key: cord-324326-q014b5ym
authors: MURAKAMI, Makoto
title: Lipoquality control by phospholipase A(2) enzymes
date: 2017-11-10
journal: Proc Jpn Acad Ser B Phys Biol Sci
DOI: 10.2183/pjab.93.043
sha: 
doc_id: 324326
cord_uid: q014b5ym

The phospholipase A(2) (PLA(2)) 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 PLA(2)s or related enzymes, which are classified into several subfamilies on the basis of their structures and functions. From a general viewpoint, the PLA(2) family has mainly been implicated in signal transduction, producing bioactive lipid mediators derived from fatty acids and lysophospholipids. Recent evidence indicates that PLA(2)s also contribute to phospholipid remodeling for membrane homeostasis or energy production for fatty acid β-oxidation. Accordingly, PLA(2) enzymes can be regarded as one of the key regulators of the quality of lipids, which I herein refer to as lipoquality. Disturbance of PLA(2)-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 PLA(2) family.

In terms of signal transduction, the phospholipase A 2 (PLA 2 ) reaction, which hydrolyzes the sn-2 position of phospholipids to yield fatty acids and lysophospholipids, has been considered to be of particular importance, since arachidonic acid (AA, C20:4), one of the polyunsaturated fatty acids (PUFAs) released from membrane phospholipids by PLA 2 , is metabolized by cyclooxygenases (COXs) and lipoxygenases (LOXs) to lipid mediators including prostaglandins (PGs) and leukotrienes (LTs), which are often referred to as eicosanoids (Fig. 1) .

Lysophospholipids or their metabolites, such as lysophosphatidic acid (LPA) and platelet-activating factor (PAF), are categorized into another class of PLA 2 -driven lipid mediators ( Fig. 2A, B) . More recently, a novel class of anti-inflammatory lipid mediators derived from B3 PUFAs, such as eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6), has also been attracting much attention (Fig. 2C ). These lipid mediators exert numerous biological actions on target cells mainly by acting on their cognate G protein-coupled receptors. The pathophysiological roles of individual lipid mediators have been summarized in recent reviews. 1)-4) However, this principal concept appears to be insufficient to fully explain the biological aspects and physiological roles of the PLA 2 family. Phospholipids comprise numerous molecular species that contain various combinations of fatty acids esterified at the sn-1 and sn-2 positions and several polar head groups at the sn-3 position. Many, if not all, PLA 2 enzymes recognize such differences in the fatty acyl and/or head group moieties in their substrate phospholipids. Moreover, several enzymes in the PLA 2 family also catalyze the phospholipase A 1 (PLA 1 ), lysophospholipase, neutral lipid lipase, or even transacylase/ acyltransferase reaction rather than or in addition to the genuine PLA 2 reaction. Therefore, the fatty acids and lysophospholipids released by different PLA 2 s are not always identical; rather, in many situations, specific fatty acids and lysophosholipids can be released by a particular PLA 2 in the presence of a given microenvironmental cue. In this context, PLA 2 enzymes act as one of the critical regulators of spatiotemporal lipid profiles, namely the quality of lipids (lipoquality). To comprehensively understand the lipoquality regulation by individual PLA 2 s in various pathophysiological contexts, their precise enzymatic, biochemical and cell biological properties, tissue and cellular distributions, and availability of phospholipid substrates in various pathophysiological settings should be taken into consideration.

Herein, I overview current understanding of the biological aspects of various PLA 2 enzymes in the context of lipoquality.

Obviously, the substrate specificity of individual PLA 2 s is the critical determinant of lipoquality. The in vitro enzymatic activity of PLA 2 s may be influenced by the assay conditions employed, such as the composition of the substrate phospholipids, concentrations of PLA 2 s and substrates, presence of detergents, and pH. Hence, the enzymatic properties of individual PLA 2 s determined in different studies may not be entirely identical. Since natural membranes contain numerous phospholipid molecular species, the results obtained using artificial phospho- lipid vesicles comprising only one or a few phospholipid species may not always reflect the true enzymatic properties of a given PLA 2 . Addition of an excess amount of recombinant or purified PLA 2 to an enzyme assay often results in hydrolysis of bulk phospholipids, which makes precise evaluation of its substrate specificity difficult. The results obtained using a commercially available PLA 2 assay kit, in which a synthetic, chromophoric phospholipid is used as a substrate, should be interpreted carefully, since some PLA 2 s are unable to hydrolyze it efficiently. In this regard, mass spectrometric examination of the in vitro hydrolysis of natural membrane phospholipids extracted from the affected tissues or cells by PLA 2 , particularly at a low (physiologically relevant) concentration of the enzyme, could provide a valuable clue to the in vivo substrates and products of this enzyme. 5)-7) The overall tendency in this in vitro assay using natural membranes is recapitulated in several in vivo systems, often with even more selective patterns of hydrolysis that are relevant to the results of studies using PLA 2 knockout and/or transgenic mice (see below). Importantly, the mobilization of distinct lipids by PLA 2 s in vivo relies not only on their intrinsic enzymatic properties, but also on tissue-or disease-specific contexts such as the lipid composition of target membranes, the spatiotemporal availability of downstream lipid-metabolizing enzymes, or the presence of cofactor(s) that can modulate the enzymatic function, which may account for why distinct PLA 2 enzymes even in the same subfamily exert specific functions with different lipid profiles in distinct settings. Hereafter, I describe the current understanding of various PLA 2 s in the context of lipoquality. The classification, distributions, properties and functions of individual PLA 2 s, whose pathophysiological functions have currently been studied using their gene-manipulated mice, are summarized in Table 1 Enzymes whose in vivo functions have been analyzed using knockout mice are summarized.

The cPLA 2 family. The cytosolic PLA 2 (cPLA 2 ) family comprises 6 isoforms (,-1), among which cPLA 2 O, /, C and 1 map to the same chromosomal locus (Fig. 3A) . 8) cPLA 2 , (also known as group IVA PLA 2 ) is undoubtedly the best known PLA 2 and its biological roles in association with lipoquality have been well documented. 9) cPLA 2 , is the only PLA 2 that shows a striking substrate specificity for AA-containing phospholipids. Strictly speaking, cPLA 2 , can also hydrolyze phospholipids containing EPA, yet the low abundance of this B3 PUFA relative to other fatty acids including B6 AA in cell membranes allows cPLA 2 , to release AA rather specifically in most situations. Upon cell activation, cPLA 2 , translocates from the cytosol to the phosphatidylcholine (PC)-rich perinuclear, endoplasmic reticulum (ER) and Golgi membranes (particularly Golgi) in response to an increase in the µM range of cytosolic Ca 2D concentration, and is maximally activated by phosphorylation through mitogen-activated protein kinases (MAPKs) and other kinases. 10),11) In addition, the phosphoinositide PIP 2 and ceramide-1-phosphate modulate the subcellular localization and activation of cPLA 2 ,. 12),13) The AA released by cPLA 2 , is converted by the sequential action of constitutive COX-1 or inducible COX-2 and terminal PG synthases to PGs or by the sequential action of 5-LOX and terminal LT synthases to LTs (Fig. 3B ).

Mice deficient in cPLA 2 , display a number of phenotypes that can be explained by reductions of PGs and/or LTs. Under physiological conditions, cPLA 2 ,-deficient mice display a hemorrhagic tendency, impaired female reproduction, gastrointestinal ulcer, and renal malfunction, among others. 14)- 18) Under pathological conditions, cPLA 2 ,-deficient mice are protected against bronchial asthma, pulmonary fibrosis, cerebral infarction, Alzheimer's disease, experimental autoimmune encephalomyelitis, collagen-induced arthritis, metabolic diseases, intestinal cancer and so on, whereas they suffer from more severe colitis and spinal cord injury. 15),19)-24) Most of these phenotypes are recapitulated in mice lacking one or more of the biosynthetic enzymes or receptors for PGs and LTs, lending strong support to the notion that cPLA 2 , lies upstream of eicosanoid biosynthesis in many situations. For instance, as is the case for cPLA 2 ,-deficient mice, mice lacking LTC 4 synthase (LTC 4 S), LTD 4 receptor (CysLT1), LTB 4 receptor (BLT1), or PGD 2 receptor (DP1) are protected from asthma, 25)-27) revealing the critical role of the cPLA 2 ,-LTB 4 /LTC 4 /PGD 2 axis in this allergic disease. Likewise, the decrease of PGE 2 in cPLA 2 ,-deficient mice can account largely, even if not solely, for the mitigation of arthritis, autoimmune encephalomyelitis, cancer and neurodegeneration as well as the exacerbation of colitis, since these phenotypes are mimicked by mice lacking PGE 2 synthase (mPGES-1) or either of the four PGE 2 receptors (EP194). 28)-32) Furthermore, cPLA 2 ,-triggered release of AA by platelets is coupled not only with biosynthesis of the pro-thrombotic eicosanoid thromboxane A 2 (TXA 2 ), but also with O-oxidationmediated bioenergetics for blood clotting. 33) Importantly, inherited human cPLA 2 , mutations are associated with reduced eicosanoid biosynthesis, platelet dysfunction, and intestinal ulceration, 34) , 35) thus mimicking cPLA 2 , deletion in mice. On the other hand, the enzymatic activities and biological functions of cPLA 2 isoforms other than cPLA 2 , have remained largely unknown. Reportedly, cPLA 2 O (group IVB PLA 2 ), which has a unique JimC domain in the N-terminal region, display PLA 1 , PLA 2 and lysophospholipase activities. 36) cPLA 2 . (group IVC PLA 2 ), which uniquely lacks the C2 domain characteristic of the cPLA 2 family, is Cterminally farnesylated and possesses lysophospholipase and transacylase activities in addition to PLA 2 activity. 37) cPLA 2 / (group IVD PLA 2 ), whose expression is elevated in human psoriatic skin, 38) shows PLA 1 activity in preference to PLA 2 activity. 36) cPLA 2 C (group IVE PLA 2 ) exhibits a unique transacylase activity that transfers sn-1 fatty acid of PC to an amino residue of phosphatidylethanolamine (PE) to form N-acyl-PE, a precursor of the endocannabinoid lipid mediator N-acylethanolamine. 39) cPLA 2 1 (group IVF PLA 2 ) displays both PLA 1 and PLA 2 activities without fatty acid selectivity. 40) However, these enzymatic properties of cPLA 2 O-1 vary according to the in vitro assays employed, implying that analyses using gene-manipulated mice for these enzymes will be necessary for clarifying their biological roles in the context of lipoquality.

The iPLA 2 /PNPLA family.

The human genome encodes 9 Ca 2D -independent PLA 2 (iPLA 2 ) enzymes (Fig. 4) . These enzymes are now more generally referred to as patatin-like phospholipase domain-containing lipases (PNPLA199), as all members in this family share a patatin domain, which was initially discovered in patatin (iPLA 2 ,), a potato protein. 41 ),42) Mammalian iPLA 2 /PNPLA isoforms include lipid hydrolases or transacylases with specificities for diverse lipids such as phospholipids, neutral lipids, sphingolipids, and retinol esters. Generally speaking, enzymes bearing a large and unique N-terminal region (PNPLA699) act mainly on phospholipids (phospholipase type), whereas those lacking the N-terminal domain (PNPLA195) act on neutral lipids (lipase type). Analysis of mutant mouse models and clinical symptoms of patients with mutations for these enzymes have provided valuable insights into the physiological roles of the iPLA 2 / PNPLA family in various forms of homeostatic lipid metabolism that are fundamental for life. Among the iPLA 2 /PNPLA family, PNPLA9 (iPLA 2 O, also known as group VIA PLA 2 ) is the only isoform that acts primarily as a PLA 2 with poor fatty acid selectivity. 43),44) Although PNPLA8 (iPLA 2 . or group VIB PLA 2 ) displays PLA 2 activity, it acts as a PLA 1 toward phospholipids bearing sn-2 PUFA. 45), 46) Accordingly, hydrolysis of PUFA-bearing phospholipids by PNPLA8/iPLA 2 . typically gives rise to 2-lysophospholipids (having a PUFA at the sn-2 position) rather than 1-lysophospholipids (having a saturated or monounsaturated fatty acid at the sn-1 position). PNPLA6 (iPLA 2 /) and its closest paralog PNPLA7 (iPLA 2 3) have lysophospholipase activity that cleaves lysophosphatidylcholine to yield fatty acid and glycerophosphocholine. 47),48) Genetic mutations or deletions of these phospholipid-targeting PNPLAs cause various forms of metabolic dysfunction and neurodegeneration. 49)-53) In particular, PNPLA9/iPLA 2 O is also referred to as the parkinsonism-associated protein PARK14, whose mutations impair Ca 2D signaling in dopaminergic neurons. 54) Apart from the metabolic and neurodegenerative phenotypes, the lack of PNPLA9/iPLA 2 O leads to male infertility through an unknown mechanism. 55) PNPLA2 (iPLA 2 1), more generally known as adipose triglyceride lipase (ATGL), is a major lipase that hydrolyzes triglycerides in lipid droplets to release fatty acids as a fuel for O-oxidation-coupled energy production, a process known as lipolysis. 56) Genetic deletion or mutation of PNPLA2 leads to massive accumulation of triglycerides in multiple tissues leading to multi-organ failures, 57) while protecting from cancer-associated cachexia by preventing fat loss. 58) The activity of PNPLA2 is regulated positively by ABHD5 (see below) and negatively by perilipin and G0S2, which modulate the accessibility of PNPLA2 to lipid droplets. 59) The fatty acids released from lipid droplets by PNPLA2 act as endogenous ligands for the nuclear receptor PPAR, or PPAR/, which accelerates energy consumption. 59), 60) The regulatory mechanisms and metabolic roles of PNPLA2 have been detailed in other elegant reviews. 61),62) Mutations of PNPLA3 (iPLA 2 C) are highly associated with non-alcoholic fatty liver disease. 63) Although the catalytic activity of PNPLA3 is controversial, it may serve as a triglyceride lipase, since its loss-of function mutation increases cellular triglyceride levels. 64) Furthermore, recent evidence suggests that PNPLA3 acts as a retinyl-palmitate lipase in hepatic stellate cells to fine-tune the plasma levels of retinoids. The expressions of PNPLA2 and PNPLA3 are nutritionally regulated in a reciprocal way; PNPLA2 is upregulated, while PNPLA3 is downregulated, upon starvation, and vice versa upon feeding. 65) Biochemical and cell biological studies have suggested that PNPLA4 (iPLA 2 2, which is absent in mice) might be involved in retinol ester metabolism 66) and that PNPLA5 might participate in triglyceride lipolysis coupled with autophagosome formation, 67) although the in vivo relevance of these in vitro observations is unclear.

Unlike most PNPLA isoforms that are ubiquitously expressed in many tissues, PNPLA1 is localized predominantly in the upper layer of the epidermis. PNPLA1 acts as a unique transacylase, catalyzing the transfer of linoleic acid (LA; C18:2) in triglyceride to the B-hydroxy residue of ultra-longchain fatty acid in ceramide to form B-O-acylceramide, a lipid component essential for skin barrier function. 68),69) Accordingly, genetic deletion or mutation of PNPLA1 hampers epidermal B-O-acylceramide formation, thereby severely impairing skin barrier function and causing ichthyosis. The unique role of PNPLA1 in the acylceramide-metabolic pathway in the epidermis is depicted in Fig. 5 .

The PAFAH family. The PAF-acetylhydrolase (PAFAH) family comprises one extracellular and three intracellular PLA 2 s that were originally found to have the capacity to deacetylate and thereby inactivate the lysophospholipid-derived lipid mediator PAF. 70),71) Type-I PAFAH is a heterotrimer composed of two catalytic subunits, group XIIIA and XIIIB PLA 2 s, and a regulatory subunit LIS-1, the causative gene for a type of Miller Diecker syndrome. 72) Deficiency of type-I PAFAH leads to male infertility through an unknown mechanism. 73) Type-II PAFAH (group VIIB PLA 2 ) preferentially hydrolyzes oxidized phospholipids (i.e., phospholipids having an oxygenated fatty acid at the sn-2 position) in cellular membranes, thereby protecting cells from oxidative damage. 74) Although plasma-type PAFAH (group VIIA PLA 2 ) is a secreted protein, it is described here as its structure is close to type-II PAFAH. Plasma-type PAFAH is now more generally called lipoprotein-associated PLA 2 (Lp-PLA 2 ), existing as a low-density lipoprotein (LDL)-bound form in human plasma. 75) A series of studies have revealed the correlation of Lp-PLA 2 with atherosclerosis, likely because this enzyme liberates toxic oxidized fatty acids from modified LDL with pro-atherogenic potential. 76),77) Furthermore, deficiency of Lp-PLA 2 decreases intestinal polyposis and colon tumorigenesis in Apc Min/D mice, 78) suggesting an anti-tumorigenic role for PAF in this setting.

Lysosomal PLA 2 . Lysosomal PLA 2 (LPLA 2 ), also known as group XV PLA 2 , is homologous with lecithin cholesterol acyltransferase (LCAT) and catalytically active under mildly acidic conditions. 79) LPLA 2 hydrolyzes both sn-1 and sn-2 fatty acids in phospholipids and contributes to phospholipid degradation in lysosomes. Genetic deletion of LPLA 2 results in unusual accumulation of non-degraded lung surfactant phospholipids in lysosomes of alveolar macrophages, leading to phospholipidosis, 80) perturbed presentation of endogenous lysophospholipid antigens to CD1d by invariant natural killer T (iNKT) cells, 81) and impairment of adaptive T cell immunity against mycobacterium. 82) The PLAAT family. The PLA-acyltransferase (PLAAT) family (3 enzymes in humans and 5 enzymes in mice) is structurally similar to lecithin retinol acyltransferase (LRAT). Members of this family, including group XVI PLA 2 (PLA2G16), display PLA 1 and PLA 2 activities, as well as acyltransferase activity that synthesizes N-acyl-PE, to various degrees. 83) PLA2G16 is highly expressed in adipocytes, and PLA2G16-deficient mice are resistant to diet-induced obesity. 84) PLA2G16 and its paralogs in this family have also been implicated in tumor invasion and metastasis, 85) vitamin A metabolism, 86) peroxisome biogenesis, 87) and cellular entry and clearance of Picornaviruses. 88) The ABHD family.

The ,/O hydrolase (ABHD) family is a newly recognized group of lipolytic enzymes, comprising at least 19 enzymes in humans. 89) Enzymes in this family typically possess both hydrolase and acyltransferase motifs. Although the functions of many of the ABHD isoforms still remain uncertain, some of them have been demonstrated to act on neutral lipids or phospholipids as lipid hydrolases. ABHD3 selectively hydrolyzes phospholipids with medium-chain fatty acids. 90 Lipoquality control by phospholipase A 2 enzymes No. 9] ABHD4 releases fatty acids from multiple classes of N-acyl-phospholipids to produce N-acyl-lysophospholipids. 91) ABHD6 acts as lysophospholipase or monoacylglycerol lipase, the latter being possibly related to the regulation of 2-arachidonoyl glycerol (2-AG) signaling. 92),93) 2-AG is an endocannabinoid lipid mediator that plays a role in the retrograde neurotransmission and is considered to be produced mainly by diacylglycerol lipase ,. 94) Interestingly, in the brain, the AA released from 2-AG by monoacylglycerol lipase, rather than that released from phospholipids by cPLA 2 , (see above), is linked to the production of a pool of PGE 2 that promotes fever. 2),95) ABHD12 hydrolyzes lysophosphatidylserine (LysoPS), and is therefore referred to as LysoPS lipase. 96) Mutations in the human ABHD12 gene result in accumulation of LysoPS in the brain and cause a disease called PHARC, which is characterized by polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract. 97) ABHD16A acts as a phosphatidylserine (PS)-selective PLA 2 (referred to as PS lipase), being located upstream of ABHD12 in the PS-catabolic pathway. 96) Although ABHD5 (also called CGI-58) does not have a catalytic activity because of the absence of a serine residue in the catalytic center, it greatly enhances PNPLA2directed hydrolysis of triglycerides in lipid droplets by acting as an essential lipolytic cofactor. 98) 4. Lipoquality control by secreted PLA 2 s General aspects. The secreted PLA 2 (sPLA 2 ) family contains 10 catalytically active isoforms and one inactive isoform in mammals. 42),99) Based on the structural and evolutional relationships, these enzymes are categorized into classical (IB, IIA, IIC, IID, IIE, IIF, V and X) and atypical (III and XII) classes (Fig. 6) . The sPLA 2 family strictly hydrolyzes the sn-2 position of phospholipids, a feature that differs from intracellular PLA 2 s that often display PLA 1 , lysophospholipase, lipase, or transacylase/acyltransferase activity (see above). Individual sPLA 2 s exhibit unique tissue and cellular distributions, suggesting their distinct biological roles. As sPLA 2 s are secreted and require Ca 2D in the mM range for their catalytic action, their principal targets are phospholipids in the extracellular space, such as microparticles, surfactant, lipoproteins, and foreign phospholipids in microbe membranes or dietary components. The biochemical properties and pathophysiological functions of sPLA 2 s have been detailed in several recent reviews. 5), 100) Here, I describe several key features of lipoquality regulation by the sPLA 2 family. In terms of the lipoquality, sPLA 2 s have long been considered to display no apparent selectivity for sn-2 fatty acid species in the substrate phospholipids. This view was based on the fact that sPLA 2 -IB and -IIA, two prototypic sPLA 2 s that were initially identified through classical protein purification from the pancreas and sites of inflammation, respectively, 101),102) as well as a number of snake venom PLA 2 s that belong to group I and II sPLA 2 s, are capable of releasing fatty acids non-selectively. However, recent lipidomics-based evaluation of the substrate specificity of sPLA 2 s toward natural membranes (see above) has revealed that several sPLA 2 s can distinguish sn-2 fatty acyl moieties in phospholipids under physiologically relevant conditions. In general terms, sPLA 2 -IB, -IIA and -IIE do not discriminate fatty acid species, sPLA 2 -V tends to prefer those with a lower degree of unsaturation such as oleic acid (OA; C18:1), and sPLA 2 -IID, -IIF, -III and -X tend to prefer PUFAs including AA and DHA. Several sPLA 2 s can also distinguish differences in the polar head groups of phospholipids. For instance, sPLA 2 -X is very active on PC, while sPLA 2 -IIA has much higher affinity for PE than for PC, and this substrate selectivity has been partly ascribed to their crystal structures. 103),104) Therefore, in order to comprehensively understand the specific biological roles of this enzyme family, it is important to consider when and where different sPLA 2 s are expressed, which isoforms are involved in what types of pathophysiology, why they are needed, and how they exhibit their unique functions by driving specific types of lipid metabolism.

Classical sPLA 2 s. sPLA 2 -IB, also known as "pancreatic sPLA 2 ", is synthesized as an inactive zymogen in the pancreas, and its N-terminal propeptide is cleaved by trypsin to yield an active enzyme in the duodenum. 101) The main role of sPLA 2 -IB is to digest dietary and biliary phospholipids in the intestinal lumen. Perturbation of this process by gene disruption or pharmacological inhibition of sPLA 2 -IB leads to resistance to diet-induced obesity, insulin resistance, and atherosclerosis due to decreased phospholipid digestion and absorption in the gastrointestinal tract. 105)-108) The human PLA2G1B gene maps to an obesity-susceptible locus. 109) sPLA 2 -IIA is often referred to as "inflammatory sPLA 2 ", since its expression is induced by proinflammatory cytokines such as TNF, and IL-1O or by bacterial products such as lipopolysaccharide. 110) In mice, however, sPLA 2 -IIA in mice is distributed only in intestinal Paneth cells (in BALB/c, C3H, NZB and DBA, etc.) or not expressed at all due to a natural frameshift mutation (in C57BL/6, A/J, C58/ J, P/J, 129/Sv and B10.RIII, etc.). 111),112) The bestknown physiological function of sPLA 2 -IIA is the degradation of bacterial membranes, thereby providing the first line of antimicrobial defense in the host. 113),114) Consistent with this, sPLA 2 -IIA preferentially hydrolyzes PE and phosphatidylglycerol, which are enriched in bacterial membranes. Under sterile conditions, sPLA 2 -IIA attacks phospholipids in microparticles, particularly those in extracellular mitochondria (an organelle that evolutionally originated from bacteria), which are released from activated platelets or leukocytes at inflamed sites. 115) Hydrolysis of microparticular phospholipids by sPLA 2 -IIA results in production of pro-inflammatory eicosanoids and lysophospholipids as well as in release of mitochondrial DNA as a danger-associated molecular pattern (DAMP). Thus, sPLA 2 -IIA is primarily involved in host defense by killing bacteria and triggering innate immunity, while over-amplification of the response leads to exacerbation of inflammation.

sPLA 2 -IIA, -IIC, -IID, -IIE and -IIF are often classified into the group II subfamily (sPLA 2 -IIC is a pseudogene in human), since they share structural characteristics and map to the same chromosome locus. sPLA 2 -IID is constitutively expressed in dendritic cells (DCs) in lymphoid organs. sPLA 2 -IID is an "immunosuppressive sPLA 2 " that attenuates DC-mediated adaptive immunity by hydrolyzing PE probably in microparticles to mobilize antiinflammatory B3 PUFAs and their metabolites such as resolvin D1 (RvD1). 7) As such, sPLA 2 -IID-null mice exhibit more severe contact hypersensitivity and psoriasis, whereas they are protected against infection and cancer because of enhanced anti-viral and anti-tumor immunity. 7),116),117) Unlike sPLA 2 -IIA, which is stimulus-inducible (see above), sPLA 2 -IID is downregulated by pro-inflammatory stimuli, consistent with its anti-inflammatory role.

In mice, sPLA 2 -IIE instead of sPLA 2 -IIA is upregulated in several tissues under inflammatory or other conditions. sPLA 2 -IIE is expressed in hair follicles in association with the growth phase of the hair cycle 118) and induced in adipose tissue in association with obesity in mice. 119) sPLA 2 -IIE hydrolyzes PE without apparent fatty acid selectivity in hair follicles and lipoproteins, and accordingly, sPLA 2 -IIE-deficient mice display subtle abnormalities in hair follicles 118) and are modestly protected from diet-induced obesity and hyperlipidemia. 119) sPLA 2 -IIF has a long C-terminal extension containing a free cysteine, which might contribute to formation of a homodimer, and is more hydrophobic than other sPLA 2 s. 120) Physiologically, sPLA 2 -IIF is an "epidermal sPLA 2 " that is expressed predominantly in the upper epidermis and induced by IL-22, a Th17 cytokine, in psoriatic skin. 6) sPLA 2 -IIF preferentially hydrolyzes PUFA-containing plasmalogen-type PE in keratinocyte-secreted phospholipids to produce plasmalogen-type lysophosphatidylethanolamine (P-LPE; lysoplasmalogen), which in turn promotes epidermal hyperplasia (Fig. 7A-C) . Accordingly, sPLA 2 -IIF-null mice are protected against epidermal-hyperplasic diseases such as psor- iasis and skin cancer, while sPLA 2 -IIF-transgenic mice spontaneously develop psoriasis-like skin. 6) Although sPLA 2 -V was previously thought to be a regulator of AA metabolism, 121), 122) it is now becoming obvious that this sPLA 2 has a preference for phospholipids having fatty acids with a lower degree of unsaturation. sPLA 2 -V is markedly induced in adipocytes during obesity as a "metabolic sPLA 2 " and hydrolyzes PC in hyperlipidemic LDL to release OA and to a lesser extent LA, which counteract adipose tissue inflammation and thereby ameliorates obesity-associated metabolic disorders. 119) Transgenic overexpression of sPLA 2 -V, but not other sPLA 2 s, results in neonatal death due to a respiratory defect, which is attributable to the ability of sPLA 2 -V to potently hydrolyze PC with palmitic acid (PA, C16:0), a major component of lung surfactant. 123) This unique substrate preference of sPLA 2 -V has also been supported by a recent lipidomics analysis of the spleen (a tissue where sPLA 2 -V is abundantly expressed), in which the levels of fatty acids with a lower degree of unsaturation (e.g. PA, OA and LA), rather than PUFAs (AA, EPA and DHA), are significantly reduced in sPLA 2 -V-deficient mice relative to wild-type mice (Fig. 8) . This is in contrast to the spleen of sPLA 2 -IID-deficient mice, in which B3 PUFAs and their metabolites are selectively diminished, 7) revealing distinct lipoquality regulation 0.0E+00 2.0E+08 4.0E+08 6.0E+08 8.0E+08 , were significantly reduced in sPLA 2 -V-deficient mice relative to control mice. Accordingly, LA metabolites, including 9-and 13-hydroxyoctadecadienoic acids (HODEs) among others, were substantially decreased in mutant mice relative to control mice, whereas none of the AA, EPA and DHA metabolites differed significantly between the genotypes. These results are consistent with the view that sPLA 2 -V has a propensity to preferentially hydrolyze phospholipids having sn-2 fatty acids with a lower degree of unsaturation, as illustrated at right bottom.

by different sPLA 2 s. Another intriguing feature of sPLA 2 -V is that it is the only "Th2-prone sPLA 2 " induced in M2 macrophages by the Th2 cytokines IL-4 and IL-13 and promotes Th2-driven pathology such as asthma. Gene ablation of sPLA 2 -V perturbs proper polarization and function of M2 macrophages in association with decreased Th2 immunity, 124) although the underlying lipid metabolism responsible for this event remains obscure. Probably because of this alteration in the macrophage phenotype, sPLA 2 -V-null macrophages have a reduced ability to phagocytose extracellular materials. Accordingly, sPLA 2 -V-null mice are more susceptible to fungal infection and arthritis due to defective clearance of hazardous fungi and immune complexes, respectively. 125),126) Likewise, sPLA 2 -V-null mice suffer from more severe lung inflammation caused by bacterial or viral infection, 127) which could also be explained by poor clearance of these microbes by alveolar macrophages. Among the mammalian sPLA 2 s, sPLA 2 -X has the highest affinity for PC leading to release of fatty acids, with an apparent tendency for PUFA preference. sPLA 2 -X is activated by cleavage of the Nterminal propeptide by furin-type convertases. 128) sPLA 2 -X is expressed abundantly in colorectal epithelial and goblet cells and has a protective role in colitis by mobilizing anti-inflammatory B3 PUFAs. 24) Consistently, sPLA 2 -X-transgenic mice exhibit global anti-inflammatory phenotypes in association with elevation of systemic B3 PUFA levels. 24) In the process of reproduction, sPLA 2 -X secreted from the acrosomes of activated spermatozoa hydrolyzes sperm membrane phospholipids to release DHA and docosapentaenioc acid (DPA, C22:5), the latter facilitating fertilization. 24),129) Additionally, sPLA 2 -X-null mice are protected from asthma, accompanied by decreased levels of pulmonary B6 AA-derived eicosanoids. 130) Unlike the situation in sPLA 2 -V-null mice (see above), however, the Th2 response per se is not affected in the asthma model 131) and the lung damage is milder following influenza infection 132) in sPLA 2 -X-null mice, illustrating the distinct actions of different sPLA 2 s in the same tissue.

Atypical sPLA 2 s. sPLA 2 -III is unusual in that it consists of three domains, in which the central sPLA 2 domain similar to bee venom group III sPLA 2 is flanked by large and unique N-and Cterminal domains. 133) The enzyme is processed to the sPLA 2 domain-only form that retains full enzymatic activity. 134) Although sPLA 2 -III does not discriminate the polar head groups, it tends to prefer sn-2 PUFAs in the substrate phospholipids. sPLA 2 -III is expressed in the epididymal epithelium and acts on immature sperm cells passing through the epididymal duct in a paracrine manner to allow sperm membrane phospholipid remodeling, a process that is prerequisite for sperm motility. 135) sPLA 2 -III is also secreted from mast cells and acts on microenvironmental fibroblasts to produce PGD 2 , which in turn promotes proper maturation of mast cells. 136) Accordingly, mice lacking sPLA 2 -III exhibit male hypofertility and reduced anaphylactic responses.

sPLA 2 -XIIA is evolutionally far distant from other sPLA 2 s. 137) sPLA 2 -XIIA is expressed in many tissues at relatively high levels, yet its enzymatic activity is weaker than that of other sPLA 2 s. The properties and physiological roles of sPLA 2 -XIIA are currently unclear and await future studies using sPLA 2 -XIIA-deficient mice. Apart from lipoquality regulation, sPLA 2 -XIIB is a catalytically inactive protein due to substitution of the catalytic center histidine by leucine. 138) sPLA 2 -XIIB deficiency impairs hepatic lipoprotein secretion, 139) although the mechanism is unclear.

Beyond the lipoquality control by sPLA 2 s, several sPLA 2 s binds to sPLA 2 receptor (PLA2R1, also known as the C-type lectin Clec13c) with different affinities. 140) In mice, PLA2R1 binds to sPLA 2 -IB, -IIA, -IIE, -IIF and -X with high affinity, sPLA 2 -V with moderate affinity, and sPLA 2 -IID, -III and -XIIA with low or no affinity. 138) PLA2R1 is homologous to sPLA 2 -inhibitory proteins present in snake plasma and exists as an integral membrane protein or as a soluble protein resulting from shedding or alternative splicing. PLA2R1 may act as a clearance receptor or endogenous inhibitor that inactivates sPLA 2 s, as a signaling receptor that transduces sPLA 2 -dependent signals in a catalytic activity-independent manner, or as a pleiotropic receptor that binds to non-sPLA 2 ligands. In support of its clearance role, Pla2r1 !/! mice show more severe asthma, likely due to defective clearance of pro-asthmatic sPLA 2 -X. 141) In support of its signaling role, PLA2R1, probably through binding to myocardial sPLA 2 s or other ways, promotes the migration and growth of myofibroblasts and thereby protects against cardiac rupture in a model of myocardial infarction. 142) PLA2R1 has recently attracted attention as a major autoantigen in membranous nephropathy, a severe autoimmune disease leading to podocyte injury and proteinuria, 143) although it is not clear whether this role of PLA2R1 is sPLA 2dependent or -independent.

By applying lipidomics approaches to knockout or transgenic mice for various PLA 2 s, it has become evident that individual enzymes regulate specific forms of lipid metabolism, perturbation of which can be eventually linked to distinct pathophysiological outcomes. Knowledge of lipoquality control by individual PLA 2 s acquired from studies using animal models should be translated to humans. Current knowledges on the relationship between PLA 2 gene mutations and human diseases are summarized in Table 2 . Nonetheless, future development of more comprehensive and highly sensitive lipidomics techniques will contribute to the discovery of novel PLA 2driven lipid pathways that could be biomarkers or druggable targets for particular diseases. Nakanishi, H., Ikeda, K., Taguchi, R., Kabashima 

Deletion of cytosolic phospholipase A 2 promotes striated muscle growth

Lipid signaling in cytosolic phospholipase A 2 ,-cyclooxygenase-2 cascade mediates cerebellar longterm depression and motor learning

Acute lung injury by sepsis and acid aspiration: a key role for cytosolic phospholipase A 2

Cytosolic phospholipase A 2 ,-deficient mice are resistant to collagen-induced arthritis

An essential role of cytosolic phospholipase A 2 , in prostaglandin E 2 -mediated bone resorption associated with inflammation

Cytosolic phospholipase A 2 ,-deficient mice are resistant to experimental autoimmune encephalomyelitis

Phospholipase A 2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease

Group X secreted phospholipase A 2 releases B3 polyunsaturated fatty acids, suppresses colitis, and promotes sperm fertility

Cysteinyl leukotrienes regulate Th2 celldependent pulmonary inflammation

Leukotriene B 4 receptor BLT1 mediates early effector T cell recruitment

Prostaglandin D 2 as a mediator of allergic asthma

Dual roles of PGE 2 -EP4

Prostaglandin E 2 -EP4 signaling promotes immune inflammation through Th1 cell differentiation and Th17 cell expansion

Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc "716 knockout mice

Involvement of prostaglandin E 2 in production of amyloid-O peptides both in vitro and in vivo

The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut

Mapping the human platelet lipidome reveals cytosolic phospholipase A 2 as a regulator of mitochondrial bioenergetics during activation

The enteropathy of prostaglandin deficiency

Inherited human cPLA 2 , deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction

Interfacial kinetic and binding properties of mammalian group IVB phospholipase A 2 (cPLA 2 O) and comparison with the other cPLA 2 isoforms

A novel calcium-independent phospholipase A 2 , cPLA 2 ., that is prenylated and contains homology to cPLA 2

Cloning of a gene for a novel epithelium-specific cytosolic phospholipase A 2 , cPLA 2 /, induced in psoriatic skin

A calcium-dependent acyltransferase that produces N-acyl phosphatidylethanolamines

Function, activity, and membrane targeting of cytosolic phospholipase A 2 1 in mouse lung fibroblasts

Mammalian patatin domain containing proteins: a family with diverse lipolytic activities involved in multiple biological functions

Recent progress in phospholipase A 2 research: from cells to animals to humans

A novel cytosolic calcium-independent phospholipase A 2 contains eight ankyrin motifs

Multiple splice variants of the human calcium-independent phospholipase A 2 and their effect on enzyme activity

Cyclooxygenase-2 mediated oxidation of 2-arachidonoyl-lysophospholipids identifies unknown lipid signaling pathways

Activation of mitochondrial calcium-independent phospholipase A 2 . (iPLA 2 .) by divalent cations mediating arachidonate release and production of downstream eicosanoids

Identification of an insulin-regulated lysophospholipase with homology to neuropathy target esterase

Evidence that mouse brain neuropathy target esterase is a lysophospholipase

Genetic ablation of calcium-independent phospholipase A 2 . prevents obesity and insulin resistance during high fat feeding by mitochondrial uncoupling and increased adipocyte fatty acid oxidation

Loss of function variants in human PNPLA8 encoding calcium-independent phospholipase A 2 . recapitulate the mitochondriopathy of the homologous null mouse

Loss-offunction mutations in PNPLA6 encoding neuropathy target esterase underlie pubertal failure and neurological deficits in Gordon Holmes syndrome

Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness

Impairment of PARK14-dependent Ca 2D signalling is a novel determinant of Parkinson's disease

Male mice that do not express group VIA phospholipase A 2 produce spermatozoa with impaired motility and have greatly reduced fertility

Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase

Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase

Adipose triglyceride lipase contributes to cancer-associated cachexia

The G 0 /G 1 switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase

ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-, and PGC-1

Lipolysis -a highly regulated multienzyme complex mediates the catabolism of cellular fat stores

Biochemistry and pathophysiology of intravascular and intracellular lipolysis

Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease

Chronic overexpression of PNPLA3 I148M in mouse liver causes hepatic steatosis

A feedforward loop amplifies nutritional regulation of PNPLA3

Identification of a novel keratinocyte retinyl ester hydrolase as a transacylase and lipase

Neutral lipid stores and lipase PNPLA5 contribute to autophagosome biogenesis

has a crucial role in skin barrier function by directing acylceramide biosynthesis

PNPLA1 is a transacylase essential for the generation of the skin barrier lipid B-O-acylceramide

Intracellular PAFacetylhydrolase type I

Intracellular plateletactivating factor acetylhydrolase, type II: A unique cellular phospholipase A 2 that hydrolyzes oxidatively modified phospholipids

Brain acetylhydrolase that inactivates plateletactivating factor is a G-protein-like trimer

Targeted disruption of intracellular type I platelet activating factor-acetylhydrolase catalytic subunits causes severe impairment in spermatogenesis

Protection against oxidative stress-induced hepatic injury by intracellular type II platelet-activating factor acetylhydrolase by metabolism of oxidized phospholipids in vivo

Antiinflammatory properties of a platelet-activating factor acetylhydrolase

Inhibition of lipoprotein-associated phospholipase A 2 reduces complex coronary atherosclerotic plaque development

Phospholipase A 2 inhibitors in atherosclerosis: the race is on

Deficiency of phospholipase A 2 group 7 decreases intestinal polyposis and colon tumorigenesis in Apc Min/D mice

Lysosomal phospholipase A 2 is selectively expressed in alveolar macrophages

Lysosomal phospholipase A 2 and phospholipidosis

Role for lysosomal phospholipase A 2 in iNKT cell-mediated CD1d recognition

Lysosomal phospholipase A 2 : a novel player in host immunity to Mycobacterium tuberculosis

Generation of N-acylphosphatidylethanolamine by members of the phospholipase A/acyltransferase

AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency

Pla2g16 phospholipase mediates gain-of-function activities of mutant p53

LRAT-specific domain facilitates vitamin A metabolism by domain swapping in HRASLS3

Interaction of phospholipase A/ acyltransferase-3 with Pex19p: a possible involvement in the down-regulation of peroxisomes

represents a switch between entry and clearance of Picornaviridae

In vivo metabolite profiling as a means to identify uncharacterized lipase function: recent success stories within the alpha beta hydrolase domain (ABHD) enzyme family

Metabolomics annotates ABHD3 as a physiologic regulator of mediumchain phospholipids

ABHD4 regulates multiple classes of N-acyl phospholipids in the mammalian central nervous system

The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors

The serine hydrolase ABHD6 Is a critical regulator of the metabolic syndrome

The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase , mediates retrograde suppression of synaptic transmission

Fever is mediated by conversion of endocannabinoid 2-arachidonoylglycerol to prostaglandin E 2

Immunomodulatory lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay

ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC

Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome

A new era of secreted phospholipase A 2

The roles of the secreted phospholipase A 2 gene family in immunology

Pancreatic phospholipase A 2 : isolation of the human gene and cDNAs from porcine pancreas and human lung

Cloning and recombinant expression of phospholipase A 2 present in rheumatoid arthritic synovial fluid

Crystal structure of human group X secreted phospholipase A 2 . Electrostatically neutral interfacial surface targets zwitterionic membranes

Structures of free and inhibited human secretory phospholipase A 2 from inflammatory exudate

Protection against diet-induced obesity and obesity-related insulin resistance in Group 1B PLA 2 -deficient mice

Group 1B phospholipase A 2 -mediated lysophospholipid absorption directly contributes to postprandial hyperglycemia

The phospholipase A 2 inhibitor methyl indoxam suppresses diet-induced obesity and glucose intolerance in mice

Group 1B phospholipase A 2 inactivation suppresses atherosclerosis and metabolic diseases in LDL receptor-deficient mice

Linkage and potential association of obesity-related phenotypes with two genes on chromosome 12q24 in a female dizygous twin cohort

Phospholipase A 2 -a mediator between proximal and distal effectors of inflammation

A natural disruption of the secretory group II phospholipase A 2 gene in inbred mouse strains

The secretory phospholipase A 2 gene is a candidate for the Mom1 locus, a major modifier of Apc Min -induced intestinal neoplasia

Mobilization of potent plasma bactericidal activity during systemic bacterial challenge. Role of group IIA phospholipase A 2

Staphylococcus aureus adenosine inhibits sPLA 2 -IIA-mediated host killing in the airways

Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A 2 to promote inflammation

Dual roles of group IID phospholipase A 2 in inflammation and cancer

Critical role of phospholipase A 2 group IID in age-related susceptibility to severe acute respiratory syndrome-CoV infection

Expression and function of group IIE phospholipase A 2 in mouse skin

The adipocyte-inducible secreted phospholipases PLA2G5 and PLA2G2E play distinct roles in obesity

On the diversity of secreted phospholipases A 2 . Cloning, tissue distribution, and functional expression of two novel mouse group II enzymes

The functions of five distinct mammalian phospholipase A 2 s in regulating arachidonic acid release. Type IIa and type V secretory phospholipase A 2 s are functionally redundant and act in concert with cytosolic phospholipase A 2

Regulation of delayed prostaglandin production in activated P388D1 macrophages by group IV cytosolic and group V secretory phospholipase A 2 s

Transgenic expression of group V, but not group X, secreted phospholipase A 2 in mice leads to neonatal lethality because of lung dysfunction

Group V secretory phospholipase A 2 is involved in macrophage activation and is sufficient for macrophage effector functions in allergic pulmonary inflammation

Group V secretory phospholipase A 2 modulates phagosome maturation and regulates the innate immune response against Candida albicans

A novel anti-inflammatory role for secretory phospholipase A 2 in immune complexmediated arthritis

Group V phospholipase A 2 in bone marrowderived myeloid cells and bronchial epithelial cells promotes bacterial clearance after Escherichia coli pneumonia

Group X secreted phospholipase A 2 proenzyme is matured by a furin-like proprotein convertase and releases arachidonic acid inside of human HEK293 cells

Group X phospholipase A 2 is released during sperm acrosome reaction and controls fertility outcome in mice

Importance of group X-secreted phospholipase A 2 in allergen-induced airway inflammation and remodeling in a mouse asthma model

Key role of group v secreted phospholipase A 2 in Th2 cytokine and dendritic celldriven airway hyperresponsiveness and remodeling

Lack of group X secreted phospholipase A 2 increases survival following pandemic H1N1 influenza infection

Novel human secreted phospholipase A 2 with homology to the group III bee venom enzyme

Cellular arachidonate-releasing function of novel classes of secretory phospholipase A 2 s (groups III and XII)

Group III secreted phospholipase A 2 regulates epididymal sperm maturation and fertility in mice

Mast cell maturation is driven via a group

Cloning and recombinant expression of a structurally novel human secreted phospholipase A 2

Novel mammalian group XII secreted phospholipase A 2 lacking enzymatic activity

Hepatocyte nuclear factor-4, regulates liver triglyceride metabolism in part through secreted phospholipase A 2 GXIIB

Biochemistry and physiology of mammalian secreted phospholipases A 2

Deficiency of phospholipase A 2 receptor exacerbates ovalbumin-induced lung inflammation

Circulating levels of secretory type II phospholipase A 2 predict coronary events in patients with coronary artery disease

Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy

Efficient phagocytosis requires triacylglycerol hydrolysis by adipose triglyceride lipase

Desnutrin/ ATGL activates PPAR/ to promote mitochondrial function for insulin secretion in islet O cells

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

Patatin-like phospholipase domain-containing 3/ adiponutrin deficiency in mice is not associated with fatty liver disease

Brainspecific deletion of neuropathy target esterase/ swisscheese results in neurodegeneration

Group VIB calcium-independent phospholipase A 2 (iPLA 2 .) regulates platelet activation, hemostasis and thrombosis in mice

Mitochondrial dysfunction and reduced prostaglandin synthesis in skeletal muscle of Group VIB Ca 2D -independent phospholipase A 2 .-deficient mice

Mice deficient in group VIB phospholipase A 2 (iPLA 2 .) exhibit relative resistance to obesity and metabolic abnormalities induced by a Western diet

Genetic ablation of calcium-independent phospholipase A 2 . leads to alterations in hippocampal cardiolipin content and molecular species distribution, mitochondrial degeneration, autophagy, and cognitive dysfunction

Genetic ablation of calcium-independent phospholipase A 2 . leads to alterations in mitochondrial lipid metabolism and function resulting in a deficient mitochondrial bioenergetic phenotype

Smooth muscle cell arachidonic acid release, migration, and proliferation are markedly attenuated in mice null for calcium-independent phospholipase A 2 O

Age-related changes in bone morphology are accelerated in group VIA phospholipase A 2 (iPLA 2 O)-null mice

Neuroaxonal dystrophy caused by group VIA phospholipase A 2 deficiency in mice: a model of human neurodegenerative disease

Group VIA phospholipase A 2 in both host and tumor cells is involved in ovarian cancer development

Platelet-activating factor and metastasis: calciumindependent phospholipase A 2 O deficiency protects against breast cancer metastasis to the lung

Loss of PAFAH1B2 reduces amyloid-O generation by promoting the degradation of amyloid precursor protein C-terminal fragments

PAF-AH catalytic subunits modulate the Wnt pathway in developing GABAergic neurons

Increase of smooth muscle cell migration and of intimal hyperplasia in mice lacking the ,/O hydrolase domain containing 2 gene

Age-related pulmonary emphysema in mice lacking ,/O hydrolase domain containing 2 gene

Skin barrier development depends on CGI-58 protein expression during late-stage keratinocyte differentiation

Growth retardation, impaired triacylglycerol catabolism, hepatic steatosis, and lethal skin barrier defect in mice lacking comparative gene identification-58 (CGI-58)

/O-hydrolase domain 6 deletion induces adipose browning and prevents obesity and type 2 diabetes

Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A 2 -IIA

Secreted phospholipases A 2 are intestinal stem cell niche factors with distinct roles in homeostasis, inflammation, and cancer

Secretory group V phospholipase A 2 regulates acute lung injury and neutrophilic inflammation caused by LPS in mice

Group v secretory phospholipase A 2 promotes atherosclerosis: evidence from genetically altered mice

Group V secretory phospholipase A 2 plays a pathogenic role in myocardial ischaemia-reperfusion injury

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

Group X secretory phospholipase A 2 regulates insulin secretion through a cyclooxygenase-2-dependent mechanism

Group X secretory phospholipase A 2 enhances TLR4 signaling in macrophages

Group X secreted phospholipase A 2 limits the development of atherosclerosis in LDL receptor-null mice

Group X secretory phospholipase A 2 augments angiotensin II-induced inflammatory responses and abdominal aortic aneurysm formation in apoE-deficient mice

Group X secretory PLA 2 in neutrophils plays a pathogenic role in abdominal aortic aneurysms in mice

mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans

The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy

Neuropathy target esterase gene mutations cause motor neuron disease

Genetic associations of nonsynonymous exonic variants with psychophysiological endophenotypes

Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi

Lipoprotein-associated phospholipase A 2 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

Tagging-SNP haplotype analysis of the secretory PLA 2 IIa gene PLA2G2A shows strong association with serum levels of sPLA 2 IIa: results from the UDACS study

Phospholipase A 2 group IIA expression in gastric adenocarcinoma is associated with prolonged survival and less frequent metastasis

A novel polymorphism in secretory phospholipase A 2 -IID is associated with body weight loss in chronic obstructive pulmonary disease

Phospholipase A 2 group III and group X have opposing associations with prognosis in colorectal cancer

a gene involved in oxidative stress induced death, is associated with Alzheimer's disease

Tagging SNP haplotype analysis of the secretory PLA 2 -V gene, PLA2G5, shows strong association with LDL and oxLDL levels, suggesting functional distinction from sPLA 2 -IIA: results from the UDACS study

Biallelic mutations in PLA2G5, encoding group V phospholipase A 2 , cause benign fleck retina