Lipoquality control by phospholipase A2 enzymes

The phospholipase A2 (PLA2) family comprises a group of lipolytic enzymes that typically hydrolyze the sn-2 position of glycerophospholipids to give rise to fatty acids and lysophospholipids. The mammalian genome encodes more than 50 PLA2s or related enzymes, which are classified into several subfamilies on the basis of their structures and functions. From a general viewpoint, the PLA2 family has mainly been implicated in signal transduction, producing bioactive lipid mediators derived from fatty acids and lysophospholipids. Recent evidence indicates that PLA2s also contribute to phospholipid remodeling for membrane homeostasis or energy production for fatty acid β-oxidation. Accordingly, PLA2 enzymes can be regarded as one of the key regulators of the quality of lipids, which I herein refer to as lipoquality. Disturbance of PLA2-regulated lipoquality hampers tissue and cellular homeostasis and can be linked to various diseases. Here I overview the current state of understanding of the classification, enzymatic properties, and physiological functions of the PLA2 family.

[1]  M. Murakami,et al.  Mitochondrial dysfunction and reduced prostaglandin synthesis in skeletal muscle of Group VIB Ca2+-independent phospholipase A2γ-deficient mice[S] , 2010, Journal of Lipid Research.

[2]  Rui Li,et al.  Phospholipase A2 group IIA expression in gastric adenocarcinoma is associated with prolonged survival and less frequent metastasis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Takao Shimizu,et al.  Cytosolic Phospholipase A2α–deficient Mice Are Resistant to Collagen-induced Arthritis , 2003, The Journal of experimental medicine.

[4]  Stephen S. H. Huang,et al.  Lack of group X secreted phospholipase A2 increases survival following pandemic H1N1 influenza infection , 2014, Virology.

[5]  M. Corson.  Phospholipase A2 inhibitors in atherosclerosis: the race is on , 2009, The Lancet.

[6]  R. Gerszten,et al.  Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment , 2003, Nature Immunology.

[7]  Krzysztof Palczewski,et al.  LRAT-specific domain facilitates Vitamin A metabolism by domain swapping in HRASLS , 2014, Nature Chemical Biology.

[8]  James G. Bollinger,et al.  Group V Phospholipase A2 in Bone Marrow-derived Myeloid Cells and Bronchial Epithelial Cells Promotes Bacterial Clearance after Escherichia coli Pneumonia* , 2011, The Journal of Biological Chemistry.

[9]  John T. Melchior,et al.  The serine hydrolase ABHD6 Is a critical regulator of the metabolic syndrome. , 2013, Cell reports.

[10]  Y. Miki,et al.  The Roles of the Secreted Phospholipase A2 Gene Family in Immunology , 2016, Advances in Immunology.

[11]  Frank Eisenhaber,et al.  Fat Mobilization in Adipose Tissue Is Promoted by Adipose Triglyceride Lipase , 2004, Science.

[12]  Y. Ouchi,et al.  Acute lung injury by sepsis and acid aspiration: a key role for cytosolic phospholipase A2 , 2000, Nature Immunology.

[13]  M. Brudno,et al.  Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness , 2015, Nature Communications.

[14]  Colin A. Johnson,et al.  PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron , 2006, Nature Genetics.

[15]  T. Proikas-Cezanne,et al.  Neutral Lipid Stores and Lipase PNPLA5 Contribute to Autophagosome Biogenesis , 2014, Current Biology.

[16]  Jonathan C. Cohen,et al.  Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. , 2012, The Journal of clinical investigation.

[17]  M. Kano,et al.  Fever Is Mediated by Conversion of Endocannabinoid 2-Arachidonoylglycerol to Prostaglandin E2 , 2015, PloS one.

[18]  J. Leonard,et al.  Cytosolic phospholipase A2α–deficient mice are resistant to experimental autoimmune encephalomyelitis , 2005, The Journal of experimental medicine.

[19]  P. Shridas,et al.  Group X Secretory Phospholipase A2 Regulates Insulin Secretion through a Cyclooxygenase-2-dependent Mechanism* , 2014, The Journal of Biological Chemistry.

[20]  K. Huggins,et al.  Group 1B phospholipase A2-mediated lysophospholipid absorption directly contributes to postprandial hyperglycemia. , 2006, Diabetes.

[21]  Alexander Pertsemlidis,et al.  Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease , 2008, Nature Genetics.

[22]  J. Carette,et al.  PLA2G16 represents a switch between entry and clearance of Picornaviridae , 2017, Nature.

[23]  David J. Miller,et al.  Male Mice That Do Not Express Group VIA Phospholipase A2 Produce Spermatozoa with Impaired Motility and Have Greatly Reduced Fertility* , 2004, Journal of Biological Chemistry.

[24]  M. Kumari,et al.  Growth Retardation, Impaired Triacylglycerol Catabolism, Hepatic Steatosis, and Lethal Skin Barrier Defect in Mice Lacking Comparative Gene Identification-58 (CGI-58)* , 2009, The Journal of Biological Chemistry.

[25]  J. Balsinde,et al.  Regulation of Delayed Prostaglandin Production in Activated P388D1 Macrophages by Group IV Cytosolic and Group V Secretory Phospholipase A2s* , 1999, The Journal of Biological Chemistry.

[26]  S. Young,et al.  Biochemistry and pathophysiology of intravascular and intracellular lipolysis. , 2013, Genes & development.

[27]  M. Gelb,et al.  The role of group IIF-secreted phospholipase A2 in epidermal homeostasis and hyperplasia , 2015, The Journal of experimental medicine.

[28]  P. Vadas,et al.  Phospholipase A2--a mediator between proximal and distal effectors of inflammation. , 1991, Immunology today.

[29]  M. Gelb,et al.  The adipocyte-inducible secreted phospholipases PLA2G5 and PLA2G2E play distinct roles in obesity. , 2014, Cell metabolism.

[30]  G. Abecasis,et al.  Genetic associations of nonsynonymous exonic variants with psychophysiological endophenotypes. , 2014, Psychophysiology.

[31]  M. Murakami,et al.  Group VIB Calcium-Independent Phospholipase A2 (iPLA2γ) Regulates Platelet Activation, Hemostasis and Thrombosis in Mice , 2014, PloS one.

[32]  O. Reiner,et al.  Frontiers in Cellular Neuroscience Cellular Neuroscience , 2022 .

[33]  Kei Yamamoto,et al.  Group X phospholipase A2 is released during sperm acrosome reaction and controls fertility outcome in mice. , 2010, The Journal of clinical investigation.

[34]  J. J. Rosa,et al.  Structures of free and inhibited human secretory phospholipase A2 from inflammatory exudate. , 1993, Science.

[35]  Masahiro Watanabe,et al.  Interaction of Phospholipase A/Acyltransferase-3 with Pex19p , 2015, The Journal of Biological Chemistry.

[36]  G. Shulman,et al.  AdPLA ablation increases lipolysis and prevents obesity induced by high fat feeding or leptin deficiency , 2009, Nature Medicine.

[37]  J. Klein,et al.  Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. , 2015, The New England journal of medicine.

[38]  J. Seilhamer,et al.  Pancreatic phospholipase A2: isolation of the human gene and cDNAs from porcine pancreas and human lung. , 1986, DNA.

[39]  James G. Bollinger,et al.  Novel mammalian group XII secreted phospholipase A2 lacking enzymatic activity. , 2003, Biochemistry.

[40]  Jelena S. Bezbradica,et al.  Role for lysosomal phospholipase A2 in iNKT cell-mediated CD1d recognition , 2013, Proceedings of the National Academy of Sciences.

[41]  J. Obata,et al.  Group V secretory phospholipase A2 plays a pathogenic role in myocardial ischaemia-reperfusion injury. , 2011, Cardiovascular research.

[42]  P. He,et al.  Age-related pulmonary emphysema in mice lacking alpha/beta hydrolase domain containing 2 gene. , 2009, Biochemical and biophysical research communications.

[43]  Kei Yamamoto,et al.  Group X Secreted Phospholipase A2 Limits the Development of Atherosclerosis in LDL Receptor–Null Mice , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[44]  O. Combarros,et al.  PLA2G3, a gene involved in oxidative stress induced death, is associated with Alzheimer's disease. , 2011, Journal of Alzheimer's disease : JAD.

[45]  M. Murakami,et al.  This information is current as Inflammation Exacerbates Ovalbumin-Induced Lung Receptor 2 Deficiency of Phospholipase , 2013 .

[46]  M. Murakami,et al.  Phospholipase A2 Group III and Group X Have Opposing Associations with Prognosis in Colorectal Cancer. , 2015, Anticancer research.

[47]  Laurie D. Smith,et al.  Loss of Function Variants in Human PNPLA8 Encoding Calcium‐Independent Phospholipase A2γ Recapitulate the Mitochondriopathy of the Homologous Null Mouse , 2015, Human mutation.

[48]  T. Spector,et al.  Linkage and potential association of obesity-related phenotypes with two genes on chromosome 12q24 in a female dizygous twin cohort , 2006, European Journal of Human Genetics.

[49]  R. Zechner,et al.  Lipolysis – A highly regulated multi-enzyme complex mediates the catabolism of cellular fat stores , 2011, Progress in lipid research.

[50]  M. Prentki,et al.  α/β-Hydrolase Domain 6 Deletion Induces Adipose Browning and Prevents Obesity and Type 2 Diabetes. , 2016, Cell reports.

[51]  R. Kriz,et al.  A Novel Cytosolic Calcium-independent Phospholipase A2 Contains Eight Ankyrin Motifs* , 1997, The Journal of Biological Chemistry.

[52]  James G. Bollinger,et al.  Key Role of Group V Secreted Phospholipase A2 in Th2 Cytokine and Dendritic Cell-Driven Airway Hyperresponsiveness and Remodeling , 2013, PloS one.

[53]  Keizo Inoue,et al.  Brain acetylhydrolase that inactivates platelet-activating factor is a G-protein-like trimer , 1997, Nature.

[54]  M. Moskowitz,et al.  Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2 , 1997, Nature.

[55]  S. Nagao,et al.  Lipid signaling in cytosolic phospholipase A2α–cyclooxygenase-2 cascade mediates cerebellar long-term depression and motor learning , 2010, Proceedings of the National Academy of Sciences.

[56]  M. Gelb,et al.  Biochemistry and physiology of mammalian secreted phospholipases A2. , 2008, Annual review of biochemistry.

[57]  G. Siuzdak,et al.  Metabolomics annotates ABHD3 as a physiologic regulator of medium-chain phospholipids , 2011, Nature chemical biology.

[58]  K. Okubo,et al.  Cloning of a Gene for a Novel Epithelium-specific Cytosolic Phospholipase A2, cPLA2δ, Induced in Psoriatic Skin* , 2004, Journal of Biological Chemistry.

[59]  James G. Bollinger,et al.  Importance of group X–secreted phospholipase A2 in allergen-induced airway inflammation and remodeling in a mouse asthma model , 2007, The Journal of experimental medicine.

[60]  W. Xing,et al.  Group V Secretory Phospholipase A2 Is Involved in Macrophage Activation and Is Sufficient for Macrophage Effector Functions in Allergic Pulmonary Inflammation , 2013, The Journal of Immunology.

[61]  V. Rotter,et al.  Pla2g16 phospholipase mediates gain-of-function activities of mutant p53 , 2014, Proceedings of the National Academy of Sciences.

[62]  T. Bird,et al.  Immunomodulatory lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay , 2014, Nature chemical biology.

[63]  Charles N. Serhan,et al.  Pro-resolving lipid mediators are leads for resolution physiology , 2014, Nature.

[64]  M. Topham,et al.  Deficiency of phospholipase A2 group 7 decreases intestinal polyposis and colon tumorigenesis in Apc(Min/+) mice. , 2013, Cancer research.

[65]  Y. Miki,et al.  Recent progress in phospholipase A₂ research: from cells to animals to humans. , 2011, Progress in lipid research.

[66]  Jay G Gao,et al.  Identification of a novel keratinocyte retinyl ester hydrolase as a transacylase and lipase. , 2005, The Journal of investigative dermatology.

[67]  M. Gelb,et al.  Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. , 2014, Blood.

[68]  Xianlin Han,et al.  Lysosomal Phospholipase A2 and Phospholipidosis , 2006, Molecular and Cellular Biology.

[69]  Kei Yamamoto,et al.  Transgenic Expression of Group V, but Not Group X, Secreted Phospholipase A2 in Mice Leads to Neonatal Lethality because of Lung Dysfunction* , 2006, Journal of Biological Chemistry.

[70]  S. Ojeda,et al.  Loss-of-function mutations in PNPLA6 encoding neuropathy target esterase underlie pubertal failure and neurological deficits in Gordon Holmes syndrome. , 2014, The Journal of clinical endocrinology and metabolism.

[71]  S. Narumiya,et al.  Fever, inflammation, pain and beyond: prostanoid receptor research during these 25 years , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[72]  H. Arai,et al.  Intracellular Platelet-Activating Factor Acetylhydrolase, Type II: A Unique Cellular Phospholipase A2 That Hydrolyzes Oxidatively Modified Phospholipids. , 2015, The Enzymes.

[73]  Takao Shimizu,et al.  Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation. , 2009, Annual review of pharmacology and toxicology.

[74]  S. Narumiya,et al.  Prostaglandin D2 as a mediator of allergic asthma. , 2000, Science.

[75]  G. Holder,et al.  Biallelic mutations in PLA2G5, encoding group V phospholipase A2, cause benign fleck retina. , 2011, American journal of human genetics.

[76]  Jonathan C. Cohen,et al.  A feed-forward loop amplifies nutritional regulation of PNPLA3 , 2010, Proceedings of the National Academy of Sciences.

[77]  M. Gelb,et al.  Dual Roles of Group IID Phospholipase A2 in Inflammation and Cancer* , 2016, The Journal of Biological Chemistry.

[78]  M. Gelb,et al.  Novel Human Secreted Phospholipase A2 with Homology to the Group III Bee Venom Enzyme* , 2000, The Journal of Biological Chemistry.

[79]  M. Boutros,et al.  Loss of PAFAH1B2 Reduces Amyloid-β Generation by Promoting the Degradation of Amyloid Precursor Protein C-Terminal Fragments , 2012, The Journal of Neuroscience.

[80]  Petra C. Kienesberger,et al.  Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome. , 2006, Cell metabolism.

[81]  Matthew J. Silva,et al.  Age-related changes in bone morphology are accelerated in group VIA phospholipase A2 (iPLA2beta)-null mice. , 2008, The American journal of pathology.

[82]  A. Abe,et al.  Lysosomal Phospholipase A2 Is Selectively Expressed in Alveolar Macrophages* , 2004, Journal of Biological Chemistry.

[83]  T. Saibara,et al.  Patatin‐like phospholipase domain‐containing protein 3 is involved in hepatic fatty acid and triglyceride metabolism through X‐box binding protein 1 and modulation of endoplasmic reticulum stress in mice , 2016, Hepatology research : the official journal of the Japan Society of Hepatology.

[84]  Clemens Diwoky,et al.  Adipose Triglyceride Lipase Contributes to Cancer-Associated Cachexia , 2011, Science.

[85]  R. Gross,et al.  Activation of Mitochondrial Calcium-independent Phospholipase A2γ (iPLA2γ) by Divalent Cations Mediating Arachidonate Release and Production of Downstream Eicosanoids*♦ , 2012, The Journal of Biological Chemistry.

[86]  Arthur M Buchberg,et al.  The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin -induced intestinal neoplasia , 1995, Cell.

[87]  S. Narumiya,et al.  The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut. , 2002, The Journal of clinical investigation.

[88]  M. Gelb,et al.  Group X secretory phospholipase A(2) augments angiotensin II-induced inflammatory responses and abdominal aortic aneurysm formation in apoE-deficient mice. , 2011, Atherosclerosis.

[89]  Xianlin Han,et al.  Genetic Ablation of Calcium-independent Phospholipase A2γ Leads to Alterations in Mitochondrial Lipid Metabolism and Function Resulting in a Deficient Mitochondrial Bioenergetic Phenotype* , 2007, Journal of Biological Chemistry.

[90]  Kei Yamamoto,et al.  Group X Secreted Phospholipase A2 Releases ω3 Polyunsaturated Fatty Acids, Suppresses Colitis, and Promotes Sperm Fertility* , 2016, The Journal of Biological Chemistry.

[91]  M. Gelb,et al.  Mast cell maturation is driven via a group III phospholipase A2-prostaglandin D2–DP1 receptor paracrine axis , 2013, Nature Immunology.

[92]  J. M. Brown,et al.  In vivo metabolite profiling as a means to identify uncharacterized lipase function: recent success stories within the alpha beta hydrolase domain (ABHD) enzyme family. , 2014, Biochimica et biophysica acta.

[93]  B. Cravatt,et al.  ABHD4 regulates multiple classes of N-acyl phospholipids in the mammalian central nervous system. , 2015, Biochemistry.

[94]  S. Dudek,et al.  Secretory group V phospholipase A2 regulates acute lung injury and neutrophilic inflammation caused by LPS in mice. , 2009, American journal of physiology. Lung cellular and molecular physiology.

[95]  U. Schaible,et al.  Lysosomal phospholipase A2: A novel player in host immunity to Mycobacterium tuberculosis , 2014, European journal of immunology.

[96]  F. Galibert,et al.  PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans , 2012, Nature Genetics.

[97]  Petra C. Kienesberger,et al.  ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1 , 2011, Nature Medicine.

[98]  C. Chalfant,et al.  Ceramide-1-phosphate Binds Group IVA Cytosolic Phospholipase a2 via a Novel Site in the C2 Domain* , 2007, Journal of Biological Chemistry.

[99]  D. Sharon,et al.  Mutations inPNPLA6are linked to photoreceptor degeneration and various forms of childhood , 2015 .

[100]  Takao Shimizu,et al.  Discrete role for cytosolic phospholipase A(2)alpha in platelets: studies using single and double mutant mice of cytosolic and group IIA secretory phospholipase A(2). , 2002, The Journal of experimental medicine.

[101]  R. Kriz,et al.  A Novel Calcium-independent Phospholipase A2, cPLA2-γ, That Is Prenylated and Contains Homology to cPLA2 * , 1998, The Journal of Biological Chemistry.

[102]  Masahiko Watanabe,et al.  The Endocannabinoid 2-Arachidonoylglycerol Produced by Diacylglycerol Lipase α Mediates Retrograde Suppression of Synaptic Transmission , 2010, Neuron.

[103]  Hirofumiyasue,et al.  Circulating Levels of Secretory Type II Phospholipase A2 Predict Coronary Events in Patients with Coronary Artery Disease , 1999 .

[104]  C. Meisinger,et al.  Lipoprotein-Associated Phospholipase A2 Adds to Risk Prediction of Incident Coronary Events by C-Reactive Protein in Apparently Healthy Middle-Aged Men From the General Population: Results From the 14-Year Follow-Up of a Large Cohort From Southern Germany , 2004, Circulation.

[105]  R. Gross,et al.  Cyclooxygenase-2 Mediated Oxidation of 2-Arachidonoyl-Lysophospholipids Identifies Unknown Lipid Signaling Pathways. , 2016, Cell chemical biology.

[106]  C. Jordan,et al.  Group V Secretory Phospholipase A2 Promotes Atherosclerosis: Evidence From Genetically Altered Mice , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[107]  B. Cravatt,et al.  A calcium-dependent acyltransferase that produces N-acyl phosphatidylethanolamines , 2016, Nature chemical biology.

[108]  James G. Bollinger,et al.  Interfacial Kinetic and Binding Properties of Mammalian Group IVB Phospholipase A2 (cPLA2β) and Comparison with the Other cPLA2 Isoforms* , 2010, The Journal of Biological Chemistry.

[109]  D. Charmot,et al.  The phospholipase A2 inhibitor methyl indoxam suppresses diet‐induced obesity and glucose intolerance in mice , 2009, British journal of pharmacology.

[110]  J. Turk,et al.  Calcium‐independent phospholipase A2β deficiency protects against breast cancer metastasis to the lung , 2011, American journal of physiology. Cell physiology.

[111]  B. Kennedy,et al.  Multiple Splice Variants of the Human Calcium-independent Phospholipase A2 and Their Effect on Enzyme Activity* , 1998, The Journal of Biological Chemistry.

[112]  Xianlin Han,et al.  Genetic Ablation of Calcium-independent Phospholipase A2γ Leads to Alterations in Hippocampal Cardiolipin Content and Molecular Species Distribution, Mitochondrial Degeneration, Autophagy, and Cognitive Dysfunction* , 2009, The Journal of Biological Chemistry.

[113]  L. Touqui,et al.  Staphylococcus aureus Adenosine Inhibits sPLA2-IIA–Mediated Host Killing in the Airways , 2015, The Journal of Immunology.

[114]  M. Murakami,et al.  The Functions of Five Distinct Mammalian Phospholipase A2s in Regulating Arachidonic Acid Release , 1998, The Journal of Biological Chemistry.

[115]  S. Humphries,et al.  Tagging SNP haplotype analysis of the secretory PLA2-V gene, PLA2G5, shows strong association with LDL and oxLDL levels, suggesting functional distinction from sPLA2-IIA: results from the UDACS study. , 2007, Human molecular genetics.

[116]  Xin Lu,et al.  The G(0)/G(1) switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase. , 2010, Cell metabolism.

[117]  E. Niki,et al.  Protection against Oxidative Stress-induced Hepatic Injury by Intracellular Type II Platelet-activating Factor Acetylhydrolase by Metabolism of Oxidized Phospholipids in Vivo* , 2008, Journal of Biological Chemistry.

[118]  F. Clavel-Chapelon,et al.  Polymorphisms in fatty-acid-metabolism-related genes are associated with colorectal cancer risk. , 2010, Carcinogenesis.

[119]  M. Gelb,et al.  Expression and Function of Group IIE Phospholipase A2 in Mouse Skin* , 2016, The Journal of Biological Chemistry.

[120]  J. Casida,et al.  Evidence that mouse brain neuropathy target esterase is a lysophospholipase , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[121]  C. Leslie,et al.  Function, Activity, and Membrane Targeting of Cytosolic Phospholipase A2ζ in Mouse Lung Fibroblasts* , 2007, Journal of Biological Chemistry.

[122]  J. Aoki,et al.  Lysophosphatidic acid as a lipid mediator with multiple biological actions. , 2015, Journal of biochemistry.

[123]  J. Miyazaki,et al.  Role of cytosolic phospholipase A2 in allergic response and parturition , 1997, Nature.

[124]  K. Akassoglou,et al.  Brain-specific deletion of neuropathy target esterase/swisscheese results in neurodegeneration. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[125]  K. Huggins,et al.  Protection against diet-induced obesity and obesity- related insulin resistance in Group 1B PLA2-deficient mice. , 2002, American journal of physiology. Endocrinology and metabolism.

[126]  M. Kirber,et al.  Impairment of PARK14-dependent Ca2+ signalling is a novel determinant of Parkinson's disease , 2016, Nature Communications.

[127]  M. Gelb,et al.  Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A2-IIA , 2015, Proceedings of the National Academy of Sciences.

[128]  M. Murakami,et al.  PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis , 2017, Nature Communications.

[129]  R. Gross,et al.  Smooth Muscle Cell Arachidonic Acid Release, Migration, and Proliferation Are Markedly Attenuated in Mice Null for Calcium-independent Phospholipase A2β* , 2008, Journal of Biological Chemistry.

[130]  J. Weiss,et al.  Mobilization of potent plasma bactericidal activity during systemic bacterial challenge. Role of group IIA phospholipase A2. , 1998, The Journal of clinical investigation.

[131]  S. Kohlwein,et al.  Identification of an Insulin-regulated Lysophospholipase with Homology to Neuropathy Target Esterase* , 2008, Journal of Biological Chemistry.

[132]  Chi-wai Wong,et al.  Hepatocyte nuclear factor‐4 alpha regulates liver triglyceride metabolism in part through secreted phospholipase A2 GXIIB , 2011, Hepatology.

[133]  W Pruzanski,et al.  Cloning and recombinant expression of phospholipase A2 present in rheumatoid arthritic synovial fluid. , 1989, The Journal of biological chemistry.

[134]  Daisuke Fujioka,et al.  A novel anti-inflammatory role for secretory phospholipase A2 in immune complex-mediated arthritis , 2010, EMBO molecular medicine.

[135]  Takao Shimizu,et al.  An Essential Role of Cytosolic Phospholipase A2α in Prostaglandin E2–mediated Bone Resorption Associated with Inflammation , 2003, The Journal of experimental medicine.

[136]  Takao Shimizu,et al.  Identification of Novel Cytosolic Phospholipase A2s, Murine cPLA2δ, ϵ, and ζ, Which Form a Gene Cluster with cPLA2β* , 2005, Journal of Biological Chemistry.

[137]  E. Matsui,et al.  Cysteinyl Leukotrienes Regulate Th2 Cell-Dependent Pulmonary Inflammation , 2007, Pediatrics.

[138]  I. Kubota,et al.  A novel polymorphism in secretory phospholipase A2-IID is associated with body weight loss in chronic obstructive pulmonary disease. , 2005, American journal of respiratory and critical care medicine.

[139]  Ping Zhang,et al.  Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development , 2008, Nature Medicine.

[140]  R. Liao,et al.  Deletion of cytosolic phospholipase A2 promotes striated muscle growth , 2003, Nature Medicine.

[141]  Y. Miki,et al.  A new era of secreted phospholipase A2 , 2015, Journal of Lipid Research.

[142]  Agnes L. Bodor,et al.  The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors , 2010, Nature Neuroscience.

[143]  H. Coon,et al.  Neuropathy target esterase gene mutations cause motor neuron disease. , 2008, American journal of human genetics.

[144]  M. Taketo,et al.  Targeted Disruption of Intracellular Type I Platelet Activating Factor-acetylhydrolase Catalytic Subunits Causes Severe Impairment in Spermatogenesis* , 2003, The Journal of Biological Chemistry.

[145]  S. Narumiya,et al.  Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ716 knockout mice , 2001, Nature Medicine.

[146]  Hiroki Nakanishi,et al.  Group III secreted phospholipase A2 regulates epididymal sperm maturation and fertility in mice. , 2010, The Journal of clinical investigation.

[147]  S. Narumiya,et al.  Involvement of Prostaglandin E2 in Production of Amyloid-β Peptides Both in Vitro and in Vivo* , 2007, Journal of Biological Chemistry.

[148]  R. Zechner,et al.  Efficient Phagocytosis Requires Triacylglycerol Hydrolysis by Adipose Triglyceride Lipase , 2010, The Journal of Biological Chemistry.

[149]  J. D. Clark,et al.  A novel arachidonic acid-selective cytosolic PLA2 contains a Ca2+-dependent translocation domain with homology to PKC and GAP , 1991, Cell.

[150]  D. Friend,et al.  Cysteinyl Leukotrienes Regulate Th2 Cell-Dependent Pulmonary Inflammation1 , 2006, The Journal of Immunology.

[151]  M. Gelb,et al.  Group V Secretory Phospholipase A2 Modulates Phagosome Maturation and Regulates the Innate Immune Response against Candida albicans 1 , 2009, The Journal of Immunology.

[152]  G. Zimmerman,et al.  Anti-inflammatory properties of a platelet-activating factor acetylhydrolase , 1995, Nature.

[153]  G. Siuzdak,et al.  ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC , 2013, Proceedings of the National Academy of Sciences.

[154]  Xianlin Han,et al.  Genetic Ablation of Calcium-independent Phospholipase A2γ Prevents Obesity and Insulin Resistance during High Fat Feeding by Mitochondrial Uncoupling and Increased Adipocyte Fatty Acid Oxidation* , 2010, The Journal of Biological Chemistry.

[155]  S. Narumiya,et al.  Dual roles of PGE2-EP4 signaling in mouse experimental autoimmune encephalomyelitis , 2010, Proceedings of the National Academy of Sciences.

[156]  E. Wagner,et al.  Defective Lipolysis and Altered Energy Metabolism in Mice Lacking Adipose Triglyceride Lipase , 2006, Science.

[157]  C. Leslie,et al.  Cytosolic phospholipase A2: physiological function and role in disease , 2015, Journal of Lipid Research.

[158]  S. Sakoda,et al.  Neuroaxonal Dystrophy Caused by Group VIA Phospholipase A2 Deficiency in Mice: A Model of Human Neurodegenerative Disease , 2008, The Journal of Neuroscience.

[159]  G. Sandusky,et al.  Group VIA phospholipase A2 in both host and tumor cells is involved in ovarian cancer development , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[160]  D. Hui,et al.  Group 1B phospholipase A₂ inactivation suppresses atherosclerosis and metabolic diseases in LDL receptor-deficient mice. , 2014, Atherosclerosis.

[161]  Stuart M. Allen,et al.  Mapping the Human Platelet Lipidome Reveals Cytosolic Phospholipase A2 as a Regulator of Mitochondrial Bioenergetics during Activation , 2016, Cell metabolism.

[162]  P. Shridas,et al.  Vascular Biology , Atherosclerosis , and Endothelium Biology Group V Secretory Phospholipase A 2 Enhances the Progression of Angiotensin II – Induced Abdominal Aortic Aneurysms but Confers Protection against Angiotensin II – Induced Cardiac Fibrosis in ApoE-Deficient Mice , 2012 .

[163]  Haowei Song,et al.  Mice deficient in group VIB phospholipase A2 (iPLA2gamma) exhibit relative resistance to obesity and metabolic abnormalities induced by a Western diet. , 2010, American journal of physiology. Endocrinology and metabolism.

[164]  D. Brenner,et al.  Inherited human cPLA(2alpha) deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction. , 2008, The Journal of clinical investigation.

[165]  Kathryn Roeder,et al.  Genome-wide association identifies multiple ulcerative colitis susceptibility loci , 2010, Nature Genetics.

[166]  J. Obata,et al.  Group X secretory PLA2 in neutrophils plays a pathogenic role in abdominal aortic aneurysms in mice. , 2012, American journal of physiology. Heart and circulatory physiology.

[167]  Y. Miki,et al.  Secreted Phospholipase A2 Specificity on Natural Membrane Phospholipids. , 2017, Methods in enzymology.

[168]  M. Gelb,et al.  Secreted Phospholipases A2 Are Intestinal Stem Cell Niche Factors with Distinct Roles in Homeostasis, Inflammation, and Cancer. , 2016, Cell stem cell.

[169]  H. Sul,et al.  Desnutrin/ATGL activates PPARδ to promote mitochondrial function for insulin secretion in islet β cells. , 2013, Cell metabolism.

[170]  M. Gelb,et al.  On the diversity of secreted phospholipases A(2). Cloning, tissue distribution, and functional expression of two novel mouse group II enzymes. , 1999, The Journal of biological chemistry.

[171]  M. Gelb,et al.  Cellular Arachidonate-releasing Function of Novel Classes of Secretory Phospholipase A2s (Groups III and XII)* , 2003, The Journal of Biological Chemistry.

[172]  J. Mudgett,et al.  A Natural Disruption of the Secretory Group II Phospholipase A2 Gene in Inbred Mouse Strains (*) , 1995, The Journal of Biological Chemistry.

[173]  Roger J. Davis,et al.  cPLA2 is phosphorylated and activated by MAP kinase , 1993, Cell.

[174]  M. Gelb,et al.  Cloning and Recombinant Expression of a Structurally Novel Human Secreted Phospholipase A2 * , 2000, The Journal of Biological Chemistry.

[175]  M. Lathrop,et al.  The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy , 2007, Nature Genetics.

[176]  M. Gelb,et al.  Group X Secretory Phospholipase A2 Enhances TLR4 Signaling in Macrophages , 2011, The Journal of Immunology.

[177]  M. Gelb,et al.  Crystal Structure of Human Group X Secreted Phospholipase A2 , 2002, The Journal of Biological Chemistry.

[178]  S. Humphries,et al.  Tagging-SNP haplotype analysis of the secretory PLA2IIa gene PLA2G2A shows strong association with serum levels of sPLA2IIa: results from the UDACS study. , 2006, Human molecular genetics.

[179]  S. Narumiya,et al.  Prostaglandin E2–EP4 signaling promotes immune inflammation through TH1 cell differentiation and TH17 cell expansion , 2009, Nature Medicine.

[180]  L. Mucke,et al.  Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease , 2008, Nature Neuroscience.

[181]  T. Suda,et al.  Increase of smooth muscle cell migration and of intimal hyperplasia in mice lacking the α/β hydrolase domain containing 2 gene , 2005 .

[182]  H. Arai,et al.  Intracellular PAF-Acetylhydrolase Type I. , 2015, The Enzymes.

[183]  A. Kihara,et al.  PNPLA1 is a transacylase essential for the generation of the skin barrier lipid ω-O-acylceramide , 2017, Nature Communications.

[184]  T. Spector,et al.  Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi , 2009, Nature Genetics.

[185]  T. Uyama,et al.  Generation of N-Acylphosphatidylethanolamine by Members of the Phospholipase A/Acyltransferase (PLA/AT) Family* , 2012, The Journal of Biological Chemistry.

[186]  D. Brenner,et al.  The enteropathy of prostaglandin deficiency , 2008, Journal of Gastroenterology.

[187]  M. Gelb,et al.  Group X Secreted Phospholipase A2 Proenzyme Is Matured by a Furin-like Proprotein Convertase and Releases Arachidonic Acid inside of Human HEK293 Cells* , 2011, The Journal of Biological Chemistry.

[188]  T. Rülicke,et al.  Skin Barrier Development Depends on CGI-58 Protein Expression during Late-Stage Keratinocyte Differentiation , 2016, The Journal of investigative dermatology.

[189]  J. Balsinde,et al.  Phosphatidylinositol 4,5-bisphosphate anchors cytosolic group IVA phospholipase A2 to perinuclear membranes and decreases its calcium requirement for translocation in live cells. , 2005, Molecular biology of the cell.

[190]  M. Gelb,et al.  Lymphoid tissue phospholipase A2 group IID resolves contact hypersensitivity by driving antiinflammatory lipid mediators , 2013, The Journal of experimental medicine.

[191]  M. Gelb,et al.  Critical role of phospholipase A2 group IID in age-related susceptibility to severe acute respiratory syndrome–CoV infection , 2015, The Journal of experimental medicine.