon M.A.
      Membrane recognition by phospholipid-binding domains.
      ,
      • Leventis P.A.
      • Grinstein S.
      The distribution and function of phosphatidylserine in cellular membranes.
      ,
      • Moravcevic K.
      • Mendrola J.M.
      • Schmitz K.R.
      • Wang Y.H.
      • Slochower D.
      • Janmey P.A.
      • Lemmon M.A.
      Kinase associated-1 domains drive MARK/PAR1 kinases to membrane targets by binding acidic phospholipids.
      ). Exceptionally, the pleckstrin homology domain of evectin-2 is reported to bind PS but not PIPs (
      • Uchida Y.
      • Hasegawa J.
      • Chinnapen D.
      • Inoue T.
      • Okazaki S.
      • Kato R.
      • Wakatsuki S.
      • Misaki R.
      • Koike M.
      • Uchiyama Y.
      • et al.
      Intracellular phosphatidylserine is essential for retrograde membrane traffic through endosomes.
      ).
      PIPs are biosynthesized by the reversible phosphorylation of three of the five hydroxyl groups on the inositol head group of PI (
      • Vicinanza M.
      • D'Angelo G.
      • Di Campli A.
      • De Matteis M.A.
      Function and dysfunction of the PI system in membrane trafficking.
      ). Arachidonic acid is the most predominant acyl chain found in the sn-2 position of PI and PIPs (
      • Patton G.M.
      • Fasulo J.M.
      • Robins S.J.
      Separation of phospholipids and individual molecular species of phospholipids by high-performance liquid chromatography.
      ,
      • Anderson K.E.
      • Kielkowska A.
      • Durrant T.N.
      • Juvin V.
      • Clark J.
      • Stephens L.R.
      • Hawkins P.T.
      Lysophosphatidylinositol-acyltransferase-1 (LPIAT1) is required to maintain physiological levels of PtdIns and PtdInsP(2) in the mouse.
      ). LPIAT1 prefers arachidonoyl-CoA as an acyl donor and generates arachidonic acid-containing PI. Because acyltransferase activities for lyso-PIPs are very low, the enrichment of arachidonic acid in PI and PIPs seems to be controlled in the PI remodeling pathway (
      • Lee H.C.
      • Inoue T.
      • Imae R.
      • Kono N.
      • Shirae S.
      • Matsuda S.
      • Gengyo-Ando K.
      • Mitani S.
      • Arai H.
      Caenorhabditis elegans mboa-7, a member of the MBOAT family, is required for selective incorporation of polyunsaturated fatty acids into phosphatidylinositol.
      ,
      • Gijón M.A.
      • Riekhof W.R.
      • Zarini S.
      • Murphy R.C.
      • Voelker D.R.
      Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils.
      ). Recently, the phenotype of LPIAT1 KO mice was reported by two different groups (
      • Anderson K.E.
      • Kielkowska A.
      • Durrant T.N.
      • Juvin V.
      • Clark J.
      • Stephens L.R.
      • Hawkins P.T.
      Lysophosphatidylinositol-acyltransferase-1 (LPIAT1) is required to maintain physiological levels of PtdIns and PtdInsP(2) in the mouse.
      ,
      • Lee H.C.
      • Inoue T.
      • Sasaki J.
      • Kubo T.
      • Matsuda S.
      • Nakasaki Y.
      • Hattori M.
      • Tanaka F.
      • Udagawa O.
      • Kono N.
      • et al.
      LPIAT1 regulates arachidonic acid content in phosphatidylinositol and is required for cortical lamination in mice.
      ). LPIAT1 KO mice were postnatal lethal and showed atrophy of the cerebral cortex and hippocampus. LPIAT1 deficiency caused abnormal cortical lamination and delayed neuronal migration in the cortex at embryonic day 18.5 (
      • Lee H.C.
      • Inoue T.
      • Sasaki J.
      • Kubo T.
      • Matsuda S.
      • Nakasaki Y.
      • Hattori M.
      • Tanaka F.
      • Udagawa O.
      • Kono N.
      • et al.
      LPIAT1 regulates arachidonic acid content in phosphatidylinositol and is required for cortical lamination in mice.
      ). Fatty acid compositions and the cellular amounts of PI and PIPs were also changed in LPIAT1 KO mice (
      • Anderson K.E.
      • Kielkowska A.
      • Durrant T.N.
      • Juvin V.
      • Clark J.
      • Stephens L.R.
      • Hawkins P.T.
      Lysophosphatidylinositol-acyltransferase-1 (LPIAT1) is required to maintain physiological levels of PtdIns and PtdInsP(2) in the mouse.
      ,
      • Lee H.C.
      • Inoue T.
      • Sasaki J.
      • Kubo T.
      • Matsuda S.
      • Nakasaki Y.
      • Hattori M.
      • Tanaka F.
      • Udagawa O.
      • Kono N.
      • et al.
      LPIAT1 regulates arachidonic acid content in phosphatidylinositol and is required for cortical lamination in mice.
      ). Further studies are needed to clarify whether the reduction or the altered fatty acid compositions of PI and PIPs contributed to the phenotypes of LPIAT1 KO mice. LPIAT1 KO mice showed an almost complete loss of LPIAT activity with arachidonoyl-CoA in brain, liver, kidney, and testis (
      • Lee H.C.
      • Inoue T.
      • Sasaki J.
      • Kubo T.
      • Matsuda S.
      • Nakasaki Y.
      • Hattori M.
      • Tanaka F.
      • Udagawa O.
      • Kono N.
      • et al.
      LPIAT1 regulates arachidonic acid content in phosphatidylinositol and is required for cortical lamination in mice.
      ). In the brains of LPIAT1 KO mice, 65% of the normal level of arachidonic acid-containing PI was present (
      • Anderson K.E.
      • Kielkowska A.
      • Durrant T.N.
      • Juvin V.
      • Clark J.
      • Stephens L.R.
      • Hawkins P.T.
      Lysophosphatidylinositol-acyltransferase-1 (LPIAT1) is required to maintain physiological levels of PtdIns and PtdInsP(2) in the mouse.
      ,
      • Lee H.C.
      • Inoue T.
      • Sasaki J.
      • Kubo T.
      • Matsuda S.
      • Nakasaki Y.
      • Hattori M.
      • Tanaka F.
      • Udagawa O.
      • Kono N.
      • et al.
      LPIAT1 regulates arachidonic acid content in phosphatidylinositol and is required for cortical lamination in mice.
      ). Thus, de novo synthesis also seems to be important for the incorporation of arachidonic acid into PI. On the other hand, it is reported that exogenously supplied palmitoleate (16:1) was preferentially incorporated into PI and induced cell proliferation (
      • Koeberle A.
      • Shindou H.
      • Harayama T.
      • Shimizu T.
      Palmitoleate is a mitogen, formed upon stimulation with growth factors, and converted to palmitoleoyl-phosphatidylinositol.
      ). In addition, a difference between the fatty acid composition of PIPs of whole cell membrane fractions and that of nuclear membrane fractions has also been reported, indicating that the acyl chains of PI and PIPs may have some specific functions (
      • Ogiso H.
      • Nakamura K.
      • Yatomi Y.
      • Shimizu T.
      • Taguchi R.
      Liquid chromatography/mass spectrometry analysis revealing preferential occurrence of non-arachidonate-containing phosphatidylinositol bisphosphate species in nuclei and changes in their levels during cell cycle.
      ). Furthermore, it has been reported that LPIAT1 mainly localizes at mitochondria-associated membranes (MAMs), where acyl-CoA synthetase long-chain 4 is expressed, and interacts with the small subunit of serine palmitoyl-transferase a (
      • Hirata Y.
      • Yamamori N.
      • Kono N.
      • Lee H.C.
      • Inoue T.
      • Arai H.
      Identification of small subunit of serine palmitoyltransferase a as a lysophosphatidylinositol acyltransferase 1-interacting protein.
      ). This report suggests that the specific localization of LPLATs through interactions with other related proteins may also be important for substrate recognition. Although LPAAT3 also has LPIAT activity with PUFA-CoA in vitro, little information concerning its biological roles is available (
      • Yuki K.
      • Shindou H.
      • Hishikawa D.
      • Shimizu T.
      Characterization of mouse lysophosphatidic acid acyltransferase 3: an enzyme with dual functions in the testis.
      ).
      PS is highly enriched in the inner leaflet of the plasma membrane and in intracellular organelles such as recycling endosomes, and acts as a tag for the recognition of apoptotic cells, coagulation, and vesicle trafficking by PS-binding proteins (
      • Leventis P.A.
      • Grinstein S.
      The distribution and function of phosphatidylserine in cellular membranes.
      ). It is known that PS in the plasma membrane is exposed to the outer leaflet during platelet activation and apoptosis by the action of Ca2+-dependent phospholipid scramblases (
      • Balasubramanian K.
      • Schroit A.J.
      Aminophospholipid asymmetry: a matter of life and death.
      ). A recent study identified TMEM16F and Xkr8 as the key molecules for PS exposure in this process (
      • Suzuki J.
      • Umeda M.
      • Sims P.J.
      • Nagata S.
      Calcium-dependent phospholipid scrambling by TMEM16F.
      ,
      • Suzuki J.
      • Denning D.P.
      • Imanishi E.
      • Horvitz H.R.
      • Nagata S.
      Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells.
      ,
      • Malvezzi M.
      • Chalat M.
      • Janjusevic R.
      • Picollo A.
      • Terashima H.
      • Menon A.K.
      • Accardi A.
      Ca2+-dependent phospholipid scrambling by a reconstituted TMEM16 ion channel.
      ). Furthermore, binding of evectin-2 to PS in the recycling endosomes is essential for retrograde membrane trafficking (
      • Uchida Y.
      • Hasegawa J.
      • Chinnapen D.
      • Inoue T.
      • Okazaki S.
      • Kato R.
      • Wakatsuki S.
      • Misaki R.
      • Koike M.
      • Uchiyama Y.
      • et al.
      Intracellular phosphatidylserine is essential for retrograde membrane traffic through endosomes.
      ,
      • Lee S.
      • Uchida Y.
      • Emoto K.
      • Umeda M.
      • Kuge O.
      • Taguchi T.
      • Arai H.
      Impaired retrograde membrane traffic through endosomes in a mutant CHO cell defective in phosphatidylserine synthesis.
      ). While the mechanisms underlying the transport of PS from the ER to the specific organelle are unknown, yeast oxysterol-binding homology (Osh)6, Osh7, human oxysterol-binding protein related protein (ORP)5, and ORP10 have been reported to bind and transport a single PS molecule between membranes (
      • Maeda K.
      • Anand K.
      • Chiapparino A.
      • Kumar A.
      • Poletto M.
      • Kaksonen M.
      • Gavin A.C.
      Interactome map uncovers phosphatidylserine transport by oxysterol-binding proteins.
      ). Because the acyl-chain composition of PS purified with Osh6 is limited when compared with yeast PS, the acyl-chain composition of PS may also be important for ligand recognition by PS transporters (
      • Maeda K.
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      Interactome map uncovers phosphatidylserine transport by oxysterol-binding proteins.
      ,
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      Global analysis of the yeast lipidome by quantitative shotgun mass spectrometry.
      ). This finding suggests that not only polar heads, but also fatty acid compositions contribute to PS transport. LPCAT3 and lyso-PE (LPE) acyltransferase (LPEAT)1 have been reported to possess lyso-PS (LPS) acyltransferase (LPSAT) activities with arachidonoyl-CoA and oleoyl-CoA, respectively (
      • Hishikawa D.
      • Shindou H.
      • Kobayashi S.
      • Nakanishi H.
      • Taguchi R.
      • Shimizu T.
      Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity.
      ,
      • Zhao Y.
      • Chen Y.Q.
      • Bonacci T.M.
      • Bredt D.S.
      • Li S.
      • Bensch W.R.
      • Moller D.E.
      • Kowala M.
      • Konrad R.J.
      • Cao G.
      Identification and characterization of a major liver lysophosphatidylcholine acyltransferase.
      ). Further studies are required to elucidate the roles of PS fatty acid composition in intracellular transport and other cellular functions.

      CONE-SHAPED GLYCEROPHOSPHOLIPIDS AND MEMBRANE CURVATURE SENSORS

      Cone-shaped glycerophospholipids with small polar heads (PE, PA, and CL) and/or bulky acyl chains (monounsaturated fatty acid-containing glycerophospholipids) are known to have important roles in membrane fusion and fission steps during endocytosis, exocytosis, cytokinesis, and vesicle trafficking (
      • Emoto K.
      • Kobayashi T.
      • Yamaji A.
      • Aizawa H.
      • Yahara I.
      • Inoue K.
      • Umeda M.
      Redistribution of phosphatidylethanolamine at the cleavage furrow of dividing cells during cytokinesis.
      ,
      • McMahon H.T.
      • Gallop J.L.
      Membrane curvature and mechanisms of dynamic cell membrane remodelling.
      ,
      • Osman C.
      • Voelker D.R.
      • Langer T.
      Making heads or tails of phospholipids in mitochondria.
      ). In the curved membrane, cone-shaped glycerophospholipids provide loosely packed regions, termed lipid-packing defects, which are recognized by membrane curvature sensors possessing amphipathic lipid-packing sensor motifs. They consist of an α-helix of 20 to 40 amino acids with a serine- or threonine-rich polar face (
      • Bigay J.
      • Antonny B.
      Curvature, lipid packing, and electrostatics of membrane organelles: defining cellular territories in determining specificity.
      ). Membrane curvature sensors containing amphipathic lipid-packing sensor motifs are important for vesicle and lipid trafficking (
      • Antonny B.
      Mechanisms of membrane curvature sensing.
      ). Recently, we reported that the Sec14 domain of Sec14-like 3 also senses lipid-packing defects in liposomes (
      • Hishikawa D.
      • Shindou H.
      • Harayama T.
      • Ogasawara R.
      • Suwabe A.
      • Shimizu T.
      Identification of Sec14-like 3 as a novel lipid-packing sensor in the lung.
      ). These reports suggest that cone-shaped glycerophospholipids are important for various cellular functions, such as lipid transport.
      LPEAT1 and LPCAT4 are reported to prefer LPE and oleoyl-CoA as substrates (
      • Hishikawa D.
      • Shindou H.
      • Kobayashi S.
      • Nakanishi H.
      • Taguchi R.
      • Shimizu T.
      Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity.
      ) and produce cone-shaped glycerophospholipids. Although the cellular functions of these enzymes are unclear, regulation of cone-shaped glycerophospholipid biosynthesis by LPEAT1 and/or LPCAT4 may affect vesicle trafficking, membrane fusion, and endocytosis/exocytosis by providing the appropriate lipid-packing defects on curved membranes. Several reports showed that inhibition of LPCAT and LPEAT activities by a broad LPLAT inhibitor, CI-976 (2,2-methyl-N-(2,4,6,-trimethoxyphenyl)dodecanamide) enhanced Golgi tubulation and membrane trafficking (
      • Ha K.D.
      • Clarke B.A.
      • Brown W.J.
      Regulation of the Golgi complex by phospholipid remodeling enzymes.
      ). Several types of PLAs were also reported to be important in intracellular membrane trafficking and fusion events (
      • Brown W.J.
      • Chambers K.
      • Doody A.
      Phospholipase A2 (PLA2) enzymes in membrane trafficking: mediators of membrane shape and function.
      ). The regulation of membrane glycerophospholipid composition in the remodeling pathway affects the cellular membrane functions.
      Disruption of the LPEAT1 gene was reported in a patient with a brachydactyly-syndactyly syndrome (
      • Dauwerse J.G.
      • de Vries B.B.
      • Wouters C.H.
      • Bakker E.
      • Rappold G.
      • Mortier G.R.
      • Breuning M.H.
      • Peters D.J.
      A t(4;6)(q12;p23) translocation disrupts a membrane-associated O-acetyl transferase gene (MBOAT1) in a patient with a novel brachydactyly-syndactyly syndrome.
      ). Thus, the cone-shaped glycerophospholipids produced by LPEAT1 may be important for normal organogenesis.

      GLYCEROPHOSPHOLIPID METABOLISM AND FUNCTION IN MITOCHONDRIA

      Mitochondria are dynamic organelles involved in crucial cellular processes, such as cell respiration and energy production. CL is a major glycerophospholipid in mitochondria, especially in the inner membrane, which affects the stability and activity of various membrane protein complexes and metabolite carriers (
      • Gonzalvez F.
      • Schug Z.T.
      • Houtkooper R.H.
      • MacKenzie E.D.
      • Brooks D.G.
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      • Vaz F.M.
      • Gottlieb E.
      Cardiolipin provides an essential activating platform for caspase-8 on mitochondria.
      ,
      • Houtkooper R.H.
      • Vaz F.M.
      Cardiolipin, the heart of mitochondrial metabolism.
      ). CL is a unique dimeric glycerophospholipid possessing two PAs, bridged by a glycerol, and four fatty acyl chains. Although the molecular mechanism of CL synthesis is not completely understood, recent studies have identified new molecules related to the process, such as a protein that transports PA from the outer membrane to the inner membrane (
      • Connerth M.
      • Tatsuta T.
      • Haag M.
      • Klecker T.
      • Westermann B.
      • Langer T.
      Intramitochondrial transport of phosphatidic acid in yeast by a lipid transfer protein.
      ,
      • Potting C.
      • Tatsuta T.
      • Konig T.
      • Haag M.
      • Wai T.
      • Aaltonen M.J.
      • Langer T.
      TRIAP1/PRELI complexes prevent apoptosis by mediating intramitochondrial transport of phosphatidic acid.
      ), a mitochondrial-type CDP-DAG synthase (
      • Tamura Y.
      • Harada Y.
      • Nishikawa S.
      • Yamano K.
      • Kamiya M.
      • Shiota T.
      • Kuroda T.
      • Kuge O.
      • Sesaki H.
      • Imai K.
      • et al.
      Tam41 is a CDP-diacylglycerol synthase required for cardiolipin biosynthesis in mitochondria.
      ), and a mammalian phosphatidylglycerolphosphate synthase (
      • Xiao J.
      • Engel J.L.
      • Zhang J.
      • Chen M.J.
      • Manning G.
      • Dixon J.E.
      Structural and functional analysis of PTPMT1, a phosphatase required for cardiolipin synthesis.
      ,
      • Zhang J.
      • Guan Z.
      • Murphy A.N.
      • Wiley S.E.
      • Perkins G.A.
      • Worby C.A.
      • Engel J.L.
      • Heacock P.
      • Nguyen O.K.
      • Wang J.H.
      • et al.
      Mitochondrial phosphatase PTPMT1 is essential for cardiolipin biosynthesis.
      ,
      • Teh P.G.
      • Chen M.J.
      • Engel J.L.
      • Worby C.A.
      • Manning G.
      • Dixon J.E.
      • Zhang J.
      Identification of a mammalian-type phosphatidylglycerophosphate phosphatase in the Eubacterium Rhodopirellula baltica.
      ). The acyl chains of CL are highly enriched with linoleic acid in the remodeling pathway (
      • Sparagna G.C.
      • Lesnefsky E.J.
      Cardiolipin remodeling in the heart.
      ). Tafazzin (TAZ) and lyso-CL (LCL) acyltransferase 1 (LCLAT1; also known as acyl-CoA:LCLAT1) were reported to remodel the acyl chains of CL by transacylation of CL and acylation of LCL, respectively (
      • Xu Y.
      • Kelley R.I.
      • Blanck T.J.
      • Schlame M.
      Remodeling of cardiolipin by phospholipid transacylation.
      ,
      • Xu Y.
      • Malhotra A.
      • Ren M.
      • Schlame M.
      The enzymatic function of tafazzin.
      ,
      • Schlame M.
      • Acehan D.
      • Berno B.
      • Xu Y.
      • Valvo S.
      • Ren M.
      • Stokes D.L.
      • Epand R.M.
      The physical state of lipid substrates provides transacylation specificity for tafazzin.
      ,
      • Cao J.
      • Liu Y.
      • Lockwood J.
      • Burn P.
      • Shi Y.
      A novel cardiolipin-remodeling pathway revealed by a gene encoding an endoplasmic reticulum-associated acyl-CoA:lysocardiolipin acyltransferase (ALCAT1) in mouse.
      ).
      Abnormal CL remodeling is observed in many pathological situations, such as aging, heart failure, and Barth syndrome (
      • Claypool S.M.
      • Koehler C.M.
      The complexity of cardiolipin in health and disease.
      ). Mitochondria from patients with Barth syndrome exhibited lower CL content and abnormal acyl-chain compositions (
      • Gonzalvez F.
      • D'Aurelio M.
      • Boutant M.
      • Moustapha A.
      • Puech J.P.
      • Landes T.
      • Arnaune-Pelloquin L.
      • Vial G.
      • Taleux N.
      • Slomianny C.
      • et al.
      Barth syndrome: cellular compensation of mitochondrial dysfunction and apoptosis inhibition due to changes in cardiolipin remodeling linked to tafazzin (TAZ) gene mutation.
      ). TAZ gene mutations are responsible for Barth syndrome (
      • Clarke S.L.
      • Bowron A.
      • Gonzalez I.L.
      • Groves S.J.
      • Newbury-Ecob R.
      • Clayton N.
      • Martin R.P.
      • Tsai-Goodman B.
      • Garratt V.
      • Ashworth M.
      • et al.
      Barth syndrome.
      ,
      • Bione S.
      • D'Adamo P.
      • Maestrini E.
      • Gedeon A.K.
      • Bolhuis P.A.
      • Toniolo D.
      A novel X-linked gene, G4.5. is responsible for Barth syndrome.
      ). Indeed, cardiac muscle from TAZ gene knockdown mice showed an accumulation of mono-LCL and decreased tetralinoleoyl-CL (
      • Soustek M.S.
      • Falk D.J.
      • Mah C.S.
      • Toth M.J.
      • Schlame M.
      • Lewin A.S.
      • Byrne B.J.
      Characterization of a transgenic short hairpin RNA-induced murine model of Tafazzin deficiency.
      ). These observations indicate that CL acyl-chain remodeling by TAZ may be critical for CL maturation and mitochondrial functions.
      In addition to TAZ, LCLAT1 is also reported to be involved in CL acyl-chain remodeling (
      • Schlame M.
      • Acehan D.
      • Berno B.
      • Xu Y.
      • Valvo S.
      • Ren M.
      • Stokes D.L.
      • Epand R.M.
      The physical state of lipid substrates provides transacylation specificity for tafazzin.
      ,
      • Cao J.
      • Liu Y.
      • Lockwood J.
      • Burn P.
      • Shi Y.
      A novel cardiolipin-remodeling pathway revealed by a gene encoding an endoplasmic reticulum-associated acyl-CoA:lysocardiolipin acyltransferase (ALCAT1) in mouse.
      ). Whereas TAZ is localized to mitochondria, LCLAT1 is localized to the ER and MAM (
      • Cao J.
      • Liu Y.
      • Lockwood J.
      • Burn P.
      • Shi Y.
      A novel cardiolipin-remodeling pathway revealed by a gene encoding an endoplasmic reticulum-associated acyl-CoA:lysocardiolipin acyltransferase (ALCAT1) in mouse.
      ,
      • Li J.
      • Romestaing C.
      • Han X.
      • Li Y.
      • Hao X.
      • Wu Y.
      • Sun C.
      • Liu X.
      • Jefferson L.S.
      • Xiong J.
      • et al.
      Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity.
      ). A recent study showed that insulin resistance induced by a high fat diet in LCLAT1 KO mice was improved (
      • Li J.
      • Romestaing C.
      • Han X.
      • Li Y.
      • Hao X.
      • Wu Y.
      • Sun C.
      • Liu X.
      • Jefferson L.S.
      • Xiong J.
      • et al.
      Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity.
      ). Furthermore, LCLAT1 overexpression in C2C12 cells leads to a reduction in the levels of linoleic and oleic acids and a slight increase in the levels of arachidonic acid and DHA in CL (
      • Li J.
      • Romestaing C.
      • Han X.
      • Li Y.
      • Hao X.
      • Wu Y.
      • Sun C.
      • Liu X.
      • Jefferson L.S.
      • Xiong J.
      • et al.
      Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity.
      ). Based on these results, it was suggested that the activation of LCLAT1 may be involved in the oxidative stress-induced inhibition of mitochondrial function through PUFA incorporation in CL. However, the acyltransferase activities of LCLAT1 for other lysophospholipids, such as LPA (
      • Agarwal A.K.
      • Barnes R.I.
      • Garg A.
      Functional characterization of human 1-acylglycerol-3-phosphate acyltransferase isoform 8: cloning, tissue distribution, gene structure, and enzymatic activity.
      ), LPI, LPG (
      • Zhao Y.
      • Chen Y.Q.
      • Li S.
      • Konrad R.J.
      • Cao G.
      The microsomal cardiolipin remodeling enzyme acyl-CoA lysocardiolipin acyltransferase is an acyltransferase of multiple anionic lysophospholipids.
      ), bis(monoacylglycero)phosphate (
      • Cao J.
      • Shen W.
      • Chang Z.
      • Shi Y.
      ALCAT1 is a polyglycerophospholipid acyltransferase potently regulated by adenine nucleotide and thyroid status.
      ), and 2-acyl-LPI (
      • Yamashita A.
      • Hayashi Y.
      • Nemoto-Sasaki Y.
      • Ito M.
      • Oka S.
      • Tanikawa T.
      • Waku K.
      • Sugiura T.
      Acyltransferases and transacylases that determine the fatty acid composition of glycerolipids and the metabolism of bioactive lipid mediators in mammalian cells and model organisms.
      ,
      • Le Guédard M.
      • Bessoule J.J.
      • Boyer V.
      • Ayciriex S.
      • Velours G.
      • Kulik W.
      • Ejsing C.S.
      • Shevchenko A.
      • Coulon D.
      • Lessire R.
      • et al.
      PSI1 is responsible for the stearic acid enrichment that is characteristic of phosphatidylinositol in yeast.
      ,
      • Imae R.
      • Inoue T.
      • Kimura M.
      • Kanamori T.
      • Tomioka N.H.
      • Kage-Nakadai E.
      • Mitani S.
      • Arai H.
      Intracellular phospholipase A1 and acyltransferase, which are involved in Caenorhabditis elegans stem cell divisions, determine the sn-1 fatty acyl chain of phosphatidylinositol.
      ,
      • Imae R.
      • Inoue T.
      • Nakasaki Y.
      • Uchida Y.
      • Ohba Y.
      • Kono N.
      • Nakanishi H.
      • Sasaki T.
      • Mitani S.
      • Arai H.
      LYCAT, a homologue of C. elegans acl-8, acl-9, and acl-10, determines the fatty acid composition of phosphatidylinositol in mice.
      ) have also been reported. Indeed, LCLAT1 KO mice showed decreased acyltransferase activities for 2-acyl-LPI and altered composition of PI without obvious changes in other glycerophospholipid acyl species (
      • Imae R.
      • Inoue T.
      • Nakasaki Y.
      • Uchida Y.
      • Ohba Y.
      • Kono N.
      • Nakanishi H.
      • Sasaki T.
      • Mitani S.
      • Arai H.
      LYCAT, a homologue of C. elegans acl-8, acl-9, and acl-10, determines the fatty acid composition of phosphatidylinositol in mice.
      ). Thus, more information is needed to determine the biochemical and physiological properties of LCLAT1.
      Recently, the involvement of mitochondrial G3P acyltransferase (GPAT) in mitochondrial fusion in Caenorhabditis elegans and HeLa cells was reported (
      • Ohba Y.
      • Sakuragi T.
      • Kage-Nakadai E.
      • Tomioka N.H.
      • Kono N.
      • Imae R.
      • Inoue A.
      • Aoki J.
      • Ishihara N.
      • Inoue T.
      • et al.
      Mitochondria-type GPAT is required for mitochondrial fusion.
      ). Because LPA supplementation and LPAAT inhibition rescued mitochondrial fragmentation in GPAT mutated C. elegans, accumulation of LPA in mitochondria seems to be important for mitochondrial fusion (
      • Ohba Y.
      • Sakuragi T.
      • Kage-Nakadai E.
      • Tomioka N.H.
      • Kono N.
      • Imae R.
      • Inoue A.
      • Aoki J.
      • Ishihara N.
      • Inoue T.
      • et al.
      Mitochondria-type GPAT is required for mitochondrial fusion.
      ). Moreover, LCLAT1 is also reported to have a role in mitochondrial fusion (
      • Li J.
      • Liu X.
      • Wang H.
      • Zhang W.
      • Chan D.C.
      • Shi Y.
      Lysocardiolipin acyltransferase 1 (ALCAT1) controls mitochondrial DNA fidelity and biogenesis through modulation of MFN2 expression.
      ). These results suggest that the glycerophospholipid composition of mitochondria is important for protein complex formation as well as for fusion.

      CONCLUSIONS

      Recent progress in LPLAT research has opened the door to understanding the contribution of membrane glycerophospholipid diversity to various cellular functions (Fig. 2). Moreover, the phenotype of LPLAT KO mice also has wide-ranging implications for the importance of membrane glycerophospholipids in various cellular processes (Table 1). However, the biological significance of: i) a single enzyme recognizing multiple substrates; ii) the accumulation of substrates in specific regions, such as MAMs; and iii) the fact that structurally dissimilar AGPAT and MBOAT family proteins can recognize the same substrate (lysophospholipids and acyl-CoAs) is as yet unknown. The substrate discrimination of LPLAT may be controlled by interactions with other proteins. Furthermore, the recent identification of the unique membrane glycerophospholipid remodeling enzymes, such as comparative gene identification 58 (CGI58), adiponutrin, cytosolic PLA2γ, and phospholipase A/acyltransferases suggest that membrane glycerophospholipid diversity is formed and maintained in many distinct ways (
      • Montero-Moran G.
      • Caviglia J.M.
      • McMahon D.
      • Rothenberg A.
      • Subramanian V.
      • Xu Z.
      • Lara-Gonzalez S.
      • Storch J.
      • Carman G.M.
      • Brasaemle D.L.
      CGI-58/ABHD5 is a coenzyme A-dependent lysophosphatidic acid acyltransferase.
      ,
      • Ghosh A.K.
      • Ramakrishnan G.
      • Chandramohan C.
      • Rajasekharan R.
      CGI-58, the causative gene for Chanarin-Dorfman syndrome, mediates acylation of lysophosphatidic acid.
      ,
      • Kumari M.
      • Schoiswohl G.
      • Chitraju C.
      • Paar M.
      • Cornaciu I.
      • Rangrez A.Y.
      • Wongsiriroj N.
      • Nagy H.M.
      • Ivanova P.T.
      • Scott S.A.
      • et al.
      Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase.
      ,
      • Yamashita A.
      • Tanaka K.
      • Kamata R.
      • Kumazawa T.
      • Suzuki N.
      • Koga H.
      • Waku K.
      • Sugiura T.
      Subcellular localization and lysophospholipase/transacylation activities of human group IVC phospholipase A2 (cPLA2gamma).
      ,
      • Shinohara N.
      • Uyama T.
      • Jin X.H.
      • Tsuboi K.
      • Tonai T.
      • Houchi H.
      • Ueda N.
      Enzymological analysis of the tumor suppressor A-C1 reveals a novel group of phospholipid-metabolizing enzymes.
      ). A more comprehensive understanding of the mechanisms and importance of membrane glycerophospholipid diversity remains to be explored in future studies.
      Figure thumbnail gr2
      Fig. 2Cellular functions of glycerophospholipid remodeling and diversity. Roles of various glycerophospholipids in mammalian cells are shown. The membrane glycerophospholipid diversity produced in the fatty acid remodeling pathway may affect various cellular functions. The details are discussed in the text. LB, lamellar body.

      Acknowledgments

      The authors are grateful to all members of our laboratories for valuable suggestions (National Center for Global Health and Medicine).

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        Journal of Lipid ResearchVol. 55Issue 11
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          The authors of “Diversity and function of membrane glycerophospholipids generated by the remodeling pathway in mammalian cells” (J. Lipid Res. 2014. 55: 799–807) have advised that they inadvertently introduced errors into their Table 1. The corrected text is shown in bold in the shaded area in the table below.
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