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Update and nomenclature proposal for mammalian lysophospholipid acyltransferases, which create membrane phospholipid diversity

Open AccessPublished:December 07, 2021DOI:https://doi.org/10.1016/j.jbc.2021.101470
      The diversity of glycerophospholipid species in cellular membranes is immense and affects various biological functions. Glycerol-3-phosphate acyltransferases (GPATs) and lysophospholipid acyltransferases (LPLATs), in concert with phospholipase A1/2s enzymes, contribute to this diversity via selective esterification of fatty acyl chains at the sn-1 or sn-2 positions of membrane phospholipids. These enzymes are conserved across all kingdoms, and in mammals four GPATs of the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) family and at least 14 LPLATs, either of the AGPAT or the membrane-bound O-acyltransferase (MBOAT) families, have been identified. Here we provide an overview of the biochemical and biological activities of these mammalian enzymes, including their predicted structures, involvements in human diseases, and essential physiological roles as revealed by gene-deficient mice. Recently, the nomenclature used to refer to these enzymes has generated some confusion due to the use of multiple names to refer to the same enzyme and instances of the same name being used to refer to completely different enzymes. Thus, this review proposes a more uniform LPLAT enzyme nomenclature, as well as providing an update of recent advances made in the study of LPLATs, continuing from our JBC mini review in 2009.

      Keywords

      Abbreviations:

      AGPAT (1-acylglycerol-3-phosphate O-acyltransferase), BAT (brown adipose tissue), CDP-DAG (cytidine diphosphate-DAG), CGL (congenital generalized lipodystrophy), CHP1 (calcineurin B homologous protein 1), CL (cardiolipin), COX (cyclooxygenase), DAG (diacylglycerol), DGAT (DAG acyltransferase), DHA (docosahexaenoic acid), ER (endoplasmic reticulum), G3P (glycerol-3-phosphate), GNPAT (glyceronephosphate O-acyltransferase), GOAT (ghrelin O-acyltransferase), GPAT (G3P acyltransferase), HHAT (hedgehog acyl-transferase), KO (knockout), LCL (lyso-CL), LCLAT (LCL acyltransferase), LPA (lyso-PA), LPAAT (LPA acyltransferase), LPC (lyso-PC), LPCAT (LPC acyltransferase), LPE (lyso-PE), LPEAT (LPE acyltransferase), LPG (lyso-PG), LPGAT (LPG acyltransferase), LPI (lyso-PI), LPIAT (LPI acyltransferase), LPL (lysophospholipid), LPLAT (LPL acyltransferase), LPS (lyso-PS), LPSAT (LPS acyltransferase), MBOAT (membrane bound O-acyltransferase), NCBI (National Center for Biotechnology Information), NEM (N-ethylmaleimide), PA (phosphatidic acid), PAF (platelet-activating factor), PAFR (PAF receptor), PAP (PA phosphatase), PC (phosphatidylcholine), PE (phosphatidylethanolamine), PG (phosphatidylglycerol), PI (phosphatidylinositol), PL (phospholipid), PLA (phospholipase A), pLDDT (predicted Local Distance Difference Test), PORCN (porcupine O-acyltransferase), PS (phosphatidylserine), sn (stereospecifically numbered), SOAT (sterol O-acyltransferase), srebp (sterol regulatory element binding protein), TAG (triacylglycerol), WAT (white adipose tissue)

      Diversity of cellular membrane glycerophospholipids

      Biological membranes of mammalian cells are comprised mostly of proteins and lipids. Glycerophospholipids (phospholipids), along with sphingolipids and cholesterol, are the major lipid components. The basic structure of membrane phospholipids, with a glycerol backbone, polar headgroup, and two hydrophobic chains, provides a template for a diverse array of chemical species to support their many biological functions. These functions include formation of lipid bilayers that form hydrophobic barriers in cellular membranes, which encapsulate and compartmentalize cells as well as provide domains of molecular interactions (
      • van Meer G.
      • Voelker D.R.
      • Feigenson G.W.
      Membrane lipids: Where they are and how they behave.
      ). Phospholipids also form monolayers, which encapsulate lipid and lipoprotein particles or form tissue surface films such as pulmonary surfactant (
      • Sturley S.L.
      • Hussain M.M.
      Lipid droplet formation on opposing sides of the endoplasmic reticulum.
      • Goerke J.
      Pulmonary surfactant: Functions and molecular composition.
      ). Phospholipids of biological membranes also provide precursor molecules for lipid mediators involved in inflammation and resolution (
      • Shimizu T.
      Lipid mediators in health and disease: Enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation.
      ,
      • Serhan C.N.
      Pro-resolving lipid mediators are leads for resolution physiology.
      ). To perform these diverse functions, a wide variety of phospholipid species exists, and their compositions in cellular membranes vary among organelles, cell types, and tissues to impart the membranes with essential properties for their biological functions (
      • van Meer G.
      • Voelker D.R.
      • Feigenson G.W.
      Membrane lipids: Where they are and how they behave.
      ,
      • Harayama T.
      • Eto M.
      • Shindou H.
      • Kita Y.
      • Otsubo E.
      • Hishikawa D.
      • Ishii S.
      • Sakimura K.
      • Mishina M.
      • Shimizu T.
      Lysophospholipid acyltransferases mediate phosphatidylcholine diversification to achieve the physical properties required in vivo.
      ).
      Chemical diversity of phospholipids is introduced largely by the choices of headgroups at the stereospecifically numbered (sn) -3 position and two fatty acids and linkages at the sn-1 and sn-2 positions of their glycerol-based structures (
      • van Meer G.
      • Voelker D.R.
      • Feigenson G.W.
      Membrane lipids: Where they are and how they behave.
      ) (Fig. 1A). For headgroups, the simplest phospholipid class, phosphatidic acid (PA), has just a phosphate. During de novo phospholipid synthesis, PA is a precursor molecule for the production of other phospholipids with more complex headgroups: phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), and cardiolipin (CL) (
      • Shindou H.
      • Shimizu T.
      Acyl-CoA:lysophospholipid acyltransferases.
      ,
      • Vance J.E.
      Phospholipid synthesis and transport in mammalian cells.
      ). Chemical diversity is also generated from the choices of fatty chains introduced at sn-1 and sn-2. Carbon chain lengths and double-bond numbers vary, usually between 12 and 24 carbons and between 0 and 6 double bonds, and the linkages of the chains to the glycerol backbone also vary. Acyl linkages are most common at both sn-1 and sn-2; however, alkyl and alkenyl linkages also occur at sn-1 to form plasmanyl- and plasmenyl-phospholipids, respectively (
      • Harayama T.
      • Riezman H.
      Understanding the diversity of membrane lipid composition.
      ). The membrane phospholipid diversity generated by the combinations of headgroups, fatty chains, and linkages is extensive and comprised of over a thousand species (
      • Shindou H.
      • Shimizu T.
      Acyl-CoA:lysophospholipid acyltransferases.
      ,
      • Sud M.
      • Fahy E.
      • Cotter D.
      • Brown A.
      • Dennis E.A.
      • Glass C.K.
      • Merrill A.H.
      • Murphy R.C.
      • Raetz C.R.
      • Russell D.W.
      • Subramaniam S.
      LMSD: LIPID MAPS structure database.
      ).
      Figure thumbnail gr1
      Figure 1Chemical structures of mammalian phospholipids and two types of acyltransferases to biosynthesize phospholipids. A, in the left panel, structures of the major classes of mammalian phospholipids are shown. "R" (highlighted in red) indicates hydrocarbon chains of fatty acids. In the right panel, several of the fatty acids most commonly esterified in mammalian phospholipids are shown. B, upper, GPATs synthesize LPA using G3P and acyl-CoA as substrates. Currently four GPATs, GPAT1 to 4, have been identified, all of the AGPAT family. B, lower, LPLATs biosynthesize phospholipids using sn-1- or sn-2-acyl LPLs and acyl-CoAs as substrates. The LPLs may be of several classes, including LPA. Currently, 14 LPLATs have been identified, all either from the AGPAT or MBOAT families.
      The choices of headgroups, fatty acids, and linkages are all essential features that affect phospholipid function. For the fatty acids, carbon chain lengths and double-bond numbers/positions are important attributes, which may affect biophysical and biological properties of phospholipid layers (
      • Antonny B.
      • Vanni S.
      • Shindou H.
      • Ferreira T.
      From zero to six double bonds: Phospholipid unsaturation and organelle function.
      ,
      • Harayama T.
      • Shimizu T.
      Roles of polyunsaturated fatty acids, from mediators to membranes.
      ). These include biomembrane fluidity, flexibility, thickness, and curvature (
      • Barelli H.
      • Antonny B.
      Lipid unsaturation and organelle dynamics.
      ,
      • Hishikawa D.
      • Hashidate T.
      • Shimizu T.
      • Shindou H.
      Diversity and function of membrane glycerophospholipids generated by the remodeling pathway in mammalian cells.
      ), as well as propensity to form signaling domains or provide specific polyunsaturated chains for conversion to lipid mediators (
      • Shimizu T.
      Lipid mediators in health and disease: Enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation.
      ,
      • Antonny B.
      • Vanni S.
      • Shindou H.
      • Ferreira T.
      From zero to six double bonds: Phospholipid unsaturation and organelle function.
      ). The diversity of fatty chain sets is determined in two distinct steps of de novo phospholipid biosynthesis and phospholipid remodeling, as described in detail in Phospholipid biosynthesis section.

      Phospholipid biosynthesis

      Phospholipids can be produced by several metabolic routes, and a key reaction that utilizes lysophospholipids and acyl-CoAs as substrates to produce phospholipids is catalyzed by a class of enzymes called lysophospholipid acyltransferases (LPLATs) (Fig. 1B). Chemical diversity is endowed to phospholipid molecules in two distinct phases of their biosynthesis, the Kennedy pathway (de novo pathway) (
      • Kennedy E.P.
      • Weiss S.B.
      The function of cytidine coenzymes in the biosynthesis of phospholipides.
      ) and the Lands cycle (remodeling pathway) (
      • Lands W.E.
      Metabolism of glycerolipides; a comparison of lecithin and triglyceride synthesis.
      ) (Fig. 2). These pathways were both first proposed in the 1950s, and multiple different LPLATs function in both pathways (
      • Valentine W.J.
      • Hashidate-Yoshida T.
      • Yamamoto S.
      • Shindou H.
      Biosynthetic enzymes of membrane glycerophospholipid diversity as therapeutic targets for drug development.
      ).
      Figure thumbnail gr2
      Figure 2Biosynthetic pathways of phospholipid diversity. Phospholipids are first produced in the Kennedy pathway by acylation of G3P by GPAT to produce LPA, and subsequent acylation by LPLAT (LPAAT reaction in this case) to produce PA. This PA may be further metabolized to DAG and used to produce PC, PE, and PS, as well as TAG. Alternatively, the PA may be used to produce CDP-DAG and further metabolized to PI, PG, and CL. The phospholipids produced in the Kennedy pathway are remodeled by the concerted action of PLA1/2 and LPLAT in the Lands cycle. Lands cycle remodeling of a sn-2-acyl chain is illustrated; however, remodeling of sn-1 may also occur. The representative fatty acids shown are palmitic acid (blue), oleic acid (orange), and arachidonic acid (red). X represents any phospholipid polar head group. CDP-DAG, cytidine diphosphate-DAG; CL, cardiolipin; DAG, diacylglycerol; G3P, glycerol-3-phosphate; GPAT, G3P acyltransferase; LPL, lysophospholipid; LPLAT, LPL acyltransferase; PA, phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PI, phosphatidylinositol; PLA, phospholipase; PS phosphatidylserine; TAG, triacylglycerol.
      In the Kennedy pathway, where phospholipids are newly synthesized, glycerol-3-phosphate (G3P) acyltransferases (GPATs) use G3P and acyl-CoA as substrates to produce a key intermediate in phospholipid synthesis, lysophosphatidic acid (LPA) (Figs. 1B and 2). This LPA is converted to phosphatidic acid (PA) through the introduction of a second fatty acid in a LPLAT-catalyzed reaction. This type of LPLAT reaction that produces PA may also be referred to as an LPA acyltransferase (LPAAT) reaction (
      • Shindou H.
      • Shimizu T.
      Acyl-CoA:lysophospholipid acyltransferases.
      ,
      • Yamashita A.
      • Hayashi Y.
      • Matsumoto N.
      • Nemoto-Sasaki Y.
      • Oka S.
      • Tanikawa T.
      • Sugiura T.
      Glycerophosphate/acylglycerophosphate acyltransferases.
      ). The PA they produce may be further converted to the other classes of phospholipids via two main routes. In one route, PA is dephosphorylated by PA phosphatases (PAPs; also known as lipins) to produce diacylglycerol (DAG). DAG may be next metabolized to PC and PE, which may be further converted to PS by PS synthases (
      • Tavasoli M.
      • Lahire S.
      • Reid T.
      • Brodovsky M.
      • McMaster C.R.
      Genetic diseases of the Kennedy pathway for phospholipid synthesis.
      ). DAG may also be utilized as substrate by DAG acyltransferases (DGATs) to produce triacylglycerol (TAG) (
      • Coleman R.A.
      • Lewin T.M.
      • Muoio D.M.
      Physiological and nutritional regulation of enzymes of triacylglycerol synthesis.
      ). In the other route, PA is changed to cytidine diphosphate (CDP)-DAG by CDP-DAG synthase and further metabolized to produce PI, PG, and CL. Through these reactions, phospholipids having a variety of chain sets and all types of polar head groups are newly biosynthesized during the Kennedy pathway (Fig. 2).
      Cellular phospholipids synthesized in the Kennedy pathway are further subjected to fatty chain remodeling reactions in the pathway known as the Lands cycle. In this cycle, fatty acids of phospholipids are selectively replaced by the concerted actions of phospholipase (PLA)1/2s and LPLATs (
      • Shindou H.
      • Shimizu T.
      Acyl-CoA:lysophospholipid acyltransferases.
      ,
      • Kita Y.
      • Shindou H.
      • Shimizu T.
      Cytosolic phospholipase A2 and lysophospholipid acyltransferases.
      ) (Figs. 1B and 2). Cells can also take up phospholipids such as by endocytosis (
      • Engelmann B.
      • Wiedmann M.K.
      Cellular phospholipid uptake: Flexible paths to coregulate the functions of intracellular lipids.
      ,
      • Batzri S.
      • Korn E.D.
      Interaction of phospholipid vesicles with cells. Endocytosis and fusion as alternate mechanisms for the uptake of lipid-soluble and water-soluble molecules.
      ), and these imported phospholipids may undergo Lands cycle remodeling. Multiple LPLATs with distinct substrate specificities are active in the Lands cycle, and the levels of these enzymes and the availability of their substrates are major determinants of the compositional diversity of phospholipid species in cells (
      • Hishikawa D.
      • Hashidate T.
      • Shimizu T.
      • Shindou H.
      Diversity and function of membrane glycerophospholipids generated by the remodeling pathway in mammalian cells.
      ).
      Now 14 mammalian LPLATs are reported that function in the Kennedy pathway and/or Lands cycle (
      • Shindou H.
      • Shimizu T.
      Acyl-CoA:lysophospholipid acyltransferases.
      ,
      • Valentine W.J.
      • Hashidate-Yoshida T.
      • Yamamoto S.
      • Shindou H.
      Biosynthetic enzymes of membrane glycerophospholipid diversity as therapeutic targets for drug development.
      ). Based on their primary structures, these LPLATs are divided into two families, the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) and the membrane bound O-acyltransferase (MBOAT) families (Fig. 3D, see also Table 1) (
      • Shindou H.
      • Shimizu T.
      Acyl-CoA:lysophospholipid acyltransferases.
      ,
      • Valentine W.J.
      • Hashidate-Yoshida T.
      • Yamamoto S.
      • Shindou H.
      Biosynthetic enzymes of membrane glycerophospholipid diversity as therapeutic targets for drug development.
      ). These two families also contain non-LPLAT members. The AGPAT family also contains GPATs and tafazzin, an enzyme with CoA-independent transacylase activity (
      • Yamashita A.
      • Hayashi Y.
      • Matsumoto N.
      • Nemoto-Sasaki Y.
      • Oka S.
      • Tanikawa T.
      • Sugiura T.
      Glycerophosphate/acylglycerophosphate acyltransferases.
      ). The MBOAT family also contains DGAT1, sterol O-acyltransferase (SOAT) 1 and 2 (also called acyl-CoA:cholesterol acyltransferase 1 and 2), and several protein acyltransferases such as ghrelin O-acyltransferase (GOAT), porcupine O-acyltransferase (PORCN), hedgehog acyltransferase (HHAT), and HHAT-like (
      • Masumoto N.
      • Lanyon-Hogg T.
      • Rodgers U.R.
      • Konitsiotis A.D.
      • Magee A.I.
      • Tate E.W.
      Membrane bound O-acyltransferases and their inhibitors.
      ). Thus, different members of the two families, AGPAT and MBOAT, possess primary activities to acylate not just lysophospholipids but also other protein and lipid substrates. The diversity of acylating activities among these enzymes is immense, and in some cases the specific primary biological activities of the enzymes in terms of specific substrates utilized and products generated are still not clear. As discussed in Nomenclature section, this also applies to some of the 14 enzymes functionally classified as LPLATs.
      Figure thumbnail gr3
      Figure 3Criteria of proposed nomenclature to overcome the current problems and dendrogram of AGPAT and MBOAT family members. A, multiple naming of individual enzymes in the current nomenclature. In several cases, the same name has been assigned to completely different enzymes. Purple shading indicates identical names shared by different enzymes, which may generate confusion. B, current nomenclature inaccurately reflects enzymatic activities. B, left, most LPLATs utilize multiple lysophospholipids as substrates. B, right, the reported substrate selectivities in vitro often differ between studies. C, the proposed nomenclature is based on three criteria, as described in section. D, the dendrogram was drawn using ClustalW (https://clustalw.ddbj.nig.ac.jp) and MEGA X. AGPAT family members include LPLATs, GPATs, Tafazzin (NP_001167018), and GNPAT (NP_034452). Tafazzin and GNPAT are reported to have transacylase and dihydroxyacetone phosphate activity, respectively (
      • Yamashita A.
      • Hayashi Y.
      • Matsumoto N.
      • Nemoto-Sasaki Y.
      • Oka S.
      • Tanikawa T.
      • Sugiura T.
      Glycerophosphate/acylglycerophosphate acyltransferases.
      ,
      • Schlame M.
      • Xu Y.
      The function of tafazzin, a mitochondrial phospholipid-lysophospholipid acyltransferase.
      ). MBOAT family members include LPLATs, diacylglycerol acyltransferase 1 (DGAT1, NP_034176), sterol O-acyltransferase 1 (SOAT1, NP_033256) and SOAT2 (NP_666176), and protein acyltransferases including MBOAT4 (also called ghrelin O-acyltransferase, GOAT, NP_001119786), porcupine O-acyltransferase (PORCN, NP_665914), hedgehog acyltransferase (HHAT, NP_659130), and HHATL (HHAT-like, NP_083371). LPLATs in both families possess motifs (either AGPAT motifs or MBOAT motifs) essential for their LPLAT activities. For LPLATs, new proposed names are shown in red, followed by the current official symbols in parentheses (in black).
      Table 1Proposed nomenclature of LPLATs
      FamilyProposed nameNCBI
      Current official symbolOrganismReference sequenceGene IDAlso known as
      AGPATLPLAT1AGPAT1HumanNM_03274110554G15; LPAATA; 1-AGPAT1; LPAAT-alpha
      Agpat1MouseNM_018862559791-A; Lpa; 1-AGP; 1-AGPAT; AW047140
      LPLAT2AGPAT2HumanNM_00641210555BSCL; BSCL1; LPAAB; 1-AGPAT2; LPAAT-beta
      Agpat2MouseNM_02621267512BSC; BSCL; BSCL1; LPAAB; LPAAT; AV000834; LPAAT-beta; 2510002J07Rik
      LPLAT3AGPAT3HumanNM_00103755356894LPAAT3; 1-AGPAT 3; LPAAT-GAMMA1
      Agpat3MouseNM_05301428169LP; lpaat3; AW061257; AW493985; D10Jhu12e
      LPLAT4AGPAT4HumanNM_020133568951-AGPAT4; dJ473J16.2; LPAAT-delta
      Agpat4MouseNM_026644682621500003P24Rik
      LPLAT5AGPAT5HumanNM_01836155326LPAATE; 1AGPAT5
      Agpat5MouseNM_02679252123D8Ertd319; D8Ertd319e; 1110013A05Rik
      LPLAT6LCLAT1HumanNM_182551253558LYCAT; AGPAT8; ALCAT1; 1AGPAT8; UNQ1849; HSRG1849
      Lclat1MouseNM_001177968225010AGP; ALC; Lyc; Gm91; Lycat; Agpat8; Alcat1; AI181996; 1-AGPAT 8
      LPLAT7LPGAT1HumanNM_0148739926NET8; FAM34A; FAM34A1
      Lpgat1MouseNM_172266226856AI649174; AW112037; BC013667
      LPLAT8LPCAT1HumanNM_02483079888AYTL2; lpcat; AGPAT9; PFAAP3; AGPAT10; LPCAT-1; lysoPAFAT
      Lpcat1MouseNM_145376210992LP; Ayt; rd1; rd11; Aytl2; LPCAT; C87117; LPCAT-1; mLPCAT1; BB137372; BC005662; lysoPAFAT; 2900035H07Rik
      LPLAT9LPCAT2HumanNM_01783954947AYTL1; AGPAT11; LysoPAFAT
      Lpcat2MouseNM_173014270084Ayt; LPC; Aytl1; Aytl1a; lpafat1; lysoPAFAT; 1-AGPAT 11; A330042H22; lysoPAFAT/LPCAT2
      LPLAT9bLpcat2bMouseNM_02759970902Aytl; Aytl1b; 4921521K07Rik
      LPLAT10LPCAT4HumanNM_153613254531AYTL3; AGPAT7; LPEAT2; LPAAT-eta
      Lpcat4MouseNM_20720699010Agp; Ayt; LPE; Aytl3; Agpat7; LPEAT2; AI505034
      MBOATLPLAT11MBOAT7HumanNM_02429879143BB1; LRC4; LENG4; LPIAT; LPLAT; MBOA7; MRT57; OACT7; hMBOA-7
      Mboat7MouseNM_02993477582Lp; BB1; Len; Leng4; Lpiat; Lpiat1; LPLAT 7; m-mboa-7; 5730589L02Rik
      LPLAT12LPCAT3HumanNM_00576810162C3F; LPCAT; LPSAT; OACT5; nessy; MBOAT5; LPLAT 5
      Lpcat3MouseNM_14513014792C3f; Oac; PTG; Mboa; Grcc3; Lpcat; Lpeat; Lpsat; Oact5; Grcc3f; Lplat5; Mboat5; Moact5
      LPLAT13MBOAT2HumanNM_138799129642LPAAT; LPEAT; OACT2; LPCAT4; LPLAT 2
      Mboat2MouseNM_02603767216Oac; Oact2; LPCAT4; Moact2; AU022889; AW547221; 2810049G06Rik
      LPLAT14MBOAT1HumanNM_001080480154141LPLAT; LPSAT; OACT1; LPEAT1; LPLAT 1; dJ434O11.1
      Mboat1MouseNM_153546218121Oac; Oact1; LPEAT1; Moact1; BC023845; 9130215M02Rik

      Nomenclature

      Because LPLATs are membrane-associated enzymes and utilize lipid substrates, their purification and identification had long been elusive after the discoveries of the Kennedy pathway and the Lands cycle in 1950s. However, several LPLATs were identified that functioned in either the Kennedy pathway or the Lands cycle in the 1990s and the 2000s, respectively; 40 to 50 years after the first discoveries of both pathways. Following completion of the human genome project in 2003, multiple additional putative LPLATs were identified in the DNA databases, and consequently their characterizations as LPLATs were performed in rapid succession, especially around 2004 to 2009 (
      • Shindou H.
      • Shimizu T.
      Acyl-CoA:lysophospholipid acyltransferases.
      ). As a result, currently a total of 14 LPLATs from the AGPAT (ten LPLATs) and MBOAT (four LPLATs) families are now known, and they are each conserved between human and mouse. In the course of these studies, many enzymes were assigned different names by different groups, and also registered in genomic databases with incorrect information of their substrate specificities as LPLATs, resulting in multiple names being assigned to each LPLAT enzyme. In several instances, the same name was assigned to completely different enzymes, which has generated some confusion in the literature and research field in referring to specific LPLATs and GPATs (Fig. 3A, Tables 1 and 2). For example, the name “lyso-PC acyltransferase (LPCAT)4” sometimes indicates either of two enzymes, MBOAT2 (Gene ID: 129642) or lyso-PE acyltransferase (LPEAT)2 (Gene ID: 254531). Another example is “AGPAT8,” which may indicate two enzymes, lyso-CL acyltransferase (LCLAT)1 (Gene ID: 253558) and GPAT3 (Gene ID: 84803). Similarly, LPCAT1 (Gene ID: 79888) and GPAT3 have each been referred to as both “AGPAT9” and “AGPAT10.”
      Table 2Current nomenclature of GPATs
      FamilyNameNCBI
      Official symbolOrganismReference sequenceGene IDAlso known as
      AGPATGPAT1GPAMhumanNM_00124494957678GPAT; GPAT1
      GpammouseNM_00814914732GPA; P90; GPAT; GPAT1; GPAT-1
      GPAT2GPAT2humanNM_207328150763CT123
      Gpat2mouseNM_001081089215456Gpa; Gm116; xGPAT1; A530057A03Rik
      GPAT3GPAT3humanNM_00125642184803MAG1; AGPAT8; AGPAT9; AGPAT10; AGPAT 10; HMFN0839; LPAAT-theta
      Gpat3mouseNM_172715231510Agp; Agpat9; GPAT-3; mGPAT3; 1-AGPAT; AGPAT 10; 1-AGPAT 9; 4933408F15; 4933407I02Rik; A230097K15Rik
      GPAT4GPAT4humanNM_178819137964AGPAT6; LPAATZ; TSARG7; 1-AGPAT 6; LPAAT-zeta
      Gpat4mouseNM_018743102247Agp; Agpat6; Tsarg7; AU041707; AW545732
      In addition to the ambiguity and confusion caused by the overlapping of names, these names incompletely describe biochemical characteristics of the enzymes. Most LPLATs utilize multiple lysophospholipids as substrates (Fig. 4). For instance, LPCAT3 acts not only on lyso-PC (LPC) but also lyso-PE (LPE) and lyso-PS (LPS), but it is unclear that the enzyme has specificity to utilize several different lysophospholipids from the name “LPCAT3” (Fig. 3B, left and Fig. 4). Another issue is that reported substrate selectivities of some LPLATs are inconsistent among different studies, as exemplified by the case of LPCAT1 (Fig. 3B, right and Fig. 4). Consistent use of the unique official gene symbols provided by the National Center for Biotechnology Information (NCBI) would alleviate confusion caused by multiple naming of individual enzymes; however, many of these contain incorrect information of their LPLAT enzymatic activities, especially regarding the lysophospholipid polar head selectivity. Therefore, to avoid confusion in this research field, a revised LPLAT nomenclature is urgently needed.
      Figure thumbnail gr4
      Figure 4In vitro activities of 14 LPLATs. The substrate recognition indicated for each enzyme is a summary based upon in vitro enzymatic activities reported in the literature. For each combination of lysophospholipid and fatty acyl-CoA substrates, red indicates the acyltransferase activity of the enzyme was “detected,” gray indicates the activity was “not detected,” and orange indicates “opposing reports” with the activity reported as both “detected” and “not detected” in different studies. For each LPLAT, the new proposed name is shown, followed by the current official symbol in parentheses. The summarized activities are based upon review of the literature for LPLAT1 (
      • Harayama T.
      • Eto M.
      • Shindou H.
      • Kita Y.
      • Otsubo E.
      • Hishikawa D.
      • Ishii S.
      • Sakimura K.
      • Mishina M.
      • Shimizu T.
      Lysophospholipid acyltransferases mediate phosphatidylcholine diversification to achieve the physical properties required in vivo.
      ,
      • West J.
      • Tompkins C.K.
      • Balantac N.
      • Nudelman E.
      • Meengs B.
      • White T.
      • Bursten S.
      • Coleman J.
      • Kumar A.
      • Singer J.W.
      • Leung D.W.
      Cloning and expression of two human lysophosphatidic acid acyltransferase cDNAs that enhance cytokine-induced signaling responses in cells.
      ,
      • Agarwal A.K.
      • Sukumaran S.
      • Cortés V.A.
      • Tunison K.
      • Mizrachi D.
      • Sankella S.
      • Gerard R.D.
      • Horton J.D.
      • Garg A.
      Human 1-acylglycerol-3-phosphate O-acyltransferase isoforms 1 and 2: Biochemical characterization and inability to rescue hepatic steatosis in Agpat2(-/-) gene lipodystrophic mice.
      ,
      • Lu B.
      • Jiang Y.J.
      • Zhou Y.
      • Xu F.Y.
      • Hatch G.M.
      • Choy P.C.
      Cloning and characterization of murine 1-acyl-sn-glycerol 3-phosphate acyltransferases and their regulation by PPARalpha in murine heart.
      ,
      • Yuki K.
      • Shindou H.
      • Hishikawa D.
      • Shimizu T.
      Characterization of mouse lysophosphatidic acid acyltransferase 3: An enzyme with dual functions in the testis.
      ,
      • Aguado B.
      • Campbell R.D.
      Characterization of a human lysophosphatidic acid acyltransferase that is encoded by a gene located in the class III region of the human major histocompatibility complex.
      ,
      • Hollenback D.
      • Bonham L.
      • Law L.
      • Rossnagle E.
      • Romero L.
      • Carew H.
      • Tompkins C.K.
      • Leung D.W.
      • Singer J.W.
      • White T.
      Substrate specificity of lysophosphatidic acid acyltransferase beta -- evidence from membrane and whole cell assays.
      ), LPLAT2 (
      • Harayama T.
      • Eto M.
      • Shindou H.
      • Kita Y.
      • Otsubo E.
      • Hishikawa D.
      • Ishii S.
      • Sakimura K.
      • Mishina M.
      • Shimizu T.
      Lysophospholipid acyltransferases mediate phosphatidylcholine diversification to achieve the physical properties required in vivo.
      ,
      • West J.
      • Tompkins C.K.
      • Balantac N.
      • Nudelman E.
      • Meengs B.
      • White T.
      • Bursten S.
      • Coleman J.
      • Kumar A.
      • Singer J.W.
      • Leung D.W.
      Cloning and expression of two human lysophosphatidic acid acyltransferase cDNAs that enhance cytokine-induced signaling responses in cells.
      ,
      • Agarwal A.K.
      • Sukumaran S.
      • Cortés V.A.
      • Tunison K.
      • Mizrachi D.
      • Sankella S.
      • Gerard R.D.
      • Horton J.D.
      • Garg A.
      Human 1-acylglycerol-3-phosphate O-acyltransferase isoforms 1 and 2: Biochemical characterization and inability to rescue hepatic steatosis in Agpat2(-/-) gene lipodystrophic mice.
      ,
      • Lu B.
      • Jiang Y.J.
      • Zhou Y.
      • Xu F.Y.
      • Hatch G.M.
      • Choy P.C.
      Cloning and characterization of murine 1-acyl-sn-glycerol 3-phosphate acyltransferases and their regulation by PPARalpha in murine heart.
      ,
      • 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.
      ,
      • 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.
      ,
      • Hollenback D.
      • Bonham L.
      • Law L.
      • Rossnagle E.
      • Romero L.
      • Carew H.
      • Tompkins C.K.
      • Leung D.W.
      • Singer J.W.
      • White T.
      Substrate specificity of lysophosphatidic acid acyltransferase beta -- evidence from membrane and whole cell assays.
      ,
      • Eberhardt C.
      • Gray P.W.
      • Tjoelker L.W.
      Human lysophosphatidic acid acyltransferase. cDNA cloning, expression, and localization to chromosome 9q34.3.
      ,
      • 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.
      ,
      • Agarwal A.K.
      • Sukumaran S.
      • Bartz R.
      • Barnes R.I.
      • Garg A.
      Functional characterization of human 1-acylglycerol-3-phosphate-O-acyltransferase isoform 9: Cloning, tissue distribution, gene structure, and enzymatic activity.
      ), LPLAT3 (
      • Harayama T.
      • Eto M.
      • Shindou H.
      • Kita Y.
      • Otsubo E.
      • Hishikawa D.
      • Ishii S.
      • Sakimura K.
      • Mishina M.
      • Shimizu T.
      Lysophospholipid acyltransferases mediate phosphatidylcholine diversification to achieve the physical properties required in vivo.
      ,
      • Lu B.
      • Jiang Y.J.
      • Zhou Y.
      • Xu F.Y.
      • Hatch G.M.
      • Choy P.C.
      Cloning and characterization of murine 1-acyl-sn-glycerol 3-phosphate acyltransferases and their regulation by PPARalpha in murine heart.
      ,
      • Koeberle A.
      • Shindou H.
      • Harayama T.
      • Shimizu T.
      Role of lysophosphatidic acid acyltransferase 3 for the supply of highly polyunsaturated fatty acids in TM4 Sertoli cells.
      ,
      • Prasad S.S.
      • Garg A.
      • Agarwal A.K.
      Enzymatic activities of the human AGPAT isoform 3 and isoform 5: Localization of AGPAT5 to mitochondria.
      ,
      • Schmidt J.A.
      • Brown W.J.
      Lysophosphatidic acid acyltransferase 3 regulates Golgi complex structure and function.
      ), LPLAT4 (
      • Lu B.
      • Jiang Y.J.
      • Zhou Y.
      • Xu F.Y.
      • Hatch G.M.
      • Choy P.C.
      Cloning and characterization of murine 1-acyl-sn-glycerol 3-phosphate acyltransferases and their regulation by PPARalpha in murine heart.
      ,
      • Eto M.
      • Shindou H.
      • Shimizu T.
      A novel lysophosphatidic acid acyltransferase enzyme (LPAAT4) with a possible role for incorporating docosahexaenoic acid into brain glycerophospholipids.
      ), LPLAT5 (
      • Lu B.
      • Jiang Y.J.
      • Zhou Y.
      • Xu F.Y.
      • Hatch G.M.
      • Choy P.C.
      Cloning and characterization of murine 1-acyl-sn-glycerol 3-phosphate acyltransferases and their regulation by PPARalpha in murine heart.
      ,
      • Prasad S.S.
      • Garg A.
      • Agarwal A.K.
      Enzymatic activities of the human AGPAT isoform 3 and isoform 5: Localization of AGPAT5 to mitochondria.
      ), LPLAT6 (
      • 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.
      ,
      • Cao J.
      • Shen W.
      • Chang Z.
      • Shi Y.
      ALCAT1 is a polyglycerophospholipid acyltransferase potently regulated by adenine nucleotide and thyroid status.
      ,
      • Kawana H.
      • Kano K.
      • Shindou H.
      • Inoue A.
      • Shimizu T.
      • Aoki J.
      An accurate and versatile method for determining the acyl group-introducing position of lysophospholipid acyltransferases.
      ,
      • 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.
      ), LPLAT7 (
      • Yang Y.
      • Cao J.
      • Shi Y.
      Identification and characterization of a gene encoding human LPGAT1, an endoplasmic reticulum-associated lysophosphatidylglycerol acyltransferase.
      ,
      • 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.
      ), LPLAT8 (
      • Harayama T.
      • Eto M.
      • Shindou H.
      • Kita Y.
      • Otsubo E.
      • Hishikawa D.
      • Ishii S.
      • Sakimura K.
      • Mishina M.
      • Shimizu T.
      Lysophospholipid acyltransferases mediate phosphatidylcholine diversification to achieve the physical properties required in vivo.
      ,
      • 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.
      ,
      • Harayama T.
      • Shindou H.
      • Shimizu T.
      Biosynthesis of phosphatidylcholine by human lysophosphatidylcholine acyltransferase 1.
      ,
      • Morimoto R.
      • Shindou H.
      • Tarui M.
      • Shimizu T.
      Rapid production of platelet-activating factor is induced by protein kinase Cα-mediated phosphorylation of lysophosphatidylcholine acyltransferase 2 protein.
      ,
      • Morimoto R.
      • Shindou H.
      • Oda Y.
      • Shimizu T.
      Phosphorylation of lysophosphatidylcholine acyltransferase 2 at Ser34 enhances platelet-activating factor production in endotoxin-stimulated macrophages.
      ,
      • Moessinger C.
      • Kuerschner L.
      • Spandl J.
      • Shevchenko A.
      • Thiele C.
      Human lysophosphatidylcholine acyltransferases 1 and 2 are located in lipid droplets where they catalyze the formation of phosphatidylcholine.
      ,
      • 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.
      ,
      • Kawana H.
      • Kano K.
      • Shindou H.
      • Inoue A.
      • Shimizu T.
      • Aoki J.
      An accurate and versatile method for determining the acyl group-introducing position of lysophospholipid acyltransferases.
      ,
      • Agarwal A.K.
      • Sukumaran S.
      • Bartz R.
      • Barnes R.I.
      • Garg A.
      Functional characterization of human 1-acylglycerol-3-phosphate-O-acyltransferase isoform 9: Cloning, tissue distribution, gene structure, and enzymatic activity.
      ,
      • Soupene E.
      • Fyrst H.
      • Kuypers F.A.
      Mammalian acyl-CoA:lysophosphatidylcholine acyltransferase enzymes.
      ), LPLAT9 (
      • Harayama T.
      • Eto M.
      • Shindou H.
      • Kita Y.
      • Otsubo E.
      • Hishikawa D.
      • Ishii S.
      • Sakimura K.
      • Mishina M.
      • Shimizu T.
      Lysophospholipid acyltransferases mediate phosphatidylcholine diversification to achieve the physical properties required in vivo.
      • Hamano F.
      • Matoba K.
      • Hashidate-Yoshida T.
      • Suzuki T.
      • Miura K.
      • Hishikawa D.
      • Harayama T.
      • Yuki K.
      • Kita Y.
      • Noda N.N.
      • Shimizu T.
      • Shindou H.
      Mutagenesis and homology modeling reveal a predicted pocket of lysophosphatidylcholine acyltransferase 2 to catch Acyl-CoA.
      ,
      • 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.
      ,
      • Morimoto R.
      • Shindou H.
      • Tarui M.
      • Shimizu T.
      Rapid production of platelet-activating factor is induced by protein kinase Cα-mediated phosphorylation of lysophosphatidylcholine acyltransferase 2 protein.
      ,
      • Morimoto R.
      • Shindou H.
      • Oda Y.
      • Shimizu T.
      Phosphorylation of lysophosphatidylcholine acyltransferase 2 at Ser34 enhances platelet-activating factor production in endotoxin-stimulated macrophages.
      ,
      • Moessinger C.
      • Kuerschner L.
      • Spandl J.
      • Shevchenko A.
      • Thiele C.
      Human lysophosphatidylcholine acyltransferases 1 and 2 are located in lipid droplets where they catalyze the formation of phosphatidylcholine.
      ,
      • 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.
      ,
      • Soupene E.
      • Fyrst H.
      • Kuypers F.A.
      Mammalian acyl-CoA:lysophosphatidylcholine acyltransferase enzymes.
      ), LPLAT10 (
      • 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.
      ,
      • Eto M.
      • Shindou H.
      • Yamamoto S.
      • Tamura-Nakano M.
      • Shimizu T.
      Lysophosphatidylethanolamine acyltransferase 2 (LPEAT2) incorporates DHA into phospholipids and has possible functions for fatty acid-induced cell death.
      ,
      • Soupene E.
      • Fyrst H.
      • Kuypers F.A.
      Mammalian acyl-CoA:lysophosphatidylcholine acyltransferase enzymes.
      ), LPLAT11 (
      • 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.
      ,
      • Gijon M.A.
      • Riekhof W.R.
      • Zarini S.
      • Murphy R.C.
      • Voelker D.R.
      Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils.
      ,
      • Caddeo A.
      • Hedfalk K.
      • Romeo S.
      • Pingitore P.
      LPIAT1/MBOAT7 contains a catalytic dyad transferring polyunsaturated fatty acids to lysophosphatidylinositol.
      ), LPLAT12 (
      • Harayama T.
      • Eto M.
      • Shindou H.
      • Kita Y.
      • Otsubo E.
      • Hishikawa D.
      • Ishii S.
      • Sakimura K.
      • Mishina M.
      • Shimizu T.
      Lysophospholipid acyltransferases mediate phosphatidylcholine diversification to achieve the physical properties required in vivo.
      ,
      • Shindou H.
      • Eto M.
      • Morimoto R.
      • Shimizu T.
      Identification of membrane O-acyltransferase family motifs.
      ,
      • 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.
      ,
      • Eto M.
      • Shindou H.
      • Yamamoto S.
      • Tamura-Nakano M.
      • Shimizu T.
      Lysophosphatidylethanolamine acyltransferase 2 (LPEAT2) incorporates DHA into phospholipids and has possible functions for fatty acid-induced cell death.
      ,
      • 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.
      ,
      • Kawana H.
      • Kano K.
      • Shindou H.
      • Inoue A.
      • Shimizu T.
      • Aoki J.
      An accurate and versatile method for determining the acyl group-introducing position of lysophospholipid acyltransferases.
      ), LPLAT13 (
      • Harayama T.
      • Eto M.
      • Shindou H.
      • Kita Y.
      • Otsubo E.
      • Hishikawa D.
      • Ishii S.
      • Sakimura K.
      • Mishina M.
      • Shimizu T.
      Lysophospholipid acyltransferases mediate phosphatidylcholine diversification to achieve the physical properties required in vivo.
      ,
      • Eto M.
      • Shindou H.
      • Yamamoto S.
      • Tamura-Nakano M.
      • Shimizu T.
      Lysophosphatidylethanolamine acyltransferase 2 (LPEAT2) incorporates DHA into phospholipids and has possible functions for fatty acid-induced cell death.
      ,
      • Hishikawa D.
      • Shindou H.
      • Kobayashi S.
      • Nakanishi H.
      • Taguchi R.
      • Shimizu T.
      Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity.
      ,
      • Gijon M.A.
      • Riekhof W.R.
      • Zarini S.
      • Murphy R.C.
      • Voelker D.R.
      Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils.
      ), and LPLAT14 (
      • Eto M.
      • Shindou H.
      • Yamamoto S.
      • Tamura-Nakano M.
      • Shimizu T.
      Lysophosphatidylethanolamine acyltransferase 2 (LPEAT2) incorporates DHA into phospholipids and has possible functions for fatty acid-induced cell death.
      ,
      • Hishikawa D.
      • Shindou H.
      • Kobayashi S.
      • Nakanishi H.
      • Taguchi R.
      • Shimizu T.
      Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity.
      ,
      • Gijon M.A.
      • Riekhof W.R.
      • Zarini S.
      • Murphy R.C.
      • Voelker D.R.
      Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils.
      ).
      In this review, we would like to propose a new nomenclature of mammalian LPLATs based on three criteria (Fig. 3C and Table 1). (i) LPLATx (x is a number) is used as a name, which does not include any information on polar head groups of substrates, i.e., type of lysophospholipid. (ii) The numbers assigned in each LPLATx name are essentially in the order of discovery. (iii) The LPLATs for which we propose nomenclature belong to two families, AGPAT and MBOAT. Although there are a few reports of enzymes with potential LPLAT activities that belong to other protein families (
      • Taylor W.A.
      • Hatch G.M.
      Identification of the human mitochondrial linoleoyl-coenzyme A monolysocardiolipin acyltransferase (MLCL AT-1).
      ,
      • Fisher A.B.
      • Dodia C.
      • Sorokina E.M.
      • Li H.
      • Zhou S.
      • Raabe T.
      • Feinstein S.I.
      A novel lysophosphatidylcholine acyl transferase activity is expressed by peroxiredoxin 6.
      ,
      • Zhang J.
      • Xu D.
      • Nie J.
      • Han R.
      • Zhai Y.
      • Shi Y.
      Comparative gene identification-58 (CGI-58) promotes autophagy as a putative lysophosphatidylglycerol acyltransferase.
      ), this review and nomenclature proposal focus only on the enzymes of these two major families. The proposed nomenclature is shown in Table 1 along with enzyme information registered in NCBI. Nomenclature for the currently known GPATs (GPAT1-4, all AGPAT-family enzymes) is generally accurate and uniformly adopted; therefore, no revision is proposed for their current nomenclature, which is shown in Table 2 along with enzyme information registered in NCBI. We will introduce the proposed LPLATx names as our working names in this review, along with official gene symbols in parentheses as needed to avoid ambiguity, beginning with the next section, which describes enzymatic motifs and structures.

      Motifs and structures

      The experimentally solved structure of a mammalian LPLAT has not been reported yet; however, the X-ray structure of PlsC, an AGPAT-family LPAAT of the bacterium Thermotoga maritima, has been determined (
      • Robertson R.M.
      • Yao J.
      • Gajewski S.
      • Kumar G.
      • Martin E.W.
      • Rock C.O.
      • White S.W.
      A two-helix motif positions the lysophosphatidic acid acyltransferase active site for catalysis within the membrane bilayer.
      ). The model supports that PlsC introduces an acyl chain at the sn-2 position of PA, and the proper arrangement of hydrophobic tunnels, termed “rulers,” determines the length of the fatty acid to be introduced. In addition, an N-terminus two-helix motif anchors the protein firmly to one leaflet of the membrane (
      • Robertson R.M.
      • Yao J.
      • Gajewski S.
      • Kumar G.
      • Martin E.W.
      • Rock C.O.
      • White S.W.
      A two-helix motif positions the lysophosphatidic acid acyltransferase active site for catalysis within the membrane bilayer.
      ). Recently, X-ray and Cryo-EM structures of human SOAT1, DGAT1, and HHAT, all non-LPLAT members of the MBOAT family, have been determined (
      • Qian H.
      • Zhao X.
      • Yan R.
      • Yao X.
      • Gao S.
      • Sun X.
      • Du X.
      • Yang H.
      • Wong C.C.L.
      • Yan N.
      Structural basis for catalysis and substrate specificity of human ACAT1.
      ,
      • Guan C.
      • Niu Y.
      • Chen S.C.
      • Kang Y.
      • Wu J.X.
      • Nishi K.
      • Chang C.C.Y.
      • Chang T.Y.
      • Luo T.
      • Chen L.
      Structural insights into the inhibition mechanism of human sterol O-acyltransferase 1 by a competitive inhibitor.
      ,
      • Sui X.
      • Wang K.
      • Gluchowski N.L.
      • Elliott S.D.
      • Liao M.
      • Walther T.C.
      • Farese R.V.
      Structure and catalytic mechanism of a human triacylglycerol-synthesis enzyme.
      ,
      • Jiang Y.
      • Benz T.L.
      • Long S.B.
      Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT.
      ), and it is hoped the structure of an LPLAT member of the MBOAT family will be determined soon.
      Conserved motifs essential for LPLAT activities are reported and are distinct between LPLATs of the AGPAT and MBOAT families (Table 3). LPLATs and GPATs of the AGPAT family have four conserved motifs that are essential for substrate recognition and enzymatic activity: Motif 1 (xHxxxxD), Motif 2 (GxxFxxR), Motif 3 (xxEGxx), and Motif 4 (xxxxPxx) (
      • Yamashita A.
      • Hayashi Y.
      • Matsumoto N.
      • Nemoto-Sasaki Y.
      • Oka S.
      • Tanikawa T.
      • Sugiura T.
      Glycerophosphate/acylglycerophosphate acyltransferases.
      • Lewin T.M.
      • Wang P.
      • Coleman R.A.
      Analysis of amino acid motifs diagnostic for the sn-glycerol-3-phosphate acyltransferase reaction.
      ,
      • Dircks L.K.
      • Ke J.
      • Sul H.S.
      A conserved seven amino acid stretch important for murine mitochondrial glycerol-3-phosphate acyltransferase activity. Significance of arginine 318 in catalysis.
      ,
      • Yamashita A.
      • Nakanishi H.
      • Suzuki H.
      • Kamata R.
      • Tanaka K.
      • Waku K.
      • Sugiura T.
      Topology of acyltransferase motifs and substrate specificity and accessibility in 1-acyl-sn-glycero-3-phosphate acyltransferase 1.
      ,
      • Harayama T.
      • Shindou H.
      • Ogasawara R.
      • Suwabe A.
      • Shimizu T.
      Identification of a novel noninflammatory biosynthetic pathway of platelet-activating factor.
      ). MBOAT family LPLATs also contain four conserved motifs, different from the AGPAT motifs that are critical for LPLAT activities: Motif A (WD), Motif B (WHGxxxGYxxxF), Motif C (YxxxxF), and Motif D (YxxxYFxxH) (
      • Shindou H.
      • Eto M.
      • Morimoto R.
      • Shimizu T.
      Identification of membrane O-acyltransferase family motifs.
      ). Recently, we reported potential acyl-CoA-binding pockets of mouse LPLAT8 (LPCAT1) and LPLAT9 (LPCAT2), both AGPAT-family LPLATs, based on homology modeling with PlsC (
      • Hamano F.
      • Matoba K.
      • Hashidate-Yoshida T.
      • Suzuki T.
      • Miura K.
      • Hishikawa D.
      • Harayama T.
      • Yuki K.
      • Kita Y.
      • Noda N.N.
      • Shimizu T.
      • Shindou H.
      Mutagenesis and homology modeling reveal a predicted pocket of lysophosphatidylcholine acyltransferase 2 to catch Acyl-CoA.
      ). In our homology models, the four AGPAT motifs surround the putative acyl-CoA-binding pocket. LPLAT8 and LPLAT9 are thought to be monotopic membrane proteins, while LPLATs in the MBOAT family are thought to possess multiple membrane spanning domains.
      Table 3Structural information of LPLATs
      FamilyOrganismEnzymeTMEHMotifEmbedded residues
      1234123456789101112
      AGPAThumanGPAT100230–235272–278313–318347–353
      humanGPAT200205–210247–253288–293323–329
      humanGPAT312228–234268–271300–306328–3293–28142–154
      humanGPAT411247–253287–290319–325347–3488–36
      humanLPLAT111104–109143–149176–181203–2096–29
      humanLPLAT21198–103137–143170–175197–2033–21
      humanLPLAT32296–101140–146174–179206305–330335–352
      humanLPLAT42298–103140–146174–179198305–330335–355
      humanLPLAT52393–103137–143171–17620614–26321–340341–362
      humanLPLAT622123–128170–176201–206233343–365369–387
      humanLPLAT711101–106144–150182–187210344–366
      humanLPLAT800135–140172–177206–211229–234
      humanLPLAT900146–151184–189218–223240–246
      mouseLPLAT9b00142–147180–185214–219236–242
      humanLPLAT1000129–134167–172201–206224–229
      FamilyEnzymeTMEHABCD123456789101112
      MBOAThumanLPLAT111111?355–366409–414426–4344–2229–4849–6773–9299–115191–213225–259342–356362–376397–421428–445
      humanLPLAT121112313–314373–384434–439451–45939–5868–8990–107112–132141–157184–194230–252265–298358–374380–397418–444453–472
      humanLPLAT131112317–318372–383428–433445–45323–4257–7576–9398–118130–143230–251269–282284–302361–373379–397412–438444–462
      humanLPLAT141112325–326380–391436–441453–46131–5065–8384–98108–126138–151185–196238–259277–310369–381387–404420–446458–470
      Conserved Motifs were predicted by using DDBJ ClustalW (http://clustalw.ddbj.nig.ac.jp/index.php?lang=ja) and previous literature (
      • Yamashita A.
      • Hayashi Y.
      • Matsumoto N.
      • Nemoto-Sasaki Y.
      • Oka S.
      • Tanikawa T.
      • Sugiura T.
      Glycerophosphate/acylglycerophosphate acyltransferases.
      ,
      • Lewin T.M.
      • Wang P.
      • Coleman R.A.
      Analysis of amino acid motifs diagnostic for the sn-glycerol-3-phosphate acyltransferase reaction.
      ,
      • Dircks L.K.
      • Ke J.
      • Sul H.S.
      A conserved seven amino acid stretch important for murine mitochondrial glycerol-3-phosphate acyltransferase activity. Significance of arginine 318 in catalysis.
      ,
      • Yamashita A.
      • Nakanishi H.
      • Suzuki H.
      • Kamata R.
      • Tanaka K.
      • Waku K.
      • Sugiura T.
      Topology of acyltransferase motifs and substrate specificity and accessibility in 1-acyl-sn-glycero-3-phosphate acyltransferase 1.
      ,
      • Harayama T.
      • Shindou H.
      • Ogasawara R.
      • Suwabe A.
      • Shimizu T.
      Identification of a novel noninflammatory biosynthetic pathway of platelet-activating factor.
      ,
      • Shindou H.
      • Eto M.
      • Morimoto R.
      • Shimizu T.
      Identification of membrane O-acyltransferase family motifs.
      ). The number of transmembrane (TM) domains and total number of embedded helices (EH), including TMs, of the AlphaFold structures modeled in flat lipid bilayer membranes were predicted using PPM 3.0 Web Server (
      • Lomize M.A.
      • Pogozheva I.D.
      • Joo H.
      • Mosberg H.I.
      • Lomize A.L.
      OPM database and PPM web server: Resources for positioning of proteins in membranes.
      ). The amino acid numbering is based on corresponding reference sequences of LPLATs and GPATs indicated in Tables 1 and 2, respectively.
      Recently, a computational machine learning method named AlphaFold has been developed that can predict protein structures with high accuracy, even if no similar experimentally solved structure is available (
      • Jumper J.
      • Evans R.
      • Pritzel A.
      • Green T.
      • Figurnov M.
      • Ronneberger O.
      • Tunyasuvunakool K.
      • Bates R.
      • Žídek A.
      • Potapenko A.
      • Bridgland A.
      • Meyer C.
      • Kohl S.A.A.
      • Ballard A.J.
      • Cowie A.
      • et al.
      Highly accurate protein structure prediction with AlphaFold.
      ). AlphaFold was utilized to generate structural predictions of almost all human proteins, including LPLATs and GPATs (
      • Tunyasuvunakool K.
      • Adler J.
      • Wu Z.
      • Green T.
      • Zielinski M.
      • Žídek A.
      • Bridgland A.
      • Cowie A.
      • Meyer C.
      • Laydon A.
      • Velankar S.
      • Kleywegt G.J.
      • Bateman A.
      • Evans R.
      • Pritzel A.
      • et al.
      Highly accurate protein structure prediction for the human proteome.
      ). Figure 5, Figure 6, Figure 7, Figure 8 summarize the AlphaFold-generated structural predictions of GPATs and LPLATs, which were predicted with high confidence in most regions of each enzyme (Fig. 5). The predicted structures for all AGPAT-family LPLATs show conserved enzymatic core structures that contain Motifs 1 to 4 (Fig. 5 and Table 3), similar to PlsC (
      • Robertson R.M.
      • Yao J.
      • Gajewski S.
      • Kumar G.
      • Martin E.W.
      • Rock C.O.
      • White S.W.
      A two-helix motif positions the lysophosphatidic acid acyltransferase active site for catalysis within the membrane bilayer.
      ). In addition, these predicted structures reveal unique regions in each structure, some of which could function as transmembrane helices (Fig. 6). Positioning of the AlphaFold structures in lipid bilayer membranes by computational modeling using PPM 3.0 Web Server (
      • Lomize M.A.
      • Pogozheva I.D.
      • Joo H.
      • Mosberg H.I.
      • Lomize A.L.
      OPM database and PPM web server: Resources for positioning of proteins in membranes.
      ) suggests that LPLAT8 to 10 are anchored to the membrane by N-terminal helices embedded in one leaflet of the membrane, similarly as reported for PlsC (
      • Robertson R.M.
      • Yao J.
      • Gajewski S.
      • Kumar G.
      • Martin E.W.
      • Rock C.O.
      • White S.W.
      A two-helix motif positions the lysophosphatidic acid acyltransferase active site for catalysis within the membrane bilayer.
      ). In contrast, LPLAT1 to 7 and GPAT3 to 4 are predicted to more strongly anchor to membranes via one or two transmembrane helices, while GPAT1 to 2 are predicted to interact weakly with the membrane surface (Fig. 7 and Table 3). Similar positioning of the AlphaFold structures for the MBOAT-family LPLATs, LPLAT11 to 14, indicated that each of these enzymes may possess 11 transmembrane helices (Fig. 7 and Table 3), comparable to the experimentally determined structures of non-LPLAT MBOAT family members such as human HHAT (12 transmembrane helices) (
      • Jiang Y.
      • Benz T.L.
      • Long S.B.
      Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT.
      ) or human DGAT1 (nine transmembrane helices) (
      • Sui X.
      • Wang K.
      • Gluchowski N.L.
      • Elliott S.D.
      • Liao M.
      • Walther T.C.
      • Farese R.V.
      Structure and catalytic mechanism of a human triacylglycerol-synthesis enzyme.
      ,
      • Wang L.
      • Qian H.
      • Nian Y.
      • Han Y.
      • Ren Z.
      • Zhang H.
      • Hu L.
      • Prasad B.V.V.
      • Laganowsky A.
      • Yan N.
      • Zhou M.
      Structure and mechanism of human diacylglycerol O-acyltransferase 1.
      ).
      Figure thumbnail gr5
      Figure 5Ribbon representation of AlphaFold structures of human GPATs and LPLATs. All structures are of human enzymes except for mouse LPLAT9b, which has no human ortholog. AGPAT/MBOAT motifs 1/A, 2/B, 3/C, and 4/D are colored green, magenta, blue, and orange, respectively. Regions predicted with low confidence (predicted Local Distance Difference Test, pLDDT, less than 50), including inherently disordered regions, are colored red. The numbered amino acid residues of the AGPAT and MBOAT motifs are indicated in .
      Figure thumbnail gr6
      Figure 6Surface charge representations of AlphaFold structures of human GPATs and LPLATs. All structures are of human enzymes except for mouse LPLAT9b, which has no human ortholog. Electrostatic charges were calculated using the default vacuum electrostatic package in PyMOL. Red and blue shading represents negatively and positively charged regions, respectively, whereas white shading represents neutral/hydrophobic regions. Protein structure regions overlapping with light-yellow shaded areas (representing lipid bilayer) indicate regions predicted to be embedded in the membrane.
      Figure thumbnail gr7
      Figure 7Membrane-interacting models of AlphaFold structures of human GPATs and LPLATs. All structures are of human enzymes except for mouse LPLAT9b, which has no human ortholog. Membrane-interacting models were obtained by positioning each AlphaFold structure in a lipid bilayer using the PPM 3.0 Web server, with the option of planar membrane. For each enzyme, two arrays of small spheres represent opposite surfaces of a lipid membrane bilayer. The numbered amino acid residues of regions predicted to be embedded in the membrane are shown in .
      Figure thumbnail gr8
      Figure 8Magnified views of both motifs and membrane-embedded models of LPLAT9 and LPLAT12. A, magnified views of AGPAT Motifs 1 to 4 in LPLAT9 and PlsC (PDB 5KYM) (
      • Robertson R.M.
      • Yao J.
      • Gajewski S.
      • Kumar G.
      • Martin E.W.
      • Rock C.O.
      • White S.W.
      A two-helix motif positions the lysophosphatidic acid acyltransferase active site for catalysis within the membrane bilayer.
      ) and MBOAT Motifs B to D in LPLAT12 and DGAT1 (PDB 6VP0) (
      • Wang L.
      • Qian H.
      • Nian Y.
      • Han Y.
      • Ren Z.
      • Zhang H.
      • Hu L.
      • Prasad B.V.V.
      • Laganowsky A.
      • Yan N.
      • Zhou M.
      Structure and mechanism of human diacylglycerol O-acyltransferase 1.
      ). For LPLAT9 and PlsC, AGPAT Motifs 1 to 4 are colored green, magenta, blue, and orange, respectively. For LPLAT12, MBOAT Motifs B to D are colored magenta, blue, and orange, respectively. For DGAT1, C18:1-CoA is shown in yellow bound to the model, with Motifs B and C of DGAT1 colored magenta and blue, respectively. B, membrane-embedded model of LPLAT9 and LPLAT12 was prepared as in . Acetyl-CoA and lyso-PAF were manually incorporated into LPLAT9, and arachidonoyl-CoA and lyso-PC were manually incorporated into LPLAT12. Surface model represents the protein surface for LPLAT9 and the cavity surface for LPLAT12. Array of spheres represents membrane surface. Note that the membrane orientation of the LPLAT12, with arachidonoyl-CoA entering from the cytosol and lyso-PC entering from the luminal side of the membrane, is opposite of a recently proposed model by Zhang et al. (
      • Zhang Q.
      • Yao D.
      • Rao B.
      • Jian L.
      • Chen Y.
      • Hu K.
      • Xia Y.
      • Li S.
      • Shen Y.
      • Qin A.
      • Zhao J.
      • Zhou L.
      • Lei M.
      • Jiang X.C.
      • Cao Y.
      The structural basis for the phospholipid remodeling by lysophosphatidylcholine acyltransferase 3.
      ) (discussed more in main text).
      As representative LPLATs of the AGPAT and MBOAT families, detailed views of the AGPAT Motifs 1 to 4 in LPLAT9 (LPCAT2) and MBOAT Motifs B-D in LPLAT12 (LPCAT3) are shown in Figure 8A. These motifs are clustered to form a cavity where acyl-CoAs and lysophospholipids might bind, as also shown in the solved structures for PlsC (
      • Robertson R.M.
      • Yao J.
      • Gajewski S.
      • Kumar G.
      • Martin E.W.
      • Rock C.O.
      • White S.W.
      A two-helix motif positions the lysophosphatidic acid acyltransferase active site for catalysis within the membrane bilayer.
      ) and DGAT1 (
      • Wang L.
      • Qian H.
      • Nian Y.
      • Han Y.
      • Ren Z.
      • Zhang H.
      • Hu L.
      • Prasad B.V.V.
      • Laganowsky A.
      • Yan N.
      • Zhou M.
      Structure and mechanism of human diacylglycerol O-acyltransferase 1.
      ) (right panels). Figure 8B, upper panel, shows a manually docked model of LPLAT9 with acetyl-CoA and lyso-platelet-activating factor (lyso-PAF), the natural substrates utilized by LPLAT9 in PAF production. LPLAT9 possesses a hydrophobic cavity that faces the cytosol at one end and the membrane surface at the other, and acetyl-CoA and lyso-PAF could enter the cavity from the cytosol and the membrane, respectively, contacting with each other in the vicinity of the catalytic His146. AGPAT Motifs 1 to 3 constitute the cavity, whereas Motif 4 functions as a backing for the cavity. Besides the motifs, Arg166 and Arg195 could function in recognizing the phosphate groups in lyso-PAF and acetyl-CoA, respectively. Figure 8B, lower panel, shows a manually docked model of LPLAT12 with arachidonoyl-CoA and lyso-PC, the natural substrates utilized by LPLAT12 in arachidonoyl-containing-PC production. LPLAT12 possesses a hydrophobic cavity at the center that penetrates the membrane, and arachidonoyl-CoA and lyso-PC could bind to the cavity from the cytosol and the luminal side of the membrane, respectively, contacting with each other in the vicinity of the catalytic His374. MBOAT Motifs B and C, but not A or D, contribute to the construction of the cavity, which possesses a hydrophobic bulge at the center that might be suitable for accommodating the arachidonoyl chain. Recently, Zhang et al. reported on the structure of the LPLAT12 ortholog in chicken as determined by x-ray crystallography, cryo-EM, and sequence analysis (
      • Zhang Q.
      • Yao D.
      • Rao B.
      • Jian L.
      • Chen Y.
      • Hu K.
      • Xia Y.
      • Li S.
      • Shen Y.
      • Qin A.
      • Zhao J.
      • Zhou L.
      • Lei M.
      • Jiang X.C.
      • Cao Y.
      The structural basis for the phospholipid remodeling by lysophosphatidylcholine acyltransferase 3.
      ). The topology of their model with an ER lumen-facing gate for acyl-CoA substrate was surprising in being oriented opposite of to other determined structures for the MBOAT proteins SOAT1, DGAT1, and HHAT (
      • Qian H.
      • Zhao X.
      • Yan R.
      • Yao X.
      • Gao S.
      • Sun X.
      • Du X.
      • Yang H.
      • Wong C.C.L.
      • Yan N.
      Structural basis for catalysis and substrate specificity of human ACAT1.
      ,
      • Guan C.
      • Niu Y.
      • Chen S.C.
      • Kang Y.
      • Wu J.X.
      • Nishi K.
      • Chang C.C.Y.
      • Chang T.Y.
      • Luo T.
      • Chen L.
      Structural insights into the inhibition mechanism of human sterol O-acyltransferase 1 by a competitive inhibitor.
      ,
      • Sui X.
      • Wang K.
      • Gluchowski N.L.
      • Elliott S.D.
      • Liao M.
      • Walther T.C.
      • Farese R.V.
      Structure and catalytic mechanism of a human triacylglycerol-synthesis enzyme.
      ,
      • Jiang Y.
      • Benz T.L.
      • Long S.B.
      Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT.
      ,
      • Wang L.
      • Qian H.
      • Nian Y.
      • Han Y.
      • Ren Z.
      • Zhang H.
      • Hu L.
      • Prasad B.V.V.
      • Laganowsky A.
      • Yan N.
      • Zhou M.
      Structure and mechanism of human diacylglycerol O-acyltransferase 1.
      ,
      • Lanyon-Hogg T.
      • Ritzefeld M.
      • Zhang L.
      • Andrei S.A.
      • Pogranyi B.
      • Mondal M.
      • Sefer L.
      • Johnston C.D.
      • Coupland C.E.
      • Greenfield J.L.
      • Newington J.
      • Fuchter M.J.
      • Magee A.I.
      • Siebold C.
      • Tate E.W.
      Photochemical Probe Identification of a Small-Molecule Inhibitor Binding Site in Hedgehog Acyltransferase (HHAT)∗.
      ). The lumen-/cytosol-facing orientations of their model is also opposite to that presented in our modeled structural prediction, and more analyses are needed to firmly establish the topology and membrane orientation of LPLAT12.
      Future experimental studies will be required to validate the predicted structures of LPLATs in both families and reveal their true forms, membrane topologies, and catalytic mechanisms. It is expected that the current advances in protein structural predictions for GPATs and LPLATs may hold potential to offer insights regarding the structural bases for substrate access, specificity, product release, and inhibitors development for all of the enzymes. Combined with experimental validation, those studies may go far to fill in the gaps that still exist in our knowledge of the biochemical activities and biological functions of each enzyme, which are summarized in the following sections for GPATs (Characteristics of GPATs section) and LPLATs (Characteristics of lysophospholipid acyltransferases section).

      Characteristics of GPATs

      GPATs function in the common biosynthetic pathways of de novo phospholipid synthesis and TAG production by esterification of a fatty acid at the sn-1 or sn-2 position of G3P to generate LPA. At present, four GPAT enzymes, GPAT1-4, have been identified (Table 2). All four GPATs belong to the AGPAT family and have AGPAT motifs (
      • Yamashita A.
      • Hayashi Y.
      • Matsumoto N.
      • Nemoto-Sasaki Y.
      • Oka S.
      • Tanikawa T.
      • Sugiura T.
      Glycerophosphate/acylglycerophosphate acyltransferases.
      ). GPAT1 and 2 are mitochondrial GPATs and localized on the outer mitochondrial membranes, while GPAT3 and 4 are microsomal GPATs and localized in the endoplasmic reticulum (ER) (
      • Yamashita A.
      • Hayashi Y.
      • Matsumoto N.
      • Nemoto-Sasaki Y.
      • Oka S.
      • Tanikawa T.
      • Sugiura T.
      Glycerophosphate/acylglycerophosphate acyltransferases.
      ,
      • Karasawa K.
      • Tanigawa K.
      • Harada A.
      • Yamashita A.
      Transcriptional regulation of acyl-CoA:glycerol-sn-3-phosphate acyltransferases.
      ). In this section, we briefly summarize the biochemical and biological characteristics of GPATs.

      GPAT1

      The mitochondrial enzyme GPAT1 (also called GPAM) is highly expressed in lipogenic tissues such as liver and adipose, where its levels are decreased by fasting and increased by insulin, indicating a metabolic function to regulate fat utilization and storage (
      • Shin D.H.
      • Paulauskis J.D.
      • Moustaïd N.
      • Sul H.S.
      Transcriptional regulation of p90 with sequence homology to Escherichia coli glycerol-3-phosphate acyltransferase.
      ,
      • Yet S.F.
      • Lee S.
      • Hahm Y.T.
      • Sul H.S.
      Expression and identification of p90 as the murine mitochondrial glycerol-3-phosphate acyltransferase.
      ). GPAT1 is resistant to N-ethylmaleimide (NEM)-induced inhibition, unlike the other three GPATs (
      • Coleman R.A.
      • Lee D.P.
      Enzymes of triacylglycerol synthesis and their regulation.
      ). GPAT1 has selectivity to incorporate saturated acyl-CoAs such as C16:0 as substrates (
      • Shin D.H.
      • Paulauskis J.D.
      • Moustaïd N.
      • Sul H.S.
      Transcriptional regulation of p90 with sequence homology to Escherichia coli glycerol-3-phosphate acyltransferase.
      ,
      • Yet S.F.
      • Lee S.
      • Hahm Y.T.
      • Sul H.S.
      Expression and identification of p90 as the murine mitochondrial glycerol-3-phosphate acyltransferase.
      ,
      • Vancura A.
      • Haldar D.
      Purification and characterization of glycerophosphate acyltransferase from rat liver mitochondria.
      ), and GPAT1-knockout (KO) mice had phospholipid alterations that included reduced C16:0 in sn-1 of PC and PE and increased C20:4 in sn-2, indicating that GPAT1 may not only function in TAG production but also influence the fatty acid compositions of phospholipids (
      • Hammond L.E.
      • Gallagher P.A.
      • Wang S.
      • Hiller S.
      • Kluckman K.D.
      • Posey-Marcos E.L.
      • Maeda N.
      • Coleman R.A.
      Mitochondrial glycerol-3-phosphate acyltransferase-deficient mice have reduced weight and liver triacylglycerol content and altered glycerolipid fatty acid composition.
      ,
      • Xu H.
      • Wilcox D.
      • Nguyen P.
      • Voorbach M.
      • Suhar T.
      • Morgan S.J.
      • An W.F.
      • Ge L.
      • Green J.
      • Wu Z.
      • Gimeno R.E.
      • Reilly R.
      • Jacobson P.B.
      • Collins C.A.
      • Landschulz K.
      • et al.
      Hepatic knockdown of mitochondrial GPAT1 in ob/ob mice improves metabolic profile.
      ). In most tissues, GPAT1 only accounts for a minority of GPAT activity (∼10%), but is abundant in the liver where it is suggested to account for 20 to 50% of all GPAT activity (
      • Coleman R.A.
      • Lee D.P.
      Enzymes of triacylglycerol synthesis and their regulation.
      ,
      • Bell R.M.
      • Coleman R.A.
      Enzymes of glycerolipid synthesis in eukaryotes.
      ).

      GPAT2

      GPAT2 (also called xGPAT1) shows selectivity to utilize C20:4-CoA as substrate in vitro assays (
      • Wang S.
      • Lee D.P.
      • Gong N.
      • Schwerbrock N.M.
      • Mashek D.G.
      • Gonzalez-Baró M.R.
      • Stapleton C.
      • Li L.O.
      • Lewin T.M.
      • Coleman R.A.
      Cloning and functional characterization of a novel mitochondrial N-ethylmaleimide-sensitive glycerol-3-phosphate acyltransferase (GPAT2).
      ). Among several tissues in mice, GPAT2 mRNA was expressed almost exclusively in testis, where it was detected in germ cells. The expression in the liver was at least 50-fold less, and even lower in other tissues including the brown adipose tissue (BAT), brain, lung, and heart (
      • Wang S.
      • Lee D.P.
      • Gong N.
      • Schwerbrock N.M.
      • Mashek D.G.
      • Gonzalez-Baró M.R.
      • Stapleton C.
      • Li L.O.
      • Lewin T.M.
      • Coleman R.A.
      Cloning and functional characterization of a novel mitochondrial N-ethylmaleimide-sensitive glycerol-3-phosphate acyltransferase (GPAT2).
      ). This expression pattern suggests GPAT2 may have a primary function in the testis but not in TAG production in most tissues (
      • Garcia-Fabiani M.B.
      • Montanaro M.A.
      • Lacunza E.
      • Cattaneo E.R.
      • Coleman R.A.
      • Pellon-Maison M.
      • Gonzalez-Baro M.R.
      Methylation of the Gpat2 promoter regulates transient expression during mouse spermatogenesis.
      ,
      • Garcia-Fabiani M.B.
      • Montanaro M.A.
      • Stringa P.
      • Lacunza E.
      • Cattaneo E.R.
      • Santana M.
      • Pellon-Maison M.
      • Gonzalez-Baro M.R.
      Glycerol-3-phosphate acyltransferase 2 is essential for normal spermatogenesis.
      ). GPAT2 is also highly expressed in tumors and was suggested to belong to a class of “cancer-testis” genes, whose expression is normally low in somatic tissues but may be upregulated in cancers of various origins (
      • Pellon-Maison M.
      • Montanaro M.A.
      • Lacunza E.
      • Garcia-Fabiani M.B.
      • Soler-Gerino M.C.
      • Cattaneo E.R.
      • Quiroga I.Y.
      • Abba M.C.
      • Coleman R.A.
      • Gonzalez-Baro M.R.
      Glycerol-3-phosphate acyltranferase-2 behaves as a cancer testis gene and promotes growth and tumorigenicity of the breast cancer MDA-MB-231 cell line.
      ).

      GPAT3

      GPAT3 (also called AGPAT8, AGPAT9, and AGPAT10) is a microsomal GPAT, but was also suggested to possess LPAAT activities (
      • Sukumaran S.
      • Barnes R.I.
      • Garg A.
      • Agarwal A.K.
      Functional characterization of the human 1-acylglycerol-3-phosphate-O-acyltransferase isoform 10/glycerol-3-phosphate acyltransferase isoform 3.
      ). During differentiation of 3T3-L1 adipocytes, GPAT3 was highly upregulated and promoted TAG storage in lipid droplets, demonstrating that GPAT3 has a major role in adipogenesis (
      • Cao J.
      • Li J.L.
      • Li D.
      • Tobin J.F.
      • Gimeno R.E.
      Molecular identification of microsomal acyl-CoA:glycerol-3-phosphate acyltransferase, a key enzyme in de novo triacylglycerol synthesis.
      ,
      • Shan D.
      • Li J.L.
      • Wu L.
      • Li D.
      • Hurov J.
      • Tobin J.F.
      • Gimeno R.E.
      • Cao J.
      GPAT3 and GPAT4 are regulated by insulin-stimulated phosphorylation and play distinct roles in adipogenesis.
      ). GPAT3-KO mice were reported to have ∼80% reduction of GPAT activity in white adipose tissue (WAT) (
      • Cao J.
      • Perez S.
      • Goodwin B.
      • Lin Q.
      • Peng H.
      • Qadri A.
      • Zhou Y.
      • Clark R.W.
      • Perreault M.
      • Tobin J.F.
      • Gimeno R.E.
      Mice deleted for GPAT3 have reduced GPAT activity in white adipose tissue and altered energy and cholesterol homeostasis in diet-induced obesity.
      ). GPAT3-KO mice had increased energy expenditures on high-fat diet, and females but not males showed decreased adiposity and body weight gain, indicating important roles of GPAT3 in energy and lipid homeostasis (
      • Cao J.
      • Perez S.
      • Goodwin B.
      • Lin Q.
      • Peng H.
      • Qadri A.
      • Zhou Y.
      • Clark R.W.
      • Perreault M.
      • Tobin J.F.
      • Gimeno R.E.
      Mice deleted for GPAT3 have reduced GPAT activity in white adipose tissue and altered energy and cholesterol homeostasis in diet-induced obesity.
      ).

      GPAT4

      GPAT4 (also called AGPAT6) is abundantly expressed in various tissues. Its expression is high in the liver, BAT, and WAT, where GPAT4 was reported to be responsible for most GPAT activity (
      • Vergnes L.
      • Beigneux A.P.
      • Davis R.
      • Watkins S.M.
      • Young S.G.
      • Reue K.
      Agpat6 deficiency causes subdermal lipodystrophy and resistance to obesity.
      ). GPAT4-KO mice had reduced body weights and were resistant to both diet- and genetically-induced obesity (
      • Vergnes L.
      • Beigneux A.P.
      • Davis R.
      • Watkins S.M.
      • Young S.G.
      • Reue K.
      Agpat6 deficiency causes subdermal lipodystrophy and resistance to obesity.
      ). GPAT4-KO mice showed increased energy expenditure, reduced TAG accumulation in BAT and WAT, and profound lack of subdermal adipose tissues. There was an overall increase in polyunsaturated and decrease of monounsaturated fatty acid chains in TAGs, DAGs, and phospholipids; suggesting GPAT4 has selectivity to incorporate monounsaturated fatty acid substrates (
      • Vergnes L.
      • Beigneux A.P.
      • Davis R.
      • Watkins S.M.
      • Young S.G.
      • Reue K.
      Agpat6 deficiency causes subdermal lipodystrophy and resistance to obesity.
      ). During lactation, GPAT4 is upregulated in mammary gland epithelia and participates in TAG and DAG synthesis required to support milk production. Indeed, GPAT4-KO mice had dramatically decreased fat droplets within mammary epithelial cells and ducts. GPAT4-KO nursing females had greatly reduced TAG and DAGs in their milk and were unable to successfully nurse their young, indicating a critical role of GPAT4 for the production of milk fat (
      • Beigneux A.P.
      • Vergnes L.
      • Qiao X.
      • Quatela S.
      • Davis R.
      • Watkins S.M.
      • Coleman R.A.
      • Walzem R.L.
      • Philips M.
      • Reue K.
      • Young S.G.
      Agpat6--a novel lipid biosynthetic gene required for triacylglycerol production in mammary epithelium.
      ).
      Recently, calcineurin B homologous protein 1 (CHP1) has been found to be an essential cofactor for GPAT4 and thereby regulate ER glycerolipid synthesis. CHP1 binding was required for GPAT4 activation, and myristoylation of CHP1 was required for the full interaction. Loss of CHP1 in mammalian cells led to severely reduced fatty acid incorporation and storage, but was partially compensated for by upregulation of glyceronephosphate O-acyltransferase (GNPAT) and increased synthesis of peroxisomal ether lipids (
      • Zhu X.G.
      • Nicholson Puthenveedu S.
      • Shen Y.
      • La K.
      • Ozlu C.
      • Wang T.
      • Klompstra D.
      • Gultekin Y.
      • Chi J.
      • Fidelin J.
      • Peng T.
      • Molina H.
      • Hang H.C.
      • Min W.
      • Birsoy K.
      CHP1 regulates compartmentalized glycerolipid synthesis by activating GPAT4.
      ).

      Characteristics of lysophospholipid acyltransferases

      In this section, biochemical and biological characteristics of each LPLAT are summarized. The new proposed names for LPLATs are also introduced, which are in the format LPLATx, where x is a number (Table 1). As described in Nomenclature section, these names are unambiguous and do not imply substrate specificities. The official gene name is given in parentheses immediately following the first instances of the new names. Enzymatic characteristics for the LPLATs are summarized in Table 4 and Figure 4. Physiological roles of LPLATs and their disease associations are summarized in Table 5.
      Table 4Characteristics of LPLATs
      FamilyLPLATTissue distributionSubcellular localization
      ER, endoplasmic reticulum, Mit, mitochondrial; NE, nuclear envelope; LD, lipid droplet.
      Amino acid numberType of remodeling
      Type 1, sn-1 remodeling; Type 2, sn-2 remodeling; Type 3, sn-1/2 remodeling.
      References
      HumanMouse
      AGPATLPLAT1ubiquitousER283285(
      • Kume K.
      • Shimizu T.
      cDNA cloning and expression of murine 1-acyl-sn-glycerol-3-phosphate acyltransferase.
      ,
      • Agarwal A.K.
      • Sukumaran S.
      • Cortés V.A.
      • Tunison K.
      • Mizrachi D.
      • Sankella S.
      • Gerard R.D.
      • Horton J.D.
      • Garg A.
      Human 1-acylglycerol-3-phosphate O-acyltransferase isoforms 1 and 2: Biochemical characterization and inability to rescue hepatic steatosis in Agpat2(-/-) gene lipodystrophic mice.
      ,
      • Lu B.
      • Jiang Y.J.
      • Zhou Y.
      • Xu F.Y.
      • Hatch G.M.
      • Choy P.C.
      Cloning and characterization of murine 1-acyl-sn-glycerol 3-phosphate acyltransferases and their regulation by PPARalpha in murine heart.
      ,
      • Aguado B.
      • Campbell R.D.
      Characterization of a human lysophosphatidic acid acyltransferase that is encoded by a gene located in the class III region of the human major histocompatibility complex.
      )
      LPLAT2adipose tissue, pancreas, liver, kidney, gut, skeletal muscleER278278(
      • Agarwal A.K.
      • Sukumaran S.
      • Cortés V.A.
      • Tunison K.
      • Mizrachi D.
      • Sankella S.
      • Gerard R.D.
      • Horton J.D.
      • Garg A.
      Human 1-acylglycerol-3-phosphate O-acyltransferase isoforms 1 and 2: Biochemical characterization and inability to rescue hepatic steatosis in Agpat2(-/-) gene lipodystrophic mice.
      ,
      • Lu B.
      • Jiang Y.J.
      • Zhou Y.
      • Xu F.Y.
      • Hatch G.M.
      • Choy P.C.
      Cloning and characterization of murine 1-acyl-sn-glycerol 3-phosphate acyltransferases and their regulation by PPARalpha in murine heart.
      ,
      • Eberhardt C.
      • Gray P.W.
      • Tjoelker L.W.
      Human lysophosphatidic acid acyltransferase. cDNA cloning, expression, and localization to chromosome 9q34.3.
      )
      LPLAT3retina, testis, brain, heart, liver, kidneyER, Golgi, NE376376(
      • Lu B.
      • Jiang Y.J.
      • Zhou Y.
      • Xu F.Y.
      • Hatch G.M.
      • Choy P.C.
      Cloning and characterization of murine 1-acyl-sn-glycerol 3-phosphate acyltransferases and their regulation by PPARalpha in murine heart.
      ,
      • Yuki K.
      • Shindou H.
      • Hishikawa D.
      • Shimizu T.
      Characterization of mouse lysophosphatidic acid acyltransferase 3: An enzyme with dual functions in the testis.
      ,
      • Shindou H.
      • Koso H.
      • Sasaki J.
      • Nakanishi H.
      • Sagara H.
      • Nakagawa K.M.
      • Takahashi Y.
      • Hishikawa D.
      • Iizuka-Hishikawa Y.
      • Tokumasu F.
      • Noguchi H.
      • Watanabe S.
      • Sasaki T.
      • Shimizu T.
      Docosahexaenoic acid preserves visual function by maintaining correct disc morphology in retinal photoreceptor cells.
      ,
      • Iizuka-Hishikawa Y.
      • Hishikawa D.
      • Sasaki J.
      • Takubo K.
      • Goto M.
      • Nagata K.
      • Nakanishi H.
      • Shindou H.
      • Okamura T.
      • Ito C.
      • Toshimori K.
      • Sasaki T.
      • Shimizu T.
      Lysophosphatidic acid acyltransferase 3 tunes the membrane status of germ cells by incorporating docosahexaenoic acid during spermatogenesis.
      ,
      • Prasad S.S.
      • Garg A.
      • Agarwal A.K.
      Enzymatic activities of the human AGPAT isoform 3 and isoform 5: Localization of AGPAT5 to mitochondria.
      ,
      • Schmidt J.A.
      • Brown W.J.
      Lysophosphatidic acid acyltransferase 3 regulates Golgi complex structure and function.
      ,
      • Koeberle A.
      • Shindou H.
      • Harayama T.
      • Yuki K.
      • Shimizu T.
      Polyunsaturated fatty acids are incorporated into maturating male mouse germ cells by lysophosphatidic acid acyltransferase 3.
      )
      LPLAT4brain, lung, stomach, spleen, intestine, colon, testis, gut, ubiquitousER378378(
      • Lu B.
      • Jiang Y.J.
      • Zhou Y.
      • Xu F.Y.
      • Hatch G.M.
      • Choy P.C.
      Cloning and characterization of murine 1-acyl-sn-glycerol 3-phosphate acyltransferases and their regulation by PPARalpha in murine heart.
      ,
      • Eto M.
      • Shindou H.
      • Shimizu T.
      A novel lysophosphatidic acid acyltransferase enzyme (LPAAT4) with a possible role for incorporating docosahexaenoic acid into brain glycerophospholipids.
      ,
      • Pagliuso A.
      • Valente C.
      • Giordano L.L.
      • Filograna A.
      • Li G.
      • Circolo D.
      • Turacchio G.
      • Marzullo V.M.
      • Mandrich L.
      • Zhukovsky M.A.
      • Formiggini F.
      • Polishchuk R.S.
      • Corda D.
      • Luini A.
      Golgi membrane fission requires the CtBP1-S/BARS-induced activation of lysophosphatidic acid acyltransferase δ.
      )
      LPLAT5brain, heart, skeletal muscle, ubiquitousER, Mit, NE364365(
      • Lu B.
      • Jiang Y.J.
      • Zhou Y.
      • Xu F.Y.
      • Hatch G.M.
      • Choy P.C.
      Cloning and characterization of murine 1-acyl-sn-glycerol 3-phosphate acyltransferases and their regulation by PPARalpha in murine heart.
      ,
      • Prasad S.S.
      • Garg A.
      • Agarwal A.K.
      Enzymatic activities of the human AGPAT isoform 3 and isoform 5: Localization of AGPAT5 to mitochondria.
      )
      LPLAT6heart, liver, kidney, skeletal muscle, pancreas, spleenER414376Type 1(
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • Kawana H.
      • Kano K.
      • Shindou H.
      • Inoue A.
      • Shimizu T.
      • Aoki J.
      An accurate and versatile method for determining the acyl group-introducing position of lysophospholipid acyltransferases.
      ,
      • 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.
      )
      LPLAT7peripheral blood, liver, lung, placenta, kidney, brainER370370(
      • Yang Y.
      • Cao J.
      • Shi Y.
      Identification and characterization of a gene encoding human LPGAT1, an endoplasmic reticulum-associated lysophosphatidylglycerol acyltransferase.
      )
      LPLAT8lung, spleenER, LD534534Type 3(
      • Harayama T.
      • Eto M.
      • Shindou H.
      • Kita Y.
      • Otsubo E.
      • Hishikawa D.
      • Ishii S.
      • Sakimura K.
      • Mishina M.
      • Shimizu T.
      Lysophospholipid acyltransferases mediate phosphatidylcholine diversification to achieve the physical properties required in vivo.
      ,
      • 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.
      ,
      • Moessinger C.
      • Kuerschner L.
      • Spandl J.
      • Shevchenko A.
      • Thiele C.
      Human lysophosphatidylcholine acyltransferases 1 and 2 are located in lipid droplets where they catalyze the formation of phosphatidylcholine.
      ,
      • Kawana H.
      • Kano K.
      • Shindou H.
      • Inoue A.
      • Shimizu T.
      • Aoki J.
      An accurate and versatile method for determining the acyl group-introducing position of lysophospholipid acyltransferases.
      ,
      • Agarwal A.K.
      • Sukumaran S.
      • Bartz R.
      • Barnes R.I.
      • Garg A.
      Functional characterization of human 1-acylglycerol-3-phosphate-O-acyltransferase isoform 9: Cloning, tissue distribution, gene structure, and enzymatic activity.
      )
      LPLAT9macrophages, microglia, neutrophils, spleen, skinER, LD544544(
      • 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.
      ,
      • Shindou H.
      • Shiraishi S.
      • Tokuoka S.M.
      • Takahashi Y.
      • Harayama T.
      • Abe T.
      • Bando K.
      • Miyano K.
      • Kita Y.
      • Uezono Y.
      • Shimizu T.
      Relief from neuropathic pain by blocking of the platelet-activating factor-pain loop.
      ,
      • Moessinger C.
      • Kuerschner L.
      • Spandl J.
      • Shevchenko A.
      • Thiele C.
      Human lysophosphatidylcholine acyltransferases 1 and 2 are located in lipid droplets where they catalyze the formation of phosphatidylcholine.
      ,
      • Cotte A.K.
      • Aires V.
      • Fredon M.
      • Limagne E.
      • Derangère V.
      • Thibaudin M.
      • Humblin E.
      • Scagliarini A.
      • de Barros J.P.
      • Hillon P.
      • Ghiringhelli F.
      • Delmas D.
      Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance.
      )
      LPLAT9b516
      LPLAT10brainER524524(
      • 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.
      ,
      • Eto M.
      • Shindou H.
      • Yamamoto S.
      • Tamura-Nakano M.
      • Shimizu T.
      Lysophosphatidylethanolamine acyltransferase 2 (LPEAT2) incorporates DHA into phospholipids and has possible functions for fatty acid-induced cell death.
      )
      MBOATLPLAT11brain, liver, testis, lungER472473(
      • Lee H.C.
      • Inoue T.
      • Sasaki J.
      • Kubo T.
      • Matsuda S.
      • Nakasaki Y.
      • Hattori M.
      • Tanaka F.
      • Udagawa O.
      • Kono N.
      • Itoh T.
      • Ogiso H.
      • Taguchi R.
      • Arita M.
      • Sasaki T.
      • et al.
      LPIAT1 regulates arachidonic acid content in phosphatidylinositol and is required for cortical lamination in mice.
      ,
      • 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.
      )
      LPLAT12liver, testis, small intestine, kidneyER487487Type 2(
      • 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.
      ,
      • Hashidate-Yoshida T.
      • Harayama T.
      • Hishikawa D.
      • Morimoto R.
      • Hamano F.
      • Tokuoka S.M.
      • Eto M.
      • Tamura-Nakano M.
      • Yanobu-Takanashi R.
      • Mukumoto Y.
      • Kiyonari H.
      • Okamura T.
      • Kita Y.
      • Shindou H.
      • Shimizu T.
      Fatty acid remodeling by LPCAT3 enriches arachidonate in phospholipid membranes and regulates triglyceride transport.
      ,
      • Rong X.
      • Wang B.
      • Dunham M.M.
      • Hedde P.N.
      • Wong J.S.
      • Gratton E.
      • Young S.G.
      • Ford D.A.
      • Tontonoz P.
      Lpcat3-dependent production of arachidonoyl phospholipids is a key determinant of triglyceride secretion.
      ,
      • Kawana H.
      • Kano K.
      • Shindou H.
      • Inoue A.
      • Shimizu T.
      • Aoki J.
      An accurate and versatile method for determining the acyl group-introducing position of lysophospholipid acyltransferases.
      )
      LPLAT13epididymis, testis, brain, ovaryER520519(
      • Hishikawa D.
      • Shindou H.
      • Kobayashi S.
      • Nakanishi H.
      • Taguchi R.
      • Shimizu T.
      Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity.
      )
      LPLAT14stomach, colon, epididymisER495492(
      • Hishikawa D.
      • Shindou H.
      • Kobayashi S.
      • Nakanishi H.
      • Taguchi R.
      • Shimizu T.
      Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity.
      )
      a ER, endoplasmic reticulum, Mit, mitochondrial; NE, nuclear envelope; LD, lipid droplet.
      b Type 1, sn-1 remodeling; Type 2, sn-2 remodeling; Type 3, sn-1/2 remodeling.
      Table 5Physiological roles of LPLATs and disease associations
      Proposed namePhenotype and lipid alterations in gene-deficient miceHuman disease associations
      LPLAT1/AGPAT1nervous and reproductive system abnormalities, impaired fat storage and lipid homeostasis (
      • Agarwal A.K.
      • Tunison K.
      • Dalal J.S.
      • Nagamma S.S.
      • Hamra F.K.
      • Sankella S.
      • Shao X.
      • Auchus R.J.
      • Garg A.
      Metabolic, reproductive, and neurologic abnormalities in Agpat1-null mice.
      )
      allelic risk association for exfoliation syndrome (
      • Aung T.
      • Ozaki M.
      • Lee M.C.
      • Schlötzer-Schrehardt U.
      • Thorleifsson G.
      • Mizoguchi T.
      • Igo R.P.
      • Haripriya A.
      • Williams S.E.
      • Astakhov Y.S.
      • Orr A.C.
      • Burdon K.P.
      • Nakano S.
      • Mori K.
      • Abu-Amero K.
      • et al.
      Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.
      )
      LPLAT2/AGPAT2lipodystrophy (
      • Cortes V.A.
      • Curtis D.E.
      • Sukumaran S.
      • Shao X.
      • Parameswara V.
      • Rashid S.
      • Smith A.R.
      • Ren J.
      • Esser V.
      • Hammer R.E.
      • Agarwal A.K.
      • Horton J.D.
      • Garg A.
      Molecular mechanisms of hepatic steatosis and insulin resistance in the AGPAT2-deficient mouse model of congenital generalized lipodystrophy.
      )
      mutational loss causes lipodystrophy (
      • Agarwal A.K.
      • Arioglu E.
      • De Almeida S.
      • Akkoc N.
      • Taylor S.I.
      • Bowcock A.M.
      • Barnes R.I.
      • Garg A.
      AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34.
      ); up-regulated in gynecological cancers (
      • Niesporek S.
      • Denkert C.
      • Weichert W.
      • Köbel M.
      • Noske A.
      • Sehouli J.
      • Singer J.W.
      • Dietel M.
      • Hauptmann S.
      Expression of lysophosphatidic acid acyltransferase beta (LPAAT-beta) in ovarian carcinoma: Correlation with tumour grading and prognosis.
      ,
      • Springett G.M.
      • Bonham L.
      • Hummer A.
      • Linkov I.
      • Misra D.
      • Ma C.
      • Pezzoni G.
      • Di Giovine S.
      • Singer J.
      • Kawasaki H.
      • Spriggs D.
      • Soslow R.
      • Dupont J.
      Lysophosphatidic acid acyltransferase-beta is a prognostic marker and therapeutic target in gynecologic malignancies.
      ,
      • Diefenbach C.S.
      • Soslow R.A.
      • Iasonos A.
      • Linkov I.
      • Hedvat C.
      • Bonham L.
      • Singer J.
      • Barakat R.R.
      • Aghajanian C.
      • Dupont J.
      Lysophosphatidic acid acyltransferase-beta (LPAAT-beta) is highly expressed in advanced ovarian cancer and is associated with aggressive histology and poor survival.
      )
      LPLAT3/AGPAT3visual dysfunction, male infertility, hepatic PUFA level control, major reduction in DHA-containing phospholipid (
      • Shindou H.
      • Koso H.
      • Sasaki J.
      • Nakanishi H.
      • Sagara H.
      • Nakagawa K.M.
      • Takahashi Y.
      • Hishikawa D.
      • Iizuka-Hishikawa Y.
      • Tokumasu F.
      • Noguchi H.
      • Watanabe S.
      • Sasaki T.
      • Shimizu T.
      Docosahexaenoic acid preserves visual function by maintaining correct disc morphology in retinal photoreceptor cells.
      ,
      • Iizuka-Hishikawa Y.
      • Hishikawa D.
      • Sasaki J.
      • Takubo K.
      • Goto M.
      • Nagata K.
      • Nakanishi H.
      • Shindou H.
      • Okamura T.
      • Ito C.
      • Toshimori K.
      • Sasaki T.
      • Shimizu T.
      Lysophosphatidic acid acyltransferase 3 tunes the membrane status of germ cells by incorporating docosahexaenoic acid during spermatogenesis.
      ,
      • Hishikawa D.
      • Yanagida K.
      • Nagata K.
      • Kanatani A.
      • Iizuka Y.
      • Hamano F.
      • Yasuda M.
      • Okamura T.
      • Shindou H.
      • Shimizu T.
      Hepatic levels of DHA-containing phospholipids instruct SREBP1-mediated synthesis and systemic delivery of polyunsaturated fatty acids.
      )
      LPLAT4/AGPAT4learning and memory deficits (
      • Bradley R.M.
      • Marvyn P.M.
      • Aristizabal Henao J.J.
      • Mardian E.B.
      • George S.
      • Aucoin M.G.
      • Stark K.D.
      • Duncan R.E.
      Acylglycerophosphate acyltransferase 4 (AGPAT4) is a mitochondrial lysophosphatidic acid acyltransferase that regulates brain phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol levels.
      ,
      • Bradley R.M.
      • Mardian E.B.
      • Bloemberg D.
      • Aristizabal Henao J.J.
      • Mitchell A.S.
      • Marvyn P.M.
      • Moes K.A.
      • Stark K.D.
      • Quadrilatero J.
      • Duncan R.E.
      Mice deficient in lysophosphatidic acid acyltransferase delta (Lpaatδ)/acylglycerophosphate acyltransferase 4 (Agpat4) have impaired learning and memory.
      ); multiple lipid alterations and compensatory upregulation of other LPLATs (
      • Bradley R.M.
      • Marvyn P.M.
      • Aristizabal Henao J.J.
      • Mardian E.B.
      • George S.
      • Aucoin M.G.
      • Stark K.D.
      • Duncan R.E.
      Acylglycerophosphate acyltransferase 4 (AGPAT4) is a mitochondrial lysophosphatidic acid acyltransferase that regulates brain phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol levels.
      ,
      • Mardian E.B.
      • Bradley R.M.
      • Aristizabal Henao J.J.
      • Marvyn P.M.
      • Moes K.A.
      • Bombardier E.
      • Tupling A.R.
      • Stark K.D.
      • Duncan R.E.
      Agpat4/Lpaatδ deficiency highlights the molecular heterogeneity of epididymal and perirenal white adipose depots.
      ,
      • Bradley R.M.
      • Bloemberg D.
      • Aristizabal Henao J.J.
      • Hashemi A.
      • Mitchell A.S.
      • Fajardo V.A.
      • Bellissimo C.
      • Mardian E.B.
      • Bombardier E.
      • Paré M.F.
      • Moes K.A.
      • Stark K.D.
      • Tupling A.R.
      • Quadrilatero J.
      • Duncan R.E.
      Lpaatδ/Agpat4 deficiency impairs maximal force contractility in soleus and alters fibre type in extensor digitorum longus muscle.
      )
      LPLAT5/AGPAT5insulin-resistance (knockdown model) (
      • Parks B.W.
      • Sallam T.
      • Mehrabian M.
      • Psychogios N.
      • Hui S.T.
      • Norheim F.
      • Castellani L.W.
      • Rau C.D.
      • Pan C.
      • Phun J.
      • Zhou Z.
      • Yang W.P.
      • Neuhaus I.
      • Gargalovic P.S.
      • Kirchgessner T.G.
      • et al.
      Genetic architecture of insulin resistance in the mouse.
      )
      LPLAT6/LCLAT1altered PIP signaling, resistant to mitochondrial and oxidative-stress-related diseases including obesity, insulin resistance (
      • Li J.
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      obesity-related trait in Pima Indians (
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      possible biomarker or therapeutic target for human allergic diseases (
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