Printer Friendly

Lipoquality control by phospholipase [A.sub.2] enzymes.

1. Introduction

In terms of signal transduction, the phospholipase [A.sub.2] ([PLA.sub.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.sub.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.sub.2]-driven lipid mediators (Fig. 2A, B). More recently, a novel class of anti-inflammatory lipid mediators derived from [omega]3 PUFAs, such as eicosa-pentaenoic 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.sub.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.sub.2] enzymes recognize such differences in the fatty acyl and/or head group moieties in their substrate phospholipids. Moreover, several enzymes in the [PLA.sub.2] family also catalyze the phospholipase [A.sub.1] ([PLA.sub.1]), lysophospholipase, neutral lipid lipase, or even transacylase/ acyltransferase reaction rather than or in addition to the genuine [PLA.sub.2] reaction. Therefore, the fatty acids and lysophospholipids released by different [PLA.sub.2] s are not always identical; rather, in many situations, specific fatty acids and lysophosholipids can be released by a particular [PLA.sub.2] in the presence of a given microenvironmental cue. In this context, [PLA.sub.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.sub.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.sub.2] enzymes in the context of lipoquality.

2. Substrate specificity of [PLA.sub.2]s; a general view

Obviously, the substrate specificity of individual [PLA.sub.2]s is the critical determinant of lipoquality. The in vitro enzymatic activity of [PLA.sub.2]s may be influenced by the assay conditions employed, such as the composition of the substrate phospholipids, concentrations of [PLA.sub.2]s and substrates, presence of detergents, and pH. Hence, the enzymatic properties of individual [PLA.sub.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 phospho-lipid species may not always reflect the true enzymatic properties of a given [PLA.sub.2]. Addition of an excess amount of recombinant or purified [PLA.sub.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.sub.2] assay kit, in which a synthetic, chromophoric phospholipid is used as a substrate, should be interpreted carefully, since some [PLA.sub.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.sub.2]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.sub.2] knockout and/or transgenic mice (see below). Importantly, the mobilization of distinct lipids by [PLA.sub.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.sub.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.sub.2]s in the context of lipoquality. The classification, distributions, properties and functions of individual [PLA.sub.2]s, whose pathophysiological functions have currently been studied using their gene-manipulated mice, are summarized in Table 1.

3. Lipoquality control by intracellular [PLA.sub.2]s

The c[PLA.sub.2] family. The cytosolic [PLA.sub.2] (c[PLA.sub.2]) family comprises 6 isoforms ([alpha]-[zeta]), among which c[PLA.sub.2][beta], [delta], [epsilon] and [zeta] map to the same chromosomal locus (Fig. 3A). (8) c[PLA.sub.2][alpha] (also known as group IVA [PLA.sub.2]) is undoubtedly the best known [PLA.sub.2] and its biological roles in association with lipoquality have been well documented. (9) c[PLA.sub.2][alpha] is the only [PLA.sub.2] that shows a striking substrate specificity for AA-containing phospholipids. Strictly speaking, c[PLA.sub.2][alpha] can also hydrolyze phospholipids containing EPA, yet the low abundance of this [omega]3 PUFA relative to other fatty acids including [omega]6 AA in cell membranes allows c[PLA.sub.2][alpha] to release AA rather specifically in most situations. Upon cell activation, c[PLA.sub.2][alpha] 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 [micro]M range of cytosolic [Ca.sup.2+] concentration, and is maximally activated by phosphorylation through mitogen-activated protein kinases (MAPKs) and other kinases. (10,11) In addition, the phosphoinositide PIP2 and ceramide-1-phosphate modulate the subcellular localization and activation of c[PLA.sub.2][alpha]. (12,13) The AA released by c[PLA.sub.2][alpha] 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 c[PLA.sub.2][alpha] display a number of phenotypes that can be explained by reductions of PGs and/or LTs. Under physiological conditions, c[PLA.sub.2][alpha]-deficient mice display a hemorrhagic tendency, impaired female reproduction, gastrointestinal ulcer, and renal malfunction, among others. (14-18) Under pathological conditions, c[PLA.sub.2][alpha]-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 c[PLA.sub.2][alpha] lies upstream of eicosanoid biosynthesis in many situations. For instance, as is the case for c[PLA.sub.2][alpha]-deficient mice, mice lacking [LTC.sub.4] synthase ([LTC.sub.4]S), [LTD.sub.4] receptor (CysLT1), [LTB.sub.4] receptor (BLT1), or [PGD.sub.2] receptor (DP1) are protected from asthma, (25-27) revealing the critical role of the c[PLA.sub.2][alpha]-[LTB.sub.4]/[LTC.sub.4]/[PGD.sub.2] axis in this allergic disease. Likewise, the decrease of [PGE.sub.2] in c[PLA.sub.2][alpha]-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.sub.2] synthase (mPGES-1) or either of the four [PGE.sub.2] receptors (EP1~4). (28-32) Furthermore, c[PLA.sub.2][alpha]-triggered release of AA by platelets is coupled not only with biosynthesis of the pro-thrombotic eicosanoid thromboxane [A.sub.2] ([TXA.sub.2]), but also with [beta]-oxidation-mediated bioenergetics for blood clotting. (33) Importantly, inherited human c[PLA.sub.2][alpha] mutations are associated with reduced eicosanoid biosynthesis, platelet dysfunction, and intestinal ulceration, (34,35) thus mimicking c[PLA.sub.2][alpha] deletion in mice.

On the other hand, the enzymatic activities and biological functions of c[PLA.sub.2] isoforms other than c[PLA.sub.2][alpha] have remained largely unknown. Reportedly, c[PLA.sub.2][beta] (group IVB [PLA.sub.2]), which has a unique JimC domain in the N-terminal region, display [PLA.sub.1], [PLA.sub.2] and lysophospholipase activities. (36) c[PLA.sub.2][gamma]. (group IVC [PLA.sub.2]), which uniquely lacks the C2 domain characteristic of the c[PLA.sub.2] family, is C-terminally farnesylated and possesses lysophospholipase and transacylase activities in addition to [PLA.sub.2] activity. (37) c[PLA.sub.2][delta] (group IVD [PLA.sub.2]), whose expression is elevated in human psoriatic skin, (38) shows [PLA.sub.1] activity in preference to [PLA.sub.2] activity. (36) c[PLA.sub.2][epsilon] (group IVE [PLA.sub.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) c[PLA.sub.2][zeta] (group IVF [PLA.sub.2]) displays both [PLA.sub.1] and [PLA.sub.2] activities without fatty acid selectivity. (40) However, these enzymatic properties of c[PLA.sub.2][beta]-[zeta] 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 i[PLA.sub.2]/PNPLA family. The human genome encodes 9 [Ca.suP.2+]-independent [PLA.sub.2] (i[PLA.sub.2]) enzymes (Fig. 4). These enzymes are now more generally referred to as patatin-like phospholipase domain-containing lipases (PNPLA1~9), as all members in this family share a patatin domain, which was initially discovered in patatin (i[PLA.sub.2][alpha]), a potato protein. (41,42) Mammalian i[PLA.sub.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 (PNPLA6~9) act mainly on phospholipids (phospholipase type), whereas those lacking the N-terminal domain (PNPLA1~5) 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 i[PLA.sub.2]/PNPLA family in various forms of homeostatic lipid metabolism that are fundamental for life.

Among the i[PLA.sub.2]/PNPLA family, PNPLA9 (i[PLA.sub.2][beta], also known as group VIA [PLA.sub.2]) is the only isoform that acts primarily as a [PLA.sub.2] with poor fatty acid selectivity. (43,44) Although PNPLA8 (i[PLA.sub.2][gamma]. or group VIB [PLA.sub.2]) displays [PLA.sub.2] activity, it acts as a [PLA.sub.1] toward phospholipids bearing sn-2 PUFA. (45,46) Accordingly, hydrolysis of PUFA-bearing phospholipids by PNPLA8/i[PLA.sub.2][gamma] 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 (i[PLA.sub.2][delta]) and its closest paralog PNPLA7 (i[PLA.sub.2][theta]) 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/i[PLA.sub.2][beta] is also referred to as the parkinsonism-associated protein PARK14, whose mutations impair [Ca.sup.2+] signaling in dopaminergic neurons. (54) Apart from the metabolic and neurodegenerative phenotypes, the lack of PNPLA9/i[PLA.sub.2][beta] leads to male infertility through an unknown mechanism. (55)

PNPLA2 (i[PLA.sub.2][zeta]), 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 [beta]-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[alpha] or PPAR[delta], 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 (i[PLA.sub.2][epsilon]) 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 (i[PLA.sub.2][eta], 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 [omega]-hydroxy residue of ultra-longchain fatty acid in ceramide to form [omega]-O-acylceramide, a lipid component essential for skin barrier function. (68,69) Accordingly, genetic deletion or mutation of PNPLA1 hampers epidermal [omega]-O-acyl-ceramide 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.sub.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.sub.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.sub.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.sub.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.sub.2] (Lp-[PLA.sub.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.sub.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.sub.2] decreases intestinal polyposis and colon tumorigenesis in [Apc.sup.Min/+] mice, (78) suggesting an anti-tumorigenic role for PAF in this setting.

Lysosomal [PLA.sub.2]. Lysosomal [PLA.sub.2] ([LPLA.sub.2]), also known as group XV [PLA.sub.2], is homologous with lecithin cholesterol acyltransferase (LCAT) and catalytically active under mildly acidic conditions. (79) [LPLA.sub.2] hydrolyzes both sn-1 and sn-2 fatty acids in phospholipids and contributes to phospholipid degradation in lysosomes. Genetic deletion of [LPLA.sub.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.sub.2] (PLA2G16), display [PLA.sub.1] and [PLA.sub.2] activities, as well as acyltransferase activity that synthesizes N-acyl-PE, to various degrees. (83) PLA2G16 is highly expressed in adipocytes, and PLAAG16-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 [alpha]/[beta] 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) 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 [alpha]. (94) Interestingly, in the brain, the AA released from 2-AG by monoacylglycerol lipase, rather than that released from phospholipids by c[PLA.sub.2][alpha] (see above), is linked to the production of a pool of [PGE.sub.2] that promotes fever. (2,95) ABHD12 hydrolyzes lysophosphatidyl-serine (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.sub.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 PNPLA2-directed hydrolysis of triglycerides in lipid droplets by acting as an essential lipolytic cofactor. (98)

4. Lipoquality control by secreted [PLA.sub.2]s

General aspects. The secreted [PLA.sub.2] (s[PLA.sub.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 s[PLA.sub.2] family strictly hydrolyzes the sn-2 position of phospholipids, a feature that differs from intracellular [PLA.sub.2]s that often display [PLA.sub.1], lysophospholipase, lipase, or transacylase/acyltransferase activity (see above). Individual s[PLA.sub.2]s exhibit unique tissue and cellular distributions, suggesting their distinct biological roles. As s[PLA.sub.2]s are secreted and require [Ca.sup.2+] 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 s[PLA.sub.2]s have been detailed in several recent reviews. (5,100) Here, I describe several key features of lipoquality regulation by the s[PLA.sub.2] family.

In terms of the lipoquality, s[PLA.sub.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 s[PLA.sub.2]-IB and -IIA, two prototypic s[PLA.sub.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.sub.2]s that belong to group I and II s[PLA.sub.2]s, are capable of releasing fatty acids non-selectively. However, recent lipidomics-based evaluation of the substrate specificity of s[PLA.sub.2]s toward natural membranes (see above) has revealed that several s[PLA.sub.2]s can distinguish sn-2 fatty acyl moieties in phospholipids under physiologically relevant conditions. In general terms, s[PLA.sub.2]-IB, -IIA and -IIE do not discriminate fatty acid species, s[PLA.sub.2]-V tends to prefer those with a lower degree of unsaturation such as oleic acid (OA; C18:1), and s[PLA.sub.2]-IID, -IIF, -III and -X tend to prefer PUFAs including AA and DHA. Several s[PLA.sub.2]s can also distinguish differences in the polar head groups of phospholipids. For instance, s[PLA.sub.2]-X is very active on PC, while s[PLA.sub.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 s[PLA.sub.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 s[PLA.sub.2]s. s[PLA.sub.2]-IB, also known as "pancreatic s[PLA.sub.2]", is synthesized as an inactive zymogen in the pancreas, and its N-terminal propep-tide is cleaved by trypsin to yield an active enzyme in the duodenum. (101) The main role of s[PLA.sub.2]-IB is to digest dietary and biliary phospholipids in the intestinal lumen. Perturbation of this process by gene disruption or pharmacological inhibition of s[PLA.sub.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)

s[PLA.sub.2]-IIA is often referred to as "inflammatory s[PLA.sub.2]", since its expression is induced by pro-inflammatory cytokines such as TNF[alpha] and IL-1[beta] or by bacterial products such as lipopolysaccharide. (110) In mice, however, s[PLA.sub.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 best-known physiological function of s[PLA.sub.2]-IIA is the degradation of bacterial membranes, thereby providing the first line of antimicrobial defense in the host. (113,114) Consistent with this, s[PLA.sub.2]-IIA preferentially hydrolyzes PE and phosphatidylglycerol, which are enriched in bacterial membranes. Under sterile conditions, s[PLA.sub.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 s[PLA.sub.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, s[PLA.sub.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.

s[PLA.sub.2]-IIA, -IIC, -IID, -IIE and -IIF are often classified into the group II subfamily (s[PLA.sub.2]-IIC is a pseudogene in human), since they share structural characteristics and map to the same chromosome locus. s[PLA.sub.2]-IID is constitutively expressed in dendritic cells (DCs) in lymphoid organs. s[PLA.sub.2]-IID is an "immunosuppressive s[PLA.sub.2]" that attenuates DC-mediated adaptive immunity by hydrolyzing PE probably in microparticles to mobilize anti-inflammatory [omega]3 PUFAs and their metabolites such as resolvin D1 (RvD1). (7) As such, s[PLA.sub.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 s[PLA.sub.2]-IIA, which is stimulus-inducible (see above), s[PLA.sub.2]-IID is downregulated by pro-inflammatory stimuli, consistent with its anti-inflammatory role.

In mice, s[PLA.sub.2]-IIE instead of s[PLA.sub.2]-IIA is upregulated in several tissues under inflammatory or other conditions. s[PLA.sub.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) s[PLA.sub.2]-IIE hydrolyzes PE without apparent fatty acid selectivity in hair follicles and lipoproteins, and accordingly, s[PLA.sub.2]-IIE-deficient mice display subtle abnormalities in hair follicles (118) and are modestly protected from diet-induced obesity and hyperlipidemia. (119)

s[PLA.sub.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 s[PLA.sub.2]s. (120) Physiologically, s[PLA.sub.2]2-IIF is an "epidermal s[PLA.sub.2]2" that is expressed predominantly in the upper epidermis and induced by IL-22, a Th17 cytokine, in psoriatic skin. (6) s[PLA.sub.2]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, s[PLA.sub.2]-IIF-null mice are protected against epidermal-hyperplasic diseases such as psoriasis and skin cancer, while s[PLA.sub.2]-IIF-transgenic mice spontaneously develop psoriasis-like skin. (6)

Although s[PLA.sub.2]-V was previously thought to be a regulator of AA metabolism, (121,122) it is now becoming obvious that this s[PLA.sub.2] has a preference for phospholipids having fatty acids with a lower degree of unsaturation. s[PLA.sub.2]-V is markedly induced in adipocytes during obesity as a "metabolic s[PLA.sub.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 s[PLA.sub.2]-V, but not other s[PLA.sub.2]s, results in neonatal death due to a respiratory defect, which is attributable to the ability of s[PLA.sub.2]-V to potently hydrolyze PC with palmitic acid (PA, C16:0), a major component of lung surfactant. (123) This unique substrate preference of s[PLA.sub.2]-V has also been supported by a recent lipidomics analysis of the spleen (a tissue where s[PLA.sub.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 s[PLA.sub.2]-V-deficient mice relative to wild-type mice (Fig. 8). This is in contrast to the spleen of s[PLA.sub.2]-IID-deficient mice, in which [omega]3 PUFAs and their metabolites are selectively diminished, (7) revealing distinct lipoquality regulation by different s[PLA.sub.2]s. Another intriguing feature of s[PLA.sub.2]-V is that it is the only "Th2-prone s[PLA.sub.2]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 s[PLA.sub.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, s[PLA.sub.2]-V-null macrophages have a reduced ability to phagocytose extracellular materials. Accordingly, s[PLA.sub.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, s[PLA.sub.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 s[PLA.sub.2]s, s[PLA.sub.2]-X has the highest affinity for PC leading to release of fatty acids, with an apparent tendency for PUFA preference. s[PLA.sub.2]-X is activated by cleavage of the N-terminal propeptide by furin-type convertases. (128) s[PLA.sub.2]-X is expressed abundantly in colorectal epithelial and goblet cells and has a protective role in colitis by mobilizing anti-inflammatory [omega]3 PUFAs. (24) Consistently, s[PLA.sub.2]-X-transgenic mice exhibit global anti-inflammatory phenotypes in association with elevation of systemic [omega]3 PUFA levels. (24) In the process of reproduction, s[PLA.sub.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, s[PLA.sub.2]-X-null mice are protected from asthma, accompanied by decreased levels of pulmonary [omega]6 AA-derived eicosanoids. (130) Unlike the situation in s[PLA.sub.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 s[PLA.sub.2]-X-null mice, illustrating the distinct actions of different s[PLA.sub.2]s in the same tissue.

Atypical s[PLA.sub.2]s x s[PLA.sub.2]-III is unusual in that it consists of three domains, in which the central s[PLA.sub.2] domain similar to bee venom group III s[PLA.sub.2] is flanked by large and unique N- and C-terminal domains. (133) The enzyme is processed to the s[PLA.sub.2] domain-only form that retains full enzymatic activity. (134) Although s[PLA.sub.2]-III does not discriminate the polar head groups, it tends to prefer sn-2 PUFAs in the substrate phospholipids. s[PLA.sub.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) s[PLA.sub.2]-III is also secreted from mast cells and acts on microenvironmental fibroblasts to produce [PGD.sub.2], which in turn promotes proper maturation of mast cells. (136) Accordingly, mice lacking s[PLA.sub.2]-III exhibit male hypofertility and reduced anaphylactic responses.

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

s[PLA.sub.2] receptor. Beyond the lipoquality control by s[PLA.sub.2]s, several s[PLA.sub.2]s binds to s[PLA.sub.2] receptor (PLA2R1, also known as the C-type lectin Clec13c) with different affinities. (140) In mice, PLA2R1 binds to s[PLA.sub.2]-IB, -IIA, -IIE, -IIF and -X with high affinity, s[PLA.sub.2]-V with moderate affinity, and s[PLA.sub.2]-IID, -III and -XIIA with low or no affinity. (138) PLA2R1 is homologous to s[PLA.sub.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 s[PLA.sub.2]s, as a signaling receptor that transduces s[PLA.sub.2]-dependent signals in a catalytic activity-independent manner, or as a pleiotropic receptor that binds to non-s[PLA.sub.2] ligands. In support of its clearance role, [Pla2r1.sup.-/-] mice show more severe asthma, likely due to defective clearance of pro-asthmatic s[PLA.sub.2]-X. (141) In support of its signaling role, PLA2R1, probably through binding to myocardial s[PLA.sub.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 s[PLA.sub.2]-dependent or -independent.

5. Concluding remarks

By applying lipidomics approaches to knockout or transgenic mice for various [PLA.sub.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.sub.2]s acquired from studies using animal models should be translated to humans. Current knowledges on the relationship between [PLA.sub.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.sub.2]-driven lipid pathways that could be biomarkers or druggable targets for particular diseases.

doi: 10.2183/pjab.93.043

Acknowledgments

I sincerely thank my laboratory members at the University of Tokyo and the Tokyo Metropolitan Institute of Medical Sciences who have contributed their expertise to acquire a better understanding of [PLA.sub.2] biology. In particular, I thank Drs. Kei Yamamoto, Tetsuya Hirabayashi, Yoshitaka Taketomi, Hiroyasu Sato, Yoshimi Miki, Remi Murase, Seiko Masuda and Noriko Ueno among others for collecting the experimental data and information on which this review is based. In the interest of brevity, I have referenced other reviews whenever possible and apologize to the authors of the numerous original papers that were not explicitly cited. This work was supported by AMED-CREST from the Japan Agency for Medical Research and Development and by JSPS KAKENHI Grant Numbers JP15H05905 and JP16H02613.

References

(1) Shimizu, T. (2009) Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation. Annu. Rev. Pharmacol. Toxicol. 49, 123-150.

(2) Narumiya, S. and Furuyashiki, T. (2011) Fever, inflammation, pain and beyond: prostanoid receptor research during these 25 years. FASEB J. 25, 813-818.

(3) Serhan, C.N. (2014) Pro-resolving lipid mediators are leads for resolution physiology. Nature 510, 92-101.

(4) Aikawa, S., Hashimoto, T., Kano, K. and Aoki, J. (2015) Lysophosphatidic acid as a lipid mediator with multiple biological actions. J. Biochem. 157, 81-89.

(5) Yamamoto, K., Miki, Y., Sato, H., Murase, R., Taketomi, Y. and Murakami, M. (2017) Secreted phospholipase [A.sub.2] specificity on natural membrane phospholipids. Methods Enzymol. 583, 101-117.

(6) Yamamoto, K., Miki, Y., Sato, M., Taketomi, Y., Nishito, Y., Taya, C., Muramatsu, K., Ikeda, K., Nakanishi, H., Taguchi, R., Kambe, N., Kabashima, K., Lambeau, G., Gelb, M.H. and Murakami, M. (2015) The role of group IIF-secreted phospholipase [A.sub.2] in epidermal homeostasis and hyperplasia. J. Exp. Med. 212, 1901-1919.

(7) Miki, Y., Yamamoto, K., Taketomi, Y., Sato, H., Shimo, K., Kobayashi, T., Ishikawa, Y., Ishii, T., Nakanishi, H., Ikeda, K., Taguchi, R., Kabashima, K., Arita, M., Arai, H., Lambeau, G., Bollinger, J.M., Hara, S., Gelb, M.H. and Murakami, M. (2013) Lymphoid tissue phospholipase [A.sub.2] group IID resolves contact hypersensitivity by driving antiinflammatory lipid mediators. J. Exp. Med. 210, 1217-1234.

(8) Ohto, T., Uozumi, N., Hirabayashi, T. and Shimizu, T. (2005) Identification of novel cytosolic phospholipase [A.sub.2]s, murine c[PLA.sub.2][delta], [epsilon], and [zeta], which form a gene cluster with c[PLA.sub.2][beta]. J. Biol. Chem. 280, 24576-24583.

(9) Leslie, C.C. (2015) Cytosolic phospholipase [A.sub.2]: physiological function and role in disease. J. Lipid Res. 56, 1386-1402.

(10) Clark, J.D., Lin, L.L., Kriz, R.W., Ramesha, C.S., Sultzman, L.A., Lin, A.Y., Milona, N. and Knopf, J.L. (1991) A novel arachidonic acid-selective cytosolic [PLA.sub.2] contains a [Ca.sup.2+]-dependent translocation domain with homology to PKC and GAP. Cell 65, 1043-1051.

(11) Lin, L.L., Wartmann, M., Lin, A.Y., Knopf, J.L., Seth, A. and Davis, R.J. (1993) c[PLA.sub.2] is phosphorylated and activated by MAP kinase. Cell 72, 269-278.

(12) Casas, J., Gijon, M.A., Vigo, A.G., Crespo, M.S., Balsinde, J. and Balboa, M.A. (2006) Phosphatidylinositol 4,5-bisphosphate anchors cytosolic group IVA phospholipase [A.sub.2] to perinuclear membranes and decreases its calcium requirement for translocation in live cells. Mol. Biol. Cell 17, 155-162.

(13) Stahelin, R.V., Subramanian, P., Vora, M., Cho, W. and Chalfant, C.E. (2007) Ceramide-1-phosphate binds group IVA cytosolic phospholipase [A.sub.2] via a novel site in the C2 domain. J. Biol. Chem. 282, 20467-20474.

(14) Bonventre, J.V., Huang, Z., Taheri, M.R., O'Leary, E., Li, E., Moskowitz, M.A. and Sapirstein, A. (1997) Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase [A.sub.2]. Nature 390, 622-625.

(15) Uozumi, N., Kume, K., Nagase, T., Nakatani, N., Ishii, S., Tashiro, F., Komagata, Y., Maki, K., Ikuta, K., Ouchi, Y., Miyazaki, J. and Shimizu, T. (1997) Role of cytosolic phospholipase [A.sub.2] in allergic response and parturition. Nature 390, 618-622.

(16) Wong, D.A., Kita, Y., Uozumi, N. and Shimizu, T. (2002) Discrete role for cytosolic phospholipase [A.sub.2][alpha] in platelets: studies using single and double mutant mice of cytosolic and group IIA secretory phospholipase [A.sub.2]. J. Exp. Med. 196, 349-357.

(17) Haq, S., Kilter, H., Michael, A., Tao, J., O'Leary, E., Sun, X.M., Walters, B., Bhattacharya, K., Chen, X., Cui, L., Andreucci, M., Rosenzweig, A., Guerrero, J.L., Patten, R., Liao, R., Molkentin, J., Picard, M., Bonventre, J.V. and Force, T. (2003) Deletion of cytosolic phospholipase [A.sub.2] promotes striated muscle growth. Nat. Med. 9, 944-951.

(18) Le, T.D., Shirai, Y., Okamoto, T., Tatsukawa, T., Nagao, S., Shimizu, T. and Ito, M. (2010) Lipid signaling in cytosolic phospholipase [A.sub.2][alpha]-cyclooxygenase-2 cascade mediates cerebellar long-term depression and motor learning. Proc. Natl. Acad. Sci. U.S.A. 107, 3198-3203.

(19) Nagase, T., Uozumi, N., Ishii, S., Kume, K., Izumi, T., Ouchi, Y. and Shimizu, T. (2000) Acute lung injury by sepsis and acid aspiration: a key role for cytosolic phospholipase [A.sub.2]. Nat. Immunol. 1, 42-46.

(20) Hegen, M., Sun, L., Uozumi, N., Kume, K., Goad, M.E., Nickerson-Nutter, C.L., Shimizu, T. and Clark, J.D. (2003) Cytosolic phospholipase [A.sub.2][alpha]-deficient mice are resistant to collagen-induced arthritis. J. Exp. Med. 197, 1297-1302.

(21) Miyaura, C., Inada, M., Matsumoto, C., Ohshiba, T., Uozumi, N., Shimizu, T. and Ito, A. (2003) An essential role of cytosolic phospholipase [A.sub.2][alpha] in prostaglandin [E.sub.2]-mediated bone resorption associated with inflammation. J. Exp. Med. 197, 1303-1310.

(22) Marusic, S., Leach, M.W., Pelker, J.W., Azoitei, M.L., Uozumi, N., Cui, J., Shen, M.W., DeClercq, C.M., Miyashiro, J.S., Carito, B.A., Thakker, P., Simmons, D.L., Leonard, J.P., Shimizu, T. and Clark, J.D. (2005) Cytosolic phospholipase [A.sub.2][alpha]-deficient mice are resistant to experimental autoimmune encephalomyelitis. J. Exp. Med. 202, 841-851.

(23) Sanchez-Mejia, R.O., Newman, J.W., Toh, S., Yu, G.Q., Zhou, Y., Halabisky, B., Cisse, M., Scearce-Levie, K., Cheng, I.H., Gan, L., Palop, J.J., Bonventre, J.V. and Mucke, L. (2008) Phospholipase [A.sub.2] reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease. Nat. Neurosci. 11, 1311-1318.

(24) Murase, R., Sato, H., Yamamoto, K., Ushida, A., Nishito, Y., Ikeda, K., Kobayashi, T., Yamamoto, T., Taketomi, Y. and Murakami, M. (2016) Group X secreted phospholipase [A.sub.2] releases [omega]3 polyunsaturated fatty acids, suppresses colitis, and promotes sperm fertility. J. Biol. Chem. 291, 6895-6911.

(25) Kim, D.C., Hsu, F.I., Barrett, N.A., Friend, D.S., Grenningloh, R., Ho, I.C., Al-Garawi, A., Lora, J.M., Lam, B.K., Austen, K.F. and Kanaoka, Y. (2006) Cysteinyl leukotrienes regulate Th2 cell-dependent pulmonary inflammation. J. Immunol. 176, 4440-4448.

(26) Tager, A.M., Bromley, S.K., Medoff, B.D., Islam, S.A., Bercury, S.D., Friedrich, E.B., Carafone, A.D., Gerszten, R.E. and Luster, A.D. (2003) Leukotriene [B.sub.4] receptor BLT1 mediates early effector T cell recruitment. Nat. Immunol. 4, 982-990.

(27) Matsuoka, T., Hirata, M., Tanaka, H., Takahashi, Y., Murata, T., Kabashima, K., Sugimoto, Y., Kobayashi, T., Ushikubi, F., Aze, Y., Eguchi, N., Urade, Y., Yoshida, N., Kimura, K., Mizoguchi, A., Honda, Y., Nagai, H. and Narumiya, S. (2000) Prostaglandin [D.sub.2] as a mediator of allergic asthma. Science 287, 2013-2017.

(28) Esaki, Y., Li, Y., Sakata, D., Yao, C., Segi-Nishida, E., Matsuoka, T., Fukuda, K. and Narumiya, S. (2010) Dual roles of [PGE.sub.2]-EP4 signaling in mouse experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. U.S.A. 107, 12233-12238.

(29) Yao, C., Sakata, D., Esaki, Y., Li, Y., Matsuoka, T., Kuroiwa, K., Sugimoto, Y. and Narumiya, S. (2009) Prostaglandin [E.sub.2]-EP4 signaling promotes immune inflammation through Th1 cell differentiation and Th17 cell expansion. Nat. Med. 15, 633-640.

(30) Sonoshita, M., Takaku, K., Sasaki, N., Sugimoto, Y., Ushikubi, F., Narumiya, S., Oshima, M. and Taketo, M.M. (2001) Acceleration of intestinal polyposis through prostaglandin receptor EP2 in [Apc.sup.[DELTA]716] knockout mice. Nat. Med. 7, 1048-1051.

(31) Hoshino, T., Nakaya, T., Homan, T., Tanaka, K., Sugimoto, Y., Araki, W., Narita, M., Narumiya, S., Suzuki, T. and Mizushima, T. (2007) Involvement of prostaglandin [E.sub.2] in production of amyloid-[beta] peptides both in vitro and in vivo. J. Biol. Chem. 282, 32676-32688.

(32) Kabashima, K., Saji, T., Murata, T., Nagamachi, M., Matsuoka, T., Segi, E., Tsuboi, K., Sugimoto, Y., Kobayashi, T., Miyachi, Y., Ichikawa, A. and Narumiya, S. (2002) The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut. J. Clin. Invest. 109, 883-893.

(33) Slatter, D.A., Aldrovandi, M., O'Connor, A., Allen, S.M., Brasher, C.J., Murphy, R.C., Mecklemann, S., Ravi, S., Darley-Usmar, V. and O'Donnell, V.B. (2016) Mapping the human platelet lipidome reveals cytosolic phospholipase [A.sub.2] as a regulator of mitochondrial bioenergetics during activation. Cell Metab. 23, 930-944.

(34) Adler, D.H., Phillips, J.A. 3rd, Cogan, J.D., Iverson, T.M., Schnetz-Boutaud, N., Stein, J.A., Brenner, D.A., Milne, G.L., Morrow, J.D., Boutaud, O. and Oates, J.A. (2009) The enteropathy of prostaglandin deficiency. J. Gastroenterol. 44 (Suppl 19), 1-7.

(35) Adler, D.H., Cogan, J.D., Phillips, J.A. 3rd, Schnetz-Boutaud, N., Milne, G.L., Iverson, T., Stein, J.A., Brenner, D.A., Morrow, J.D., Boutaud, O. and Oates, J.A. (2008) Inherited human c[PLA.sub.2][alpha], deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction. J. Clin. Invest. 118, 2121-2131.

(36) Ghomashchi, F., Naika, G.S., Bollinger, J.G., Aloulou, A., Lehr, M., Leslie, C.C. and Gelb, M.H. (2010) Interfacial kinetic and binding properties of mammalian group IVB phospholipase [A.sub.2] (c[PLA.sub.2][beta]) and comparison with the other c[PLA.sub.2] isoforms. J. Biol. Chem. 285, 36100-36111.

(37) Underwood, K.W., Song, C., Kriz, R.W., Chang, X.J., Knopf, J.L. and Lin, L.L. (1998) A novel calcium-independent phospholipase [A.sub.2], c[PLA.sub.2][gamma], that is prenylated and contains homology to c[PLA.sub.2]. J. Biol. Chem. 273, 21926-21932.

(38) Chiba, H., Michibata, H., Wakimoto, K., Seishima, M., Kawasaki, S., Okubo, K., Mitsui, H., Torii, H. and Imai, Y. (2004) Cloning of a gene for a novel epithelium-specific cytosolic phospholipase [A.sub.2], c[PLA.sub.2][delta], induced in psoriatic skin. J. Biol. Chem. 279, 12890-12897.

(39) Ogura, Y., Parsons, W.H., Kamat, S.S. and Cravatt, B.F. (2016) A calcium-dependent acyl-transferase that produces N-acyl phosphatidylethanolamines. Nat. Chem. Biol. 12, 669-671.

(40) Ghosh, M., Loper, R., Ghomashchi, F., Tucker, D.E., Bonventre, J.V., Gelb, M.H. and Leslie, C.C. (2007) Function, activity, and membrane targeting of cytosolic phospholipase [A.sub.2][zeta] in mouse lung fibroblasts. J. Biol. Chem. 282, 11676-11686.

(41) Kienesberger, P.C., Oberer, M., Lass, A. and Zechner, R. (2009) Mammalian patatin domain containing proteins: a family with diverse lipolytic activities involved in multiple biological functions. J. Lipid Res. 50 (Suppl), S63-S68.

(42) Murakami, M., Taketomi, Y., Miki, Y., Sato, H., Hirabayashi, T. and Yamamoto, K. (2011) Recent progress in phospholipase [A.sub.2] research: from cells to animals to humans. Prog. Lipid Res. 50, 152-192.

(43) Tang, J., Kriz, R.W., Wolfman, N., Shaffer, M., Seehra, J. and Jones, S.S. (1997) A novel cytosolic calcium-independent phospholipase [A.sub.2] contains eight ankyrin motifs. J. Biol. Chem. 272, 8567-8575.

(44) Larsson, P.K., Claesson, H.E. and Kennedy, B.P. (1998) Multiple splice variants of the human calcium-independent phospholipase [A.sub.2] and their effect on enzyme activity. J. Biol. Chem. 273, 207-214.

(45) Liu, X., Moon, S.H., Jenkins, C.M., Sims, H.F. and Gross, R.W. (2016) Cyclooxygenase-2 mediated oxidation of 2-arachidonoyl-lysophospholipids identifies unknown lipid signaling pathways. Cell Chem. Biol. 23, 1217-1227.

(46) Moon, S.H., Jenkins, C.M., Liu, X., Guan, S., Mancuso, D.J. and Gross, R.W. (2012) Activation of mitochondrial calcium-independent phospholipase [A.sub.2][gamma]. (i[PLA.sub.2][gamma]) by divalent cations mediating arachidonate release and production of downstream eicosanoids. J. Biol. Chem. 287, 14880-14895.

(47) Kienesberger, P.C., Lass, A., Preiss-Landl, K., Wolinski, H., Kohlwein, S.D., Zimmermann, R. and Zechner, R. (2008) Identification of an insulin-regulated lysophospholipase with homology to neuropathy target esterase. J. Biol. Chem. 283, 5908-5917.

(48) Quistad, G.B., Barlow, C., Winrow, C.J., Sparks, S.E. and Casida, J.E. (2003) Evidence that mouse brain neuropathy target esterase is a lysophospholipase. Proc. Natl. Acad. Sci. U.S.A. 100, 7983-7987.

(49) Morgan, N.V., Westaway, S.K., Morton, J.E., Gregory, A., Gissen, P., Sonek, S., Cangul, H., Coryell, J., Canham, N., Nardocci, N., Zorzi, G., Pasha, S., Rodriguez, D., Desguerre, I., Mubaidin, A., Bertini, E., Trembath, R.C., Simonati, A., Schanen, C., Johnson, C.A., Levinson, B., Woods, C.G., Wilmot, B., Kramer, P., Gitschier, J., Maher, E.R. and Hayflick, S.J. (2006) PLA2G6, encoding a phospholipase [A.sub.2], is mutated in neurodegenerative disorders with high brain iron. Nat. Genet. 38, 752-754.

(50) Mancuso, D.J., Sims, H.F., Yang, K., Kiebish, M.A., Su, X., Jenkins, C.M., Guan, S., Moon, S.H., Pietka, T., Nassir, F., Schappe, T., Moore, K., Han, X., Abumrad, N.A. and Gross, R.W. (2010) Genetic ablation of calcium-independent phospholipase [A.sub.2][gamma] prevents obesity and insulin resistance during high fat feeding by mitochondrial uncoupling and increased adipocyte fatty acid oxidation. J. Biol. Chem. 285, 36495-36510.

(51) Saunders, C.J., Moon, S.H., Liu, X., Thiffault, I., Coffman, K., LePichon, J.B., Taboada, E., Smith, L.D., Farrow, E.G., Miller, N., Gibson, M., Patterson, M., Kingsmore, S.F. and Gross, R.W. (2015) Loss of function variants in human PNPLA8 encoding calcium-independent phospholipase [A.sub.2][gamma] recapitulate the mitochondriopathy of the homologous null mouse. Hum. Mutat. 36, 301-306.

(52) Topaloglu, A.K., Lomniczi, A., Kretzschmar, D., Dissen, G.A., Kotan, L.D., McArdle, C.A., Koc, A.F., Hamel, B.C., Guclu, M., Papatya, E.D., Eren, E., Mengen, E., Gurbuz, F., Cook, M., Castellano, J.M., Kekil, M.B., Mungan, N.O., Yuksel, B. and Ojeda, S.R. (2014) Loss-of-function mutations in PNPLA6 encoding neuropathy target esterase underlie pubertal failure and neurological deficits in Gordon Holmes syndrome. J. Clin. Endocrinol. Metab. 99, E2067-E2075.

(53) Kmoch, S., Majewski, J., Ramamurthy, V., Cao, S., Fahiminiya, S., Ren, H., MacDonald, I.M., Lopez, I., Sun, V., Keser, V., Khan, A., Stranecky, V., Hartmannova, H., Pristoupilova, A., Hodanova, K., Piherova, L., Kuchar, L., Baxova, A., Chen, R., Barsottini, O.G., Pyle, A., Griffin, H., Splitt, M., Sallum, J., Tolmie, J.L., Sampson, J.R., Chinnery, P., Care4Rare Canada, Banin, E., Sharon, D., Dutta, S., Grebler, R., Helfrich-Foerster, C., Pedroso, J.L., Kretzschmar, D., Cayouette, M. and Koenekoop, R.K. (2015) Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness. Nat. Commun. 6, 5614.

(54) Zhou, Q., Yen, A., Rymarczyk, G., Asai, H., Trengrove, C., Aziz, N., Kirber, M.T., Mostoslavsky, G., Ikezu, T., Wolozin, B. and Bolotina, V.M. (2016) Impairment of PARK14-dependent [Ca.sup.2+] signalling is a novel determinant of Parkinson's disease. Nat. Commun. 7, 10332.

(55) Bao, S., Miller, D.J., Ma, Z., Wohltmann, M., Eng, G., Ramanadham, S., Moley, K. and Turk, J. (2004) Male mice that do not express group VIA phospholipase [A.sub.2] produce spermatozoa with impaired motility and have greatly reduced fertility. J. Biol. Chem. 279, 38194-38200.

(56) Zimmermann, R., Strauss, J.G., Haemmerle, G., Schoiswohl, G., Birner-Gruenberger, R., Riederer, M., Lass, A., Neuberger, G., Eisenhaber, F., Hermetter, A. and Zechner, R. (2004) Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306, 1383-1386.

(57) Haemmerle, G., Lass, A., Zimmermann, R., Gorkiewicz, G., Meyer, C., Rozman, J., Heldmaier, G., Maier, R., Theussl, C., Eder, S., Kratky, D., Wagner, E.F., Klingenspor, M., Hoefler, G. and Zechner, R. (2006) Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science 312, 734-737.

(58) Das, S.K., Eder, S., Schauer, S., Diwoky, C., Temmel, H., Guertl, B., Gorkiewicz, G., Tamilarasan, K.P., Kumari, P., Trauner, M., Zimmermann, R., Vesely, P., Haemmerle, G., Zechner, R. and Hoefler, G. (2011) Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 333, 233-238.

(59) Yang, X., Lu, X., Lombes, M., Rha, G.B., Chi, Y.I., Guerin, T.M., Smart, E.J. and Liu, J. (2010) The [G.sub.0]/[G.sub.1] switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase. Cell Metab. 11, 194-205.

(60) Haemmerle, G., Moustafa, T., Woelkart, G., Buttner, S., Schmidt, A., van de Weijer, T., Hesselink, M., Jaeger, D., Kienesberger, P.C., Zierler, K., Schreiber, R., Eichmann, T., Kolb, D., Kotzbeck, P., Schweiger, M., Kumari, M., Eder, S., Schoiswohl, G., Wongsiriroj, N., Pollak, N.M., Radner, F.P., Preiss-Landl, K., Kolbe, T., Rulicke, T., Pieske, B., Trauner, M., Lass, A., Zimmermann, R., Hoefler, G., Cinti, S., Kershaw, E.E., Schrauwen, P., Madeo, F., Mayer, B. and Zechner, R. (2011) ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-[alpha] and PGC-1. Nat. Med. 17, 1076-1085.

(61) Lass, A., Zimmermann, R., Oberer, M. and Zechner, R. (2011) Lipolysis--a highly regulated multi-enzyme complex mediates the catabolism of cellular fat stores. Prog. Lipid Res. 50, 14-27.

(62) Young, S.G. and Zechner, R. (2013) Biochemistry and pathophysiology of intravascular and intracellular lipolysis. Genes Dev. 27, 459-484.

(63) Romeo, S., Kozlitina, J., Xing, C., Pertsemlidis, A., Cox, D., Pennacchio, L.A., Boerwinkle, E., Cohen, J.C. and Hobbs, H.H. (2008) Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461-1465.

(64) Li, J.Z., Huang, Y., Karaman, R., Ivanova, P.T., Brown, H.A., Roddy, T., Castro-Perez, J., Cohen, J.C. and Hobbs, H.H. (2012) Chronic overexpression of [PNPLA3.sup.I148M] in mouse liver causes hepatic steatosis. J. Clin. Invest. 122, 4130-4144.

(65) Huang, Y., He, S., Li, J.Z., Seo, Y.K., Osborne, T.F., Cohen, J.C. and Hobbs, H.H. (2010) A feedforward loop amplifies nutritional regulation of PNPLA3. Proc. Natl. Acad. Sci. U.S.A. 107, 7892-7897.

(66) Gao, J. and Simon, M. (2005) Identification of a novel keratinocyte retinyl ester hydrolase as a transacylase and lipase. J. Invest. Dermatol. 124, 1259-1266.

(67) Dupont, N., Chauhan, S., Arko-Mensah, J., Castillo, E.F., Masedunskas, A., Weigert, R., Robenek, H., Proikas-Cezanne, T. and Deretic, V. (2014) Neutral lipid stores and lipase PNPLA5 contribute to autophagosome biogenesis. Curr. Biol. 24, 609-620.

(68) Hirabayashi, T., Anjo, T., Kaneko, A., Senoo, Y., Shibata, A., Takama, H., Yokoyama, K., Nishito, Y., Ono, T., Taya, C., Muramatsu, K., Fukami, K., Munoz-Garcia, A., Brash, A.R., Ikeda, K., Arita, M., Akiyama, M. and Murakami, M. (2017) PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis. Nat. Commun. 8, 14609.

(69) Ohno, Y., Kamiyama, N., Nakamichi, S. and Kihara, A. (2017) PNPLA1 is a transacylase essential for the generation of the skin barrier lipid [omega]-O-acylceramide. Nat. Commun. 8, 14610.

(70) Hattori, M. and Arai, H. (2015) Intracellular PAF-acetylhydrolase type I. Enzymes 38, 23-36.

(71) Kono, N. and Arai, H. (2015) Intracellular platelet activating factor acetylhydrolase, type II: A unique cellular phospholipase [A.sub.2] that hydrolyzes oxidatively modified phospholipids. Enzymes 38, 43-54.

(72) Ho, Y.S., Swenson, L., Derewenda, U., Serre, L., Wei, Y., Dauter, Z., Hattori, M., Adachi, T., Aoki, J., Arai, H., Inoue, K. and Derewenda, Z.S. (1997) Brain acetylhydrolase that inactivates platelet-activating factor is a G-protein-like trimer. Nature 385, 89-93.

(73) Koizumi, H., Yamaguchi, N., Hattori, M., Ishikawa, T.O., Aoki, J., Taketo, M.M., Inoue, K. and Arai, H. (2003) Targeted disruption of intracellular type I platelet activating factor-acetylhydrolase catalytic subunits causes severe impairment in spermatogenesis. J. Biol. Chem. 278, 12489-12494.

(74) Kono, N., Inoue, T., Yoshida, Y., Sato, H., Matsusue, T., Itabe, H., Niki, E., Aoki, J. and Arai, H. (2008) Protection against oxidative stress-induced hepatic injury by intracellular type II platelet-activating factor acetylhydrolase by metabolism of oxidized phospholipids in vivo. J. Biol. Chem. 283, 1628-1636.

(75) Tjoelker, L.W., Wilder, C., Eberhardt, C., Stafforini, D.M., Dietsch, G., Schimpf, B., Hooper, S., Le Trong, H., Cousens, L.S., Zimmerman, G.A., Yamada, Y., McIntyre, T.M., Prescott, S.M. and Gray, P.W. (1995) Anti-inflammatory properties of a platelet-activating factor acetylhydrolase. Nature 374, 549-553.

(76) Wilensky, R.L., Shi, Y., Mohler, E.R. 3rd, Hamamdzic, D., Burgert, M.E., Li, J., Postle, A., Fenning, R.S., Bollinger, J.G., Hoffman, B.E., Pelchovitz, D.J., Yang, J., Mirabile, R.C., Webb, C.L., Zhang, L., Zhang, P., Gelb, M.H., Walker, M.C., Zalewski, A. and Macphee, C.H. (2008) Inhibition of lipoprotein-associated phospholipase [A.sub.2] reduces complex coronary atherosclerotic plaque development. Nat. Med. 14, 1059-1066.

(77) Corson, M.A. (2009) Phospholipase [A.sub.2] inhibitors in atherosclerosis: the race is on. Lancet 373, 608-610.

(78) Xu, C., Reichert, E.C., Nakano, T., Lohse, M., Gardner, A.A., Revelo, M.P., Topham, M.K. and Stafforini, D.M. (2013) Deficiency of phospholipase [A.sub.2] group 7 decreases intestinal polyposis and colon tumorigenesis in [Apc.sup.Min/+] mice. Cancer Res. 73, 2806-2816.

(79) Abe, A., Hiraoka, M., Wild, S., Wilcoxen, S.E., Paine, R. 3rd and Shayman, J.A. (2004) Lysosomal phospholipase [A.sub.2]is selectively expressed in alveolar macrophages. J. Biol. Chem. 279, 42605-42611.

(80) Hiraoka, M., Abe, A., Lu, Y., Yang, K., Han, X., Gross, R.W. and Shayman, J.A. (2006) Lysosomal phospholipase [A.sub.2] and phospholipidosis. Mol. Cell. Biol. 26, 6139-6148.

(81) Paduraru, C., Bezbradica, J.S., Kunte, A., Kelly, R., Shayman, J.A., Veerapen, N., Cox, L.R., Besra, G.S. and Cresswell, P. (2013) Role for lysosomal phospholipase [A.sub.2] in iNKT cell-mediated CD1d recognition. Proc. Natl. Acad. Sci. U.S.A. 110, 5097-5102.

(82) Schneider, B.E., Behrends, J., Hagens, K., Harmel, N., Shayman, J.A. and Schaible, U.E. (2014) Lysosomal phospholipase [A.sub.2]: a novel player in host immunity to Mycobacterium tuberculosis. Eur. J. Immunol. 44, 2394-2404.

(83) Uyama, T., Ikematsu, N., Inoue, M., Shinohara, N., Jin, X.H., Tsuboi, K., Tonai, T., Tokumura, A. and Ueda, N. (2012) Generation of N-acylphos-phatidylethanolamine by members of the phospholipase A/acyltransferase (PLA/AT) family. J. Biol. Chem. 287, 31905-31919.

(84) Jaworski, K., Ahmadian, M., Duncan, R.E., Sarkadi-Nagy, E., Varady, K.A., Hellerstein, M.K., Lee, H.Y., Samuel, V.T., Shulman, G.I., Kim, K.H., de Val, S., Kang, C. and Sul, H.S. (2009) AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency. Nat. Med. 15, 159-168.

(85) Xiong, S., Tu, H., Kollareddy, M., Pant, V., Li, Q., Zhang, Y., Jackson, J.G., Suh, Y.A., ElizondoFraire, A.C., Yang, P., Chau, G., Tashakori, M., Wasylishen, A.R., Ju, Z., Solomon, H., Rotter, V., Liu, B., El-Naggar, A.K., Donehower, L.A., Martinez, L.A. and Lozano, G. (2014) Pla2g16 phospholipase mediates gain-of-function activities of mutant p53. Proc. Natl. Acad. Sci. U.S.A. 111, 11145-11150.

(86) Golczak, M., Sears, A.E., Kiser, P.D. and Palczewski, K. (2015) LRAT-specific domain facilitates vitamin A metabolism by domain swapping in HRASLS3. Nat. Chem. Biol. 11, 26-32.

(87) Uyama, T., Kawai, K., Kono, N., Watanabe, M., Tsuboi, K., Inoue, T., Araki, N., Arai, H. and Ueda, N. (2015) Interaction of phospholipase A/in acyltransferase-3 with Pex19p: a possible involvement the down-regulation of peroxisomes. J. Biol. Chem. 290, 17520-17534.

(88) Staring, J., von Castelmur, E., Blomen, V.A., van den Hengel, L.G., Brockmann, M., Baggen, J., Thibaut, H.J., Nieuwenhuis, J., Janssen, H., van Kuppeveld, F.J., Perrakis, A., Carette, J.E. and Brummelkamp, T.R. (2017) PLA2G16 represents a switch between entry and clearance of Picornaviridae. Nature 541, 412-416.

(89) Thomas, G., Brown, A.L. and Brown, J.M. (2014) In vivo metabolite profiling as a means to identify uncharacterized lipase function: recent success stories within the alpha beta hydrolase domain (ABHD) enzyme family. Biochim. Biophys. Acta 1841, 1097-1101.

(90) Long, J.Z., Cisar, J.S., Milliken, D., Niessen, S., Wang, C., Trauger, S.A., Siuzdak, G. and Cravatt, B.F. (2011) Metabolomics annotates ABHD3 as a physiologic regulator of medium-chain phospholipids. Nat. Chem. Biol. 7, 763-765.

(91) Lee, H.C., Simon, G.M. and Cravatt, B.F. (2015) ABHD4 regulates multiple classes of N-acyl phospholipids in the mammalian central nervous system. Biochemistry 54, 2539-2549.

(92) Marrs, W.R., Blankman, J.L., Horne, E.A., Thomazeau, A., Lin, Y.H., Coy, J., Bodor, A.L., Muccioli, G.G., Hu, S.S., Woodruff, G., Fung, S., Lafourcade, M., Alexander, J.P., Long, J.Z., Li, W., Xu, C., Moller, T., Mackie, K., Manzoni, O.J., Cravatt, B.F. and Stella, N. (2010) The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nat. Neurosci. 13, 951-957.

(93) Thomas, G., Betters, J.L., Lord, C.C., Brown, A.L., Marshall, S., Ferguson, D., Sawyer, J., Davis, M.A., Melchior, J.T., Blume, L.C., Howlett, A.C., Ivanova, P.T., Milne, S.B., Myers, D.S., Mrak, I., Leber, V., Heier, C., Taschler, U., Blankman, J.L., Cravatt, B.F., Lee, R.G., Crooke, R.M., Graham, M.J., Zimmermann, R., Brown, H.A. and Brown, J.M. (2013) The serine hydrolase ABHD6 Is a critical regulator of the metabolic syndrome. Cell Rep. 5, 508-520.

(94) Tanimura, A., Yamazaki, M., Hashimotodani, Y., Uchigashima, M., Kawata, S., Abe, M., Kita, Y., Hashimoto, K., Shimizu, T., Watanabe, M., Sakimura, K. and Kano, M. (2010) The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase, mediates retrograde suppression of synaptic transmission. Neuron 65, 320-327.

(95) Kita, Y., Yoshida, K., Tokuoka, S.M., Hamano, F., Yamazaki, M., Sakimura, K., Kano, M. and Shimizu, T. (2015) Fever is mediated by conversion of endocannabinoid 2-arachidonoylglycerol to prostaglandin [E.sub.2]. PLoS One 10, e0133663.

(96) Kamat, S.S., Camara, K., Parsons, W.H., Chen, D.H., Dix, M.M., Bird, T.D., Howell, A.R. and Cravatt, B.F. (2015) Immunomodulatory lyso-phosphatidylserines are regulated by ABHD16A and ABHD12 interplay. Nat. Chem. Biol. 11, 164-171.

(97) Blankman, J.L., Long, J.Z., Trauger, S.A., Siuzdak, G. and Cravatt, B.F. (2013) ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC. Proc. Natl. Acad. Sci. U.S.A. 110, 1500-1505.

(98) Lass, A., Zimmermann, R., Haemmerle, G., Riederer, M., Schoiswohl, G., Schweiger, M., Kienesberger, P., Strauss, J.G., Gorkiewicz, G. and Zechner, R. (2006) Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome. Cell Metab. 3, 309-319.

(99) Murakami, M., Sato, H., Miki, Y., Yamamoto, K. and Taketomi, Y. (2015) A new era of secreted phospholipase [A.sub.2]. J. Lipid Res. 56, 1248-1261.

(100) Murakami, M., Yamamoto, K., Miki, Y., Murase, R., Sato, H. and Taketomi, Y. (2016) The roles of the secreted phospholipase [A.sub.2] gene family in immunology. Adv. Immunol. 132, 91-134.

(101) Seilhamer, J.J., Randall, T.L., Yamanaka, M. and Johnson, L.K. (1986) Pancreatic phospholipase [A.sub.2]: isolation of the human gene and cDNAs from porcine pancreas and human lung. DNA 5, 519-527.

(102) Seilhamer, J.J., Pruzanski, W., Vadas, P., Plant, S., Miller, J.A., Kloss, J. and Johnson, L.K. (1989) Cloning and recombinant expression of phospholipase [A.sub.2] present in rheumatoid arthritic synovial fluid. J. Biol. Chem. 264, 5335-5338.

(103) Pan, Y.H., Yu, B.Z., Singer, A.G., Ghomashchi, F., Lambeau, G., Gelb, M.H., Jain, M.K. and Bahnson, B.J. (2002) Crystal structure of human group X secreted phospholipase [A.sub.2]. Electrostatically neutral interfacial surface targets zwitterionic membranes. J. Biol. Chem. 277, 29086-29093.

(104) Scott, D.L., White, S.P., Browning, J.L., Rosa, J.J., Gelb, M.H. and Sigler, P.B. (1991) Structures of free and inhibited human secretory phospholipase [A.sub.2] from inflammatory exudate. Science 254, 1007-1010.

(105) Huggins, K.W., Boileau, A.C. and Hui, D.Y. (2002) Protection against diet-induced obesity and obesity-related insulin resistance in Group 1B [PLA.sub.2]-deficient mice. Am. J. Physiol. Endocrinol. Metab. 283, E994-E1001.

(106) Labonte, E.D., Kirby, R.J., Schildmeyer, N.M., Cannon, A.M., Huggins, K.W. and Hui, D.Y. (2006) Group 1B phospholipase [A.sub.2]-mediated lysophospholipid absorption directly contributes to postprandial hyperglycemia. Diabetes 55, 935-941.

(107) Hui, D.Y., Cope, M.J., Labonte, E.D., Chang, H.T., Shao, J., Goka, E., Abousalham, A., Charmot, D. and Buysse, J. (2009) The phospholipase [A.sub.2] inhibitor methyl indoxam suppresses diet-induced obesity and glucose intolerance in mice. Br. J. Pharmacol. 157, 1263-1269.

(108) Hollie, N.I., Konaniah, E.S., Goodin, C. and Hui, D.Y. (2014) Group 1B phospholipase [A.sub.2] inactivation suppresses atherosclerosis and metabolic diseases in LDL receptor-deficient mice. Atherosclerosis 234, 377-380.

(109) Wilson, S.G., Adam, G., Langdown, M., Reneland, R., Braun, A., Andrew, T., Surdulescu, G.L., Norberg, M., Dudbridge, F., Reed, P.W., Sambrook, P.N., Kleyn, P.W. and Spector, T.D. (2006) Linkage and potential association of obesity-related phenotypes with two genes on chromosome 12q24 in a female dizygous twin cohort. Eur. J. Hum. Genet. 14, 340-348.

(110) Pruzanski, W. and Vadas, P. (1991) Phospholipase [A.sub.2]--a mediator between proximal and distal effectors of inflammation. Immunol. Today 12, 143-146.

(111) Kennedy, B.P., Payette, P., Mudgett, J., Vadas, P., Pruzanski, W., Kwan, M., Tang, C., Rancourt, D.E. and Cromlish, W.A. (1995) A natural disruption of the secretory group II phospholipase [A.sub.2] gene in inbred mouse strains. J. Biol. Chem. 270, 22378-22385.

(112) MacPhee, M., Chepenik, K.P., Liddell, R.A., Nelson, K.K., Siracusa, L.D. and Buchberg, A.M. (1995) The secretory phospholipase [A.sub.2] gene is a candidate for the Mom1 locus, a major modifier of [Apc.sup.Min]-induced intestinal neoplasia. Cell 81, 957-966.

(113) Weinrauch, Y., Abad, C., Liang, N.S., Lowry, S.F. and Weiss, J. (1998) Mobilization of potent plasma bactericidal activity during systemic bacterial challenge. Role of group IIA phospholipase [A.sub.2]. J. Clin. Invest. 102, 633-638.

(114) Pernet, E., Brunet, J., Guillemot, L., Chignard, M., Touqui, L. and Wu, Y. (2015) Staphylococcus aureus adenosine inhibits s[PLA.sub.2]-IIA-mediated host killing in the airways. J. Immunol. 194, 5312-5319.

(115) Boudreau, L.H., Duchez, A.C., Cloutier, N., Soulet, D., Martin, N., Bollinger, J., Pare, A., Rousseau, M., Naika, G.S., Levesque, T., Laflamme, C., Marcoux, G., Lambeau, G., Farndale, R.W., Pouliot, M., Hamzeh-Cognasse, H., Cognasse, F., Garraud, O., Nigrovic, P.A., Guderley, H., Lacroix, S., Thibault, L., Semple, J.W., Gelb, M.H. and Boilard, E. (2014) Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase [A.sub.2] to promote inflammation. Blood 124, 2173-2183.

(116) Miki, Y., Kidoguchi, Y., Sato, M., Taketomi, Y., Taya, C., Muramatsu, K., Gelb, M.H., Yamamoto, K. and Murakami, M. (2016) Dual roles of group IID phospholipase [A.sub.2] in inflammation and cancer. J. Biol. Chem. 291, 15588-15601.

(117) Vijay, R., Hua, X., Meyerholz, D.K., Miki, Y., Yamamoto, K., Gelb, M., Murakami, M. and Perlman, S. (2015) Critical role of phospholipase [A.sub.2] group IID in age-related susceptibility to severe acute respiratory syndrome-CoV infection. J. Exp. Med. 212, 1851-1868.

(118) Yamamoto, K., Miki, Y., Sato, H., Nishito, Y., Gelb, M.H., Taketomi, Y. and Murakami, M. (2016) Expression and function of group IIE phospholipase [A.sub.2] in mouse skin. J. Biol. Chem. 291, 15602-15613.

(119) Sato, H., Taketomi, Y., Ushida, A., Isogai, Y., Kojima, T., Hirabayashi, T., Miki, Y., Yamamoto, K., Nishito, Y., Kobayashi, T., Ikeda, K., Taguchi, R., Hara, S., Ida, S., Miyamoto, Y., Watanabe, M., Baba, H., Miyata, K., Oike, Y., Gelb, M.H. and Murakami, M. (2014) The adipocyte-inducible secreted phospholipases PLA2G and PLA2G2E play distinct roles in obesity. Cell Metab. 20, 119-132.

(120) Valentin, E., Ghomashchi, F., Gelb, M.H., Lazdunski, M. and Lambeau, G. (1999) On the diversity of secreted phospholipases [A.sub.2]. Cloning, tissue distribution, and functional expression of two novel mouse group II enzymes. J. Biol. Chem. 274, 31195-31202.

(121) Murakami, M., Shimbara, S., Kambe, T., Kuwata, H., Winstead, M.V., Tischfield, J.A. and Kudo, I. (1998) The functions of five distinct mammalian phospholipase [A.sub.2]s in regulating arachidonic acid release. Type IIa and type V secretory phospholipase [A.sub.2]s are functionally redundant and act in concert with cytosolic phospholipase [A.sub.2]. J. Biol. Chem. 273, 14411-14423.

(122) Shinohara, H., Balboa, M.A., Johnson, C.A., Balsinde, J. and Dennis, E.A. (1999) Regulation of delayed prostaglandin production in activated P388D1 macrophages by group IV cytosolic and group V secretory phospholipase [A.sub.2]s. J. Biol. Chem. 274, 12263-12268.

(123) Ohtsuki, M., Taketomi, Y., Arata, S., Masuda, S., Ishikawa, Y., Ishii, T., Takanezawa, Y., Aoki, J., Arai, H., Yamamoto, K., Kudo, I. and Murakami, M. (2006) Transgenic expression of group V, but not group X, secreted phospholipase [A.sub.2] in mice leads to neonatal lethality because of lung dysfunction. J. Biol. Chem. 281, 36420-36433.

(124) Ohta, S., Imamura, M., Xing, W., Boyce, J.A. and Balestrieri, B. (2013) Group V secretory phospholipase [A.sub.2] is involved in macrophage activation and is sufficient for macrophage effector functions in allergic pulmonary inflammation. J. Immunol. 190, 5927-5938.

(125) Balestrieri, B., Maekawa, A., Xing, W., Gelb, M.H., Katz, H.R. and Arm, J.P. (2009) Group V secretory phospholipase [A.sub.2] modulates phagosome maturation and regulates the innate immune response against Candida albicans. J. Immunol. 182, 4891-4898.

(126) Boilard, E., Lai, Y., Larabee, K., Balestrieri, B., Ghomashchi, F., Fujioka, D., Gobezie, R., Coblyn, J.S., Weinblatt, M.E., Massarotti, E.M., Thornhill, T.S., Divangahi, M., Remold, H., Lambeau, G., Gelb, M.H., Arm, J.P. and Lee, D.M. (2010) A novel anti-inflammatory role for secretory phospholipase [A.sub.2] in immune complex-mediated arthritis. EMBO Mol. Med. 2, 172-187.

(127) Degousee, N., Kelvin, D.J., Geisslinger, G., Hwang, D.M., Stefanski, E., Wang, X.H., Danesh, A., Angioni, C., Schmidt, H., Lindsay, T.F., Gelb, M.H., Bollinger, J., Payre, C., Lambeau, G., Arm, J.P., Keating, A. and Rubin, B.B. (2011) Group V phospholipase [A.sub.2] in bone marrow-derived myeloid cells and bronchial epithelial cells promotes bacterial clearance after Escherichia coli pneumonia. J. Biol. Chem. 286, 35650-35662.

(128) Jemel, I., Ii, H., Oslund, R.C., Payre, C., Dabert Gay, A.S., Douguet, D., Chargui, K., Scarzello, S., Gelb, M.H. and Lambeau, G. (2011) Group X secreted phospholipase [A.sub.2] proenzyme is matured by a furin-like proprotein convertase and releases arachidonic acid inside of human HEK293 cells. J. Biol. Chem. 286, 36509-36521.

(129) Escoffier, J., Jemel, I., Tanemoto, A., Taketomi, Y., Payre, C., Coatrieux, C., Sato, H., Yamamoto, K., Masuda, S., Pernet-Gallay, K., Pierre, V., Hara, S., Murakami, M., De Waard, M., Lambeau, G. and Arnoult, C. (2010) Group X phospholipase [A.sub.2] is released during sperm acrosome reaction and controls fertility outcome in mice. J. Clin. Invest. 120, 1415-1428.

(130) Henderson, W.R. Jr., Chi, E.Y., Bollinger, J.G., Tien, Y.T., Ye, X., Castelli, L., Rubtsov, Y.P., Singer, A.G., Chiang, G.K., Nevalainen, T., Rudensky, A.Y. and Gelb, M.H. (2007) Importance of group X-secreted phospholipase [A.sub.2] in allergen-induced airway inflammation and remodeling in a mouse asthma model. J. Exp. Med. 204, 865-877.

(131) Henderson, W.R. Jr., Ye, X., Lai, Y., Ni, Z., Bollinger, J.G., Tien, Y.T., Chi, E.Y. and Gelb, M.H. (2013) Key role of group v secreted phospholipase [A.sub.2] in Th2 cytokine and dendritic cell-driven airway hyperresponsiveness and remodeling. PLoS One 8, e56172.

(132) Kelvin, A.A., Degousee, N., Banner, D., Stefanski, E., Leomicronn, A.J., Angoulvant, D., Paquette, S.G., Huang, S.S., Danesh, A., Robbins, C.S., Noyan, H., Husain, M., Lambeau, G., Gelb, M., Kelvin, D.J. and Rubin, B.B. (2014) Lack of group X secreted phospholipase [A.sub.2] increases survival following pandemic H1N1 influenza infection. Virology 454-455, 78-92.

(133) Valentin, E., Ghomashchi, F., Gelb, M.H., Lazdunski, M. and Lambeau, G. (2000) Novel human secreted phospholipase [A.sub.2] with homology to the group III bee venom enzyme. J. Biol. Chem. 275, 7492-7496.

(134) Murakami, M., Masuda, S., Shimbara, S., Bezzine, S., Lazdunski, M., Lambeau, G., Gelb, M.H., Matsukura, S., Kokubu, F., Adachi, M. and Kudo, I. (2003) Cellular arachidonate-releasing function of novel classes of secretory phospholipase [A.sub.2]s (groups III and XII). J. Biol. Chem. 278, 10657-10667.

(135) Sato, H., Taketomi, Y., Isogai, Y., Miki, Y., Yamamoto, K., Masuda, S., Hosono, T., Arata, S., Ishikawa, Y., Ishii, T., Kobayashi, T., Nakanishi, H., Ikeda, K., Taguchi, R., Hara, S., Kudo, I. and Murakami, M. (2010) Group III secreted phospholipase [A.sub.2] regulates epididymal sperm maturation and fertility in mice. J. Clin. Invest. 120, 1400-1414.

(136) Taketomi, Y., Ueno, N., Kojima, T., Sato, H., Murase, R., Yamamoto, K., Tanaka, S., Sakanaka, M., Nakamura, M., Nishito, Y., Kawana, M., Kambe, N., Ikeda, K., Taguchi, R., Nakamizo, S., Kabashima, K., Gelb, M.H., Arita, M., Yokomizo, T., Nakamura, M., Watanabe, K., Hirai, H., Nakamura, M., Okayama, Y., Ra, C., Aritake, K., Urade, Y., Morimoto, K., Sugimoto, Y., Shimizu, T., Narumiya, S., Hara, S. and Murakami, M. (2013) Mast cell maturation is driven via a group III phospholipase [A.sub.2]-prostaglandin [D.sub.2]-DP1 receptor paracrine axis. Nat. Immunol. 14, 554-563.

(137) Gelb, M.H., Valentin, E., Ghomashchi, F., Lazdunski, M. and Lambeau, G. (2000) Cloning and recombinant expression of a structurally novel human secreted phospholipase [A.sub.2]. J. Biol. Chem. 275, 39823-39826.

(138) Rouault, M., Bollinger, J.G., Lazdunski, M., Gelb, M.H. and Lambeau, G. (2003) Novel mammalian group XII secreted phospholipase [A.sub.2] lacking enzymatic activity. Biochemistry 42, 11494-11503.

(139) Guan, M., Qu, L., Tan, W., Chen, L. and Wong, C.W. (2011) Hepatocyte nuclear factor-4, regulates liver triglyceride metabolism in part through secreted phospholipase [A.sub.2] GXIIB. Hepatology 53, 458-466.

(140) Lambeau, G. and Gelb, M.H. (2008) Biochemistry and physiology of mammalian secreted phospholipases [A.sub.2]. Annu. Rev. Biochem. 77, 495-520.

(141) Tamaru, S., Mishina, H., Watanabe, Y., Watanabe, K., Fujioka, D., Takahashi, S., Suzuki, K., Nakamura, T., Obata, J.E., Kawabata, K., Yokota, Y., Murakami, M., Hanasaki, K. and Kugiyama, K. (2013) Deficiency of phospholipase [A.sub.2] receptor exacerbates ovalbumin-induced lung inflammation. J. Immunol. 191, 1021-1028.

(142) Kugiyama, K., Ota, Y., Takazoe, K., Moriyama, Y., Kawano, H., Miyao, Y., Sakamoto, T., Soejima, H., Ogawa, H., Doi, H., Sugiyama, S. and Yasue, H. (1999) Circulating levels of secretory type II phospholipase [A.sub.2] predict coronary events in patients with coronary artery disease. Circulation 100, 1280-1284.

(143) Tomas, N.M., Beck, L.H. Jr., Meyer-Schwesinger, C., Seitz-Polski, B., Ma, H., Zahner, G., Dolla, G., Hoxha, E., Helmchen, U., Dabert-Gay, A.S., Debayle, D., Merchant, M., Klein, J., Salant, D.J., Stahl, R.A. and Lambeau, G. (2014) Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N. Engl. J. Med. 371, 2277-2287.

(144) Chandak, P.G., Radovic, B., Aflaki, E., Kolb, D., Buchebner, M., Frohlich, E., Magnes, C., Sinner, F., Haemmerle, G., Zechner, R., Tabas, I., Levak-Frank, S. and Kratky, D. (2010) Efficient phagocytosis requires triacylglycerol hydrolysis by adipose triglyceride lipase. J. Biol. Chem. 285, 20192-20201.

(145) Tang, T., Abbott, M.J., Ahmadian, M., Lopes, A.B., Wang, Y. and Sul, H.S. (2013) Desnutrin/ATGL activates PPAR/ to promote mitochon drial function for insulin secretion in islet [beta] cells. Cell Metab. 18, 883-895.

(146) Ochi, T., Munekage, K., Ono, M., Higuchi, T., Tsuda, M., Hayashi, Y., Okamoto, N., Toda, K., Sakamoto, S., Oben, J.A. and Saibara, T. (2016) 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. Hepatol. Res. 46, 584-592.

(147) Chen, W., Chang, B., Li, L. and Chan, L. (2010) Patatin-like phospholipase domain-containing 3/adiponutrin deficiency in mice is not associated with fatty liver disease. Hepatology 52, 1134-1142.

(148) Akassoglou, K., Malester, B., Xu, J., Tessarollo, L., Rosenbluth, J. and Chao, M.V. (2004) Brain-specific deletion of neuropathy target esterase/swisscheese results in neurodegeneration. Proc. Natl. Acad. Sci. U.S.A. 101, 5075-5080.

(149) Yoda, E., Rai, K., Ogawa, M., Takakura, Y., Kuwata, H., Suzuki, H., Nakatani, Y., Murakami, M. and Hara, S. (2014) Group VIB calcium-independent phospholipase [A.sub.2] (iPLA.sub.2][gamma]) regulates platelet activation, hemostasis and thrombosis in mice. PLoS One 9, e109409.

(150) Yoda, E., Hachisu, K., Taketomi, Y., Yoshida, K., Nakamura, M., Ikeda, K., Taguchi, R., Nakatani, Y., Kuwata, H., Murakami, M., Kudo, I. and Hara, S. (2010) Mitochondrial dysfunction and reduced prostaglandin synthesis in skeletal muscle of Group VIB [Ca.sup.2+]-independent phospholipase [A.sub.2][gamma]-deficient mice. J. Lipid Res. 51, 3003-3015.

(151) Song, H., Wohltmann, M., Bao, S., Ladenson, J.H., Semenkovich, C.F. and Turk, J. (2010) Mice deficient in group VIB phospholipase [A.sub.2] (iPLA.sub.2][gamma]) exhibit relative resistance to obesity and metabolic abnormalities induced by a Western diet. Am. J. Physiol. Endocrinol. Metab. 298, E1097-E1114.

(152) Mancuso, D.J., Kotzbauer, P., Wozniak, D.F., Sims, H.F., Jenkins, C.M., Guan, S., Han, X., Yang, K., Sun, G., Malik, I., Conyers, S., Green, K.G., Schmidt, R.E. and Gross, R.W. (2009) Genetic ablation of calcium-independent phospholipase [A.sub.2][gamma] leads to alterations in hippocampal cardiolipin content and molecular species distribution, mitochondrial degeneration, autophagy, and cognitive dysfunction. J. Biol. Chem. 284, 35632-35644.

(153) Mancuso, D.J., Sims, H.F., Han, X., Jenkins, C.M., Guan, S.P., Yang, K., Moon, S.H., Pietka, T., Abumrad, N.A., Schlesinger, P.H. and Gross, R.W. (2007) Genetic ablation of calcium-independent phospholipase [A.sub.2]. leads to alterations in mitochondrial lipid metabolism and function resulting in a deficient mitochondrial bioenergetic phenotype. J. Biol. Chem. 282, 34611-34622.

(154) Moon, S.H., Jenkins, C.M., Mancuso, D.J., Turk, J. and Gross, R.W. (2008) Smooth muscle cell arachidonic acid release, migration, and proliferation are markedly attenuated in mice null for calcium-independent phospholipase [A.sub.2][beta]. J. Biol. Chem. 283, 33975-33987.

(155) Ramanadham, S., Yarasheski, K.E., Silva, M.J., Wohltmann, M., Novack, D.V., Christiansen, B., Tu, X., Zhang, S., Lei, X. and Turk, J. (2008) Age-related changes in bone morphology are accelerated in group VIA phospholipase [A.sub.2] (i[PLA.sub.2][beta])-null mice. Am. J. Pathol. 172, 868-881.

(156) Shinzawa, K., Sumi, H., Ikawa, M., Matsuoka, Y., Okabe, M., Sakoda, S. and Tsujimoto, Y. (2008) Neuroaxonal dystrophy caused by group VIA phospholipase [A.sub.2] deficiency in mice: a model of human neurodegenerative disease. J. Neurosci. 28, 2212-2220.

(157) Li, H., Zhao, Z., Wei, G., Yan, L., Wang, D., Zhang, H., Sandusky, G.E., Turk, J. and Xu, Y. (2010) Group VIA phospholipase [A.sub.2] in both host and tumor cells is involved in ovarian cancer development. FASEB J. 24, 4103-4116.

(158) McHowat, J., Gullickson, G., Hoover, R.G., Sharma, J., Turk, J. and Kornbluth, J. (2011) Platelet-activating factor and metastasis: calcium-independent phospholipase [A.sub.2][beta] deficiency protects against breast cancer metastasis to the lung. Am. J. Physiol. Cell Physiol. 300, C825-C832.

(159) Page, R.M., Munch, A., Horn, T., Kuhn, P.H., Colombo, A., Reiner, O., Boutros, M., Steiner, H., Lichtenthaler, S.F. and Haass, C. (2012) Loss of PAFAH1B2 reduces amyloid-[beta] generation by promoting the degradation of amyloid precursor protein C-terminal fragments. J. Neurosci. 32, 18204-18214.

(160) Livnat, I., Finkelshtein, D., Ghosh, I., Arai, H. and Reiner, O. (2010) PAF-AH catalytic subunits modulate the Wnt pathway in developing GABAergic neurons. Front. Cell. Neurosci. 4, 19.

(161) Miyata, K., Oike, Y., Hoshii, T., Maekawa, H., Ogawa, H., Suda, T., Araki, K. and Yamamura, K. (2005) Increase of smooth muscle cell migration and of intimal hyperplasia in mice lacking the [alpha]/[beta] hydrolase domain containing 2 gene. Biochem. Biophys. Res. Commun. 329, 296-304.

(162) Jin, S., Zhao, G., Li, Z., Nishimoto, Y., Isohama, Y., Shen, J., Ito, T., Takeya, M., Araki, K., He, P. and Yamamura, K. (2009) Age-related pulmonary emphysema in mice lacking [alpha]/[beta] hydrolase domain containing 2 gene. Biochem. Biophys. Res. Commun. 380, 419-424.

(163) Grond, S., Radner, F.P., Eichmann, T.O., Kolb, D., Grabner, G.F., Wolinski, H., Gruber, R., Hofer, P., Heier, C., Schauer, S., Rulicke, T., Hoefler, G., Schmuth, M., Elias, P.M., Lass, A., Zechner, R. and Haemmerle, G. (2017) Skin barrier development depends on CGI-58 protein expression during late-stage keratinocyte differentiation. J. Invest. Dermatol. 137, 403-413.

(164) Radner, F.P., Streith, I.E., Schoiswohl, G., Schweiger, M., Kumari, M., Eichmann, T.O., Rechberger, G., Koefeler, H.C., Eder, S., Schauer, S., Theussl, H.C., Preiss-Landl, K., Lass, A., Zimmermann, R., Hoefler, G., Zechner, R. and Haemmerle, G. (2010) Growth retardation, impaired triacylglycerol catabolism, hepatic steatosis, and lethal skin barrier defect in mice lacking comparative gene identification-58 (CGI-58). J. Biol. Chem. 285, 7300-7311.

(165) Zhao, S., Mugabo, Y., Ballentine, G., Attane, C., Iglesias, J., Poursharifi, P., Zhang, D., Nguyen, T.A., Erb, H., Prentki, R., Peyot, M.L., Joly, E., Tobin, S., Fulton, S., Brown, J.M., Madiraju, S.R. and Prentki, M. (2016) [alpha]/[beta]-hydrolase domain 6 deletion induces adipose browning and prevents obesity and type 2 diabetes. Cell Rep. 14, 2872-2888.

(166) Duchez, A.C., Boudreau, L.H., Naika, G.S., Bollinger, J., Belleannee, C., Cloutier, N., Laffont, B., Mendoza-Villarroel, R.E., Levesque, T., Rollet-Labelle, E., Rousseau, M., Allaeys, I., Tremblay, J.J., Poubelle, P.E., Lambeau, G., Pouliot, M., Provost, P., Soulet, D., Gelb, M.H. and Boilard, E. (2015) Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase [A.sub.2]-IIA. Proc. Natl. Acad. Sci. U.S.A. 112, E3564-E3573.

(167) Schewe, M., Franken, P.F., Sacchetti, A., Schmitt, M., Joosten, R., Bottcher, R., van Royen, M.E., Jeammet, L., Payre, C., Scott, P.M., Webb, N.R., Gelb, M., Cormier, R.T., Lambeau, G. and Fodde, R. (2016) Secreted phospholipases [A.sub.2] are intestinal stem cell niche factors with distinct roles in homeostasis, inflammation, and cancer. Cell Stem Cell 19, 38-51.

(168) Munoz, N.M., Meliton, A.Y., Meliton, L.N., Dudek, S.M. and Leff, A.R. (2009) Secretory group V phospholipase [A.sub.2] regulates acute lung injury and neutrophilic inflammation caused by LPS in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 296, L879-L887.

(169) Bostrom, M.A., Boyanovsky, B.B., Jordan, C.T., Wadsworth, M.P., Taatjes, D.J., de Beer, F.C. and Webb, N.R. (2007) Group v secretory phospholipase [A.sub.2] promotes atherosclerosis: evidence from genetically altered mice. Arterioscler. Thromb. Vasc. Biol. 27, 600-606.

(170) Yano, T., Fujioka, D., Saito, Y., Kobayashi, T., Nakamura, T., Obata, J.E., Kawabata, K., Watanabe, K., Watanabe, Y., Mishina, H., Tamaru, S. and Kugiyama, K. (2011) Group V secretory phospholipase [A.sub.2] plays a pathogenic role in myocardial ischaemia-reperfusion injury. Cardiovasc. Res. 90, 335-343.

(171) Boyanovsky, B.B., Bailey, W., Dixon, L., Shridas, P. and Webb, N.R. (2012) Group V secretory phospholipase [A.sub.2] enhances the progression of angiotensin II-induced abdominal aortic aneurysms but confers protection against angiotensin II-induced cardiac fibrosis in apoE-deficient mice. Am. J. Pathol. 181, 1088-1098.

(172) Shridas, P., Zahoor, L., Forrest, K.J., Layne, J.D. and Webb, N.R. (2014) Group X secretory phospholipase [A.sub.2] regulates insulin secretion through a cyclooxygenase-2-dependent mechanism. J. Biol. Chem. 289, 27410-27417.

(173) Shridas, P., Bailey, W.M., Talbott, K.R., Oslund, R.C., Gelb, M.H. and Webb, N.R. (2011) Group X secretory phospholipase [A.sub.2] enhances TLR4 signaling in macrophages. J. Immunol. 187, 482-489.

(174) Ait-Oufella, H., Herbin, O., Lahoute, C., Coatrieux, C., Loyer, X., Joffre, J., Laurans, L., Ramkhelawon, B., Blanc-Brude, O., Karabina, S., Girard, C.A., Payre, C., Yamamoto, K., Binder, C.J., Murakami, M., Tedgui, A., Lambeau, G. and Mallat, Z. (2013) Group X secreted phospholipase [A.sub.2] limits the development of atherosclerosis in LDL receptor-null mice. Arterioscler. Thromb. Vasc. Biol. 33, 466-473.

(175) Zack, M., Boyanovsky, B.B., Shridas, P., Bailey, W., Forrest, K., Howatt, D.A., Gelb, M.H., de Beer, F.C., Daugherty, A. and Webb, N.R. (2011) Group X secretory phospholipase [A.sub.2] augments angiotensin II-induced inflammatory responses and abdominal aortic aneurysm formation in apoE-deficient mice. Atherosclerosis 214, 58-64.

(176) Watanabe, K., Fujioka, D., Saito, Y., Nakamura, T., Obata, J.E., Kawabata, K., Watanabe, Y., Mishina, H., Tamaru, S., Hanasaki, K. and Kugiyama, K. (2012) Group X secretory [PLA.sub.2] in neutrophils plays a pathogenic role in abdominal aortic aneurysms in mice. Am. J. Physiol. Heart Circ. Physiol. 302, H95-H104.

(177) Grall, A., Guaguere, E., Planchais, S., Grond, S., Bourrat, E., Hausser, I., Hitte, C., Le Gallo, M., Derbois, C., Kim, G.J., Lagoutte, L., DegorceRubiales, F., Radner, F.P., Thomas, A., Kury, S., Bensignor, E., Fontaine, J., Pin, D., Zimmermann, R., Zechner, R., Lathrop, M., Galibert, F., Andre, C. and Fischer, J. (2012) PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans. Nat. Genet. 44, 140-147.

(178) Fischer, J., Lefevre, C., Morava, E., Mussini, J.M., Laforet, P., Negre-Salvayre, A., Lathrop, M. and Salvayre, R. (2007) The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy. Nat. Genet. 39, 28-30.

(179) Rainier, S., Bui, M., Mark, E., Thomas, D., Tokarz, D., Ming, L., Delaney, C., Richardson, R.J., Albers, J.W., Matsunami, N., Stevens, J., Coon, H., Leppert, M. and Fink, J.K. (2008) Neuropathy target esterase gene mutations cause motor neuron disease. Am. J. Hum. Genet. 82, 780-785.

(180) Vrieze, S.I., Malone, S.M., Pankratz, N., Vaidyanathan, U., Miller, M.B., Kang, H.M., McGue, M., Abecasis, G. and Iacono, W.G. (2014) Genetic associations of nonsynonymous exonic variants with psychophysiological endo-phenotypes. Psychophysiology 51, 1300-1308.

(181) Falchi, M., Bataille, V., Hayward, N.K., Duffy, D.L., Bishop, J.A., Pastinen, T., Cervino, A., Zhao, Z.Z., Deloukas, P., Soranzo, N., Elder, D.E., Barrett, J.H., Martin, N.G., Bishop, D.T., Montgomery, G.W. and Spector, T.D. (2009) Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi. Nat. Genet. 41, 915-919.

(182) Koenig, W., Khuseyinova, N., Lowel, H., Trischler, G. and Meisinger, C. (2004) Lipoprotein-associated phospholipase [A.sub.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. Circulation 110, 1903-1908.

(183) Wootton, P.T., Drenos, F., Cooper, J.A., Thompson, S.R., Stephens, J.W., Hurt-Camejo, E., Wiklund, O., Humphries, S.E. and Talmud, P.J. (2006) Tagging-SNP haplotype analysis of the secretory [PLA.sub.2]IIa gene PLA2G2A shows strong association with serum levels of s[PLA.sub.2]IIa: results from the UDACS study. Hum. Mol. Genet. 15, 355-361.

(184) Leung, S.Y., Chen, X., Chu, K.M., Yuen, S.T., Mathy, J., Ji, J., Chan, A.S., Li, R., Law, S., Troyanskaya, O.G., Tu, I.P., Wong, J., So, S., Botstein, D. and Brown, P.O. (2002) Phospholipase [A.sub.2] group IIA expression in gastric adenocarcinoma is associated with prolonged survival and less frequent metastasis. Proc. Natl. Acad. Sci. U.S.A. 99, 16203-16208.

(185) Takabatake, N., Sata, M., Inoue, S., Shibata, Y., Abe, S., Wada, T., Machiya, J., Ji, G., Matsuura, T., Takeishi, Y., Muramatsu, M. and Kubota, I. (2005) A novel polymorphism in secretory phospholipase [A.sub.2]-IID is associated with body weight loss in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 172, 1097-1104.

(186) McGovern, D.P., Gardet, A., Torkvist, L., Goyette, P., Essers, J., Taylor, K.D., Neale, B.M., Ong, R.T., Lagace, C., Li, C., Green, T., Stevens, C.R., Beauchamp, C., Fleshner, P.R., Carlson, M., D'Amato, M., Halfvarson, J., Hibberd, M.L., Lordal, M., Padyukov, L., Andriulli, A., Colombo, E., Latiano, A., Palmieri, O., Bernard, E.J., Deslandres, C., Hommes, D.W., de Jong, D.J., Stokkers, P.C., Weersma, R.K., Consortium, N.I.G., Sharma, Y., Silverberg, M.S., Cho, J.H., Wu, J., Roeder, K., Brant, S.R., Schumm, L.P., Duerr, R.H., Dubinsky, M.C., Glazer, N.L., Haritunians, T., Ippoliti, A., Melmed, G.Y., Siscovick, D.S., Vasiliauskas, E.A., Targan, S.R., Annese, V., Wijmenga, C., Pettersson, S., Rotter, J.I., Xavier, R.J., Daly, M.J., Rioux, J.D. and Seielstad, M. (2010) Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat. Genet. 42, 332-337.

(187) Kazama, S., Kitayama, J., Hiyoshi, M., Taketomi, Y., Murakami, M., Nishikawa, T., Tanaka, T., Tanaka, J., Kiyomatsu, T., Kawai, K., Hata, K., Yamaguchi, H., Nozawa, H., Ishihara, S., Sunami, E. and Watanabe, T. (2015) Phospholipase [A.sub.2] group III and group X have opposing associations with prognosis in colorectal cancer. Anticancer Res. 35, 2983-2990.

(188) Hoeft, B., Linseisen, J., Beckmann, L., Muller Decker, K., Canzian, F., Husing, A., Kaaks, R., Vogel, U., Jakobsen, M.U., Overvad, K., Hansen, R.D., Knuppel, S., Boeing, H., Trichopoulou, A., Koumantaki, Y., Trichopoulos, D., Berrino, F., Palli, D., Panico, S., Tumino, R., Bueno-deMesquita, H.B., van Duijnhoven, F.J., van Gils, C.H., Peeters, P.H., Dumeaux, V., Lund, E., Huerta Castano, J.M., Munoz, X., Rodriguez, L., Barricarte, A., Manjer, J., Jirstrom, K., Van Guelpen, B., Hallmans, G., Spencer, E.A., Crowe, F.L., Khaw, K.T., Wareham, N., Morois, S., Boutron-Ruault, M.C., Clavel-Chapelon, F., Chajes, V., Jenab, M., Boffetta, P., Vineis, P., Mouw, T., Norat, T., Riboli, E. and Nieters, A. (2010) Polymorphisms in fatty-acid-metabolism-related genes are associated with colorectal cancer risk. Carcinogenesis 31, 466-472.

(189) Martinez-Garcia, A., Sastre, I., Recuero, M., Aldudo, J., Vilella, E., Mateo, I., Sanchez-Juan, P., Vargas, T., Carro, E., Bermejo-Pareja, F., Rodriguez-Rodriguez, E., Combarros, O., Rosich-Estrago, M., Frank, A., Valdivieso, F. and Bullido, M.J. (2010) PLA2G3, a gene involved in oxidative stress induced death, is associated with Alzheimer's disease. J. Alzheimers Dis. 22, 1181-1187.

(190) Wootton, P.T., Arora, N.L., Drenos, F., Thompson, S.R., Cooper, J.A., Stephens, J.W., Hurel, S.J., Hurt-Camejo, E., Wiklund, O., Humphries, S.E. and Talmud, P.J. (2007) Tagging SNP haplotype analysis of the secretory [PLA.sub.2]-V gene, PLA2G, shows strong association with LDL and oxLDL levels, suggesting functional distinction from s[PLA.sub.2]-IIA: results from the UDACS study. Hum. Mol. Genet. 16, 1437-1444.

(191) Sergouniotis, P.I., Davidson, A.E., Mackay, D.S., Lenassi, E., Li, Z., Robson, A.G., Yang, X., Kam, J.H., Isaacs, T.W., Holder, G.E., Jeffery, G., Beck, J.A., Moore, A.T., Plagnol, V. and Webster, A.R. (2011) Biallelic mutations in PLA2G, encoding group V phospholipase [A.sub.2], cause benign fleck retina. Am. J. Hum. Genet. 89, 782-791.

(Received May 9, 2017; accepted July 19, 2017)

Profile

Makoto Murakami was born in Nagano Prefecture in 1964 and graduated from Faculty of Pharmaceutical Sciences, the University of Tokyo, in 1986. He received a M.S. degree in 1988 and a Ph.D. degree in 1991 from the University of Tokyo. He worked as a postdoctoral fellow at the University of Tokyo under a support of the Japan Society for the Promotion of Science from 1991 to 1993 and then at Harvard Medical School under Professor K. Frank Austen from 1993 to 1995. He then worked as an associate professor at School of Pharmaceutical Sciences, Showa University, from 1995 to 2005 and as a project leader of the Lipid Metabolism project, Tokyo Metropolitan Institute of Medical Science, from 2005 to 2016. He is now working as a professor at Graduate School of Medicine, the University of Tokyo, since 2017. He has authored 180 original articles and 54 review articles (in English) and 100 review articles (in Japanese) on phospholipase [A.sub.2]s and lipid mediators. He is now a committee member of the Japanese Biochemical Society, Japanese Lipid Biochemistry Society, and Japanese Society of Inflammation and Regeneration. He received the Young Investigator Awards for the Pharmaceutical Society of Japan in 1999 and the Japanese Society of Inflammation and Regeneration in 2000, Investigator Awards for the Tokyo Metropolitan Institute of Medical Science in 2008, Award for the Terumo Science Foundation in 2014, and the Bureau of Social Welfare and Public Health at Tokyo Metropolitan Government in 2015.

By Makoto MURAKAMI * [1], * [2], * [3], ([dagger])

(Communicated by Kunihiko SUZUKI, M.J.A.)

* [1] Laboratory of Environmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.

* [2] Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

* [3] AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan.

([dagger]) Correspondence should be addressed: M. Murakami, Laboratory of Environmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan (e-mail: makmurak@m.utokyo.ac.jp).

Caption: Fig. 1. The eicosanoid-biosynthetic pathway (AA metabolism). The AA released by [PLA.sub.2] from cellular membrane is metabolized to various eicosanoids through the COX and LOX pathways. Structures and representative bioactivities of individual eicosanoids and their biosynthetic enzymes are shown. H- and L-PGDS, hematopoietic and lipocalin-type [PGD.sub.2] synthases, respectively; PGFS, [PGF.sub.2[alpha]], synthase, PGIS, [PGI.sub.2] synthase; mPGES-1, microsomal [PGE.sub.2] synthase-1; TXS, TX synthase; 12-HHT, 12-hydroxyheptadecatrenoic acid; 12-HETE, 12-hydroxyeicosatetraenoic acid; FLAP, 5-LOX-activating protein; [LTA.sub.4]H, [LTA.sub.4] hydrolase; [LTC.sub.4]S, [LTC.sub.4] synthase.

Caption: Fig. 2. Lysophospholipid-derived lipid mediators (LPA and PAF) and PUFA-derived anti-inflammatory lipid mediators (lipoxin, resolvin and protectin). (A) Two biosynthetic pathways for LPA. LPA is produced by fatty acid deacylation of phosphatidic acid (PA) by [PLA.sub.2] (or [PLA.sub.1]), or by removal of the polar head group of lysophosphatidylcholine (LPC), which is produced from PC by [PLA.sub.2] (or [PLA.sub.1]), by a lysophospholipase D termed autotaxin (ATX). In most if not all in vivo situations, the ATX-dependent route is dominant for the production of LPA. DAG, diacylglycerol; DGK, diacylglycerol kinase; PLD, phospholipase D. (B) Biosynthesis and degradation of PAF. Alkyl-PC is converted by [PLA.sub.2] to alkyl-LPC (LysoPAF), which is then acetylated by LPC acyltransferase 2 (LPCAT2) to give rise to PAF. PAF is deacetylated to LysoPAF by PAFAH, a unique group of [PLA.sub.2]s. LysoPAF is converted back to alkyl-PC by LPCAT3. (C) Anti-inflammatory PUFA metabolites derived from [omega]6 AA (lipoxin [A.sub.4]; [LXA.sub.4]), [omega]3 EPA (resolvin E1; RvE1), and [omega]3 DHA (RvD1 and protectin D1; PD1). The double bond characteristic of the [omega]3 and [omega]6 PUFAs is shadowed.

Caption: Fig. 3. The c[PLA.sub.2] family. (A) Structures of c[PLA.sub.2] enzymes ([alpha]-[zeta]). The C2 domain, which is essential for [Ca.sup.2+]-dependent membrane translocation, is conserved in c[PLA.sub.2] enzymes except for c[PLA.sub.2][gamma], whose C-terminal region is farnesylated. (B) A schematic diagram of stimulus-induced c[PLA.sub.2][alpha] activation. For details, see the text.

Caption: Fig. 4. The i[PLA.sub.2]/PNPLA family. Structures of i[PLA.sub.2]/PNPLA enzymes (PNPLA1~9), which are subdivided into lipase and phospholipase types, are shown. The patatin domain, which is characteristic of this family, is conserved in all of these enzymes. The biological functions and enzymatic properties of the individual enzymes are indicated on the right. For details, see the text.

Caption: Fig. 5. The role of PNPLA1 in epidermal acylceramide biosynthesis. Structures of the metabolites and enzymes or transporters responsible for individual steps in the acylceramide-biosynthetic pathway are indicated. Mutations or deletions of these enzymes cause ichthyosis in both human and mouse. PNPLA1 catalyzes the transacylation of LA from triglyceride to [omega]-OH ceramide, leading to the formation of [omega]-O-acylceramide, which is an essential component of lipid lamellae and the cornified lipid envelope in the uppermost epidermis. For details, see the text. ELOVL6, fatty acid elongase 6; CYP4F22/39, cytochrome P450 family F22 (in human) and F39 (in mouse); CERS3, ceramide synthase 3; ABCA12, ABC transporter 12; UGCG, UDP-glucose ceramide glucosyltransferase; GBA, [beta]-glucocerebrosidase; ALOXE3, epidermal-type lipoxygenase 3; ALOX12B, 12R-lipoxygenase; TGM1, transglutaminase 1.

Caption: Fig. 6. The s[PLA.sub.2] family. The phylogenetic tree of s[PLA.sub.2] isoforms, which are subdivided into classical s[PLA.sub.2]s (I/II/V/X branch) and atypical s[PLA.sub.2]s (III and XII branches), is shown. The pathophysiological roles and related types of lipid metabolism (target substrates or products; shown in blue) for the individual isoforms are indicated. For details, see the text.

Caption: Fig. 7. Properties of s[PLA.sub.2]-IIF. (A) A schematic procedure for identification of the lipid metabolism driven by s[PLA.sub.2]-IIF in differentiating keratinocytes. Phospholipids extracted from the culture supernatants of mouse keratinocytes (a representative mass spectrometric profile of phospholipids is shown; IS, internal standard; cps, count per second) were incubated with a physiologically relevant concentration of recombinant s[PLA.sub.2]-IIF and then taken for the lipidomics analysis. (B) In the assay shown in (A), s[PLA.sub.2]-IIF preferentially increased plasmalogen-type (P-) lysophosphatidylethanolamine (LPE) species as well as PUFAs. Values represent AUC (area under the curve; mean [+ or -] SEM, n = 4). (C) The results shown in (B), together with in vivo analyses using s[PLA.sub.2]-IIF-transgenic and knockout mice, (6) indicate that s[PLA.sub.2]-IIF preferentially hydrolyzes P-PE bearing DHA to liberate P-LPE and DHA under physiological conditions. For more details, please see ref. 6.

Caption: Fig. 8. Fatty acid selectivity of s[PLA.sub.2]-V. Lipids extracted from the spleen of 1-year-old s[PLA.sub.2]-V-deficient (-/-) and littermate control (+/+) mice were subjected to mass spectrometric lipidomics analysis (values are mean [+ or -] SEM, * P <0.05 and ** P <0.01). Experiments were performed in accordance with the procedure described previously (5). Y-axis indicate relative abundance (AUC; area under the curve) of each product per mg tissue. Free fatty acid (FFA) species with a lower degree of unsaturation, including PA (16:0), palmitoleic acid (16:1), stearic acid (18:0; SA), OA (18:1), LA (18:2), eicosanoic acid (20:0) and eicosenoic acid (C20:1), but not PUFAs including AA (20:4), EPA (20:5), DPA (22:5) and DHA (22:6), were significantly reduced in s[PLA.sub.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 s[PLA.sub.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.
Table 1. Properties of PLA2 subtypes and their biological roles

Family           Number of     Nomenclature     General names
                 isozymes

c[PLA.sub.2]     6             PLA2G4A          c[PLA.sub.2][alpha]

i[PLA.sub.2]     9             PNPLA1

                               PNPLA2           i[PLA.sub.2]
                                                [zeta]/ATGL

                               PMPLA3           i[PLA.sub.2]
                                                [epsilon]/
                                                Adiponutrin

                               PNPLA6           i[PLA.sub.2]
                                                [delta]/NTE

                               PNPLA7           i[PLA.sub.2]
                                                [theta]/NRE

                               PNPLA8           i[PLA.sub.2]
                                                [gamma]/PLA2G6B

                               PNPLA9           i[PLA.sub.2]
                                                [beta]/PLA2G6

PAF-AH           4             PLA2G7           PAFAH/
                                                Lp-[PLA.sub.2]

                               PAFAH2           PAFAH2/
                                                PLA2G7B

                               PAFAH1B2         PLA2G8A/
                                                PAFAH1
                                                [alpha]1
                                                subunit

                               PAFAH1B3         PLA2G8B/
                                                PAFAH1
                                                [alpha]2
                                                subunit

LPLA2            1             PLA2G15          Lysosomal
                                                [PLA.sub.2]

PLAAT            5             PLA2G16          HRASLS3/
                                                H-rev 107/
                                                PLAAT3

ABHD             19            ABHD2

                               ABHD3

                               ABHD4

                               ABHD5            CGI-58

                               ABHD6

                               ABHD12

                               ABHD16A

s[PLA.sub.2]     11            PLA2G1B          s[PLA.sub.2]-IB

                               PLA2G2A          s[PLA.sub.2]-IIA

                               PLA2G2D          s[PLA.sub.2]-IID

                               PLA2G2E          s[PLA.sub.2]-IIE

                               PLA2G2F          s[PLA.sub.2]-IIF

                               PLA2G5           s[PLA.sub.2]-V

                               PLA2G10          s[PLA.sub.2]-X

                               PLA2G3           s[PLA.sub.2]-III

                               PLA2G12B         s[PLA.sub.2]-XIIB

Family          Nomenclature     Distributions

c[PLA.sub.2]    PLA2G4A          Ubiquitous

i[PLA.sub.2]    PNPLA1           Epidermal
                                 keratinocytes

                PNPLA2           Ubiquitous (Abundant
                                 in adipose tissue
                                 and skeletal muscle)

                PMPLA3           Ubiquitous (Abundant
                                 in liver and adipose
                                 tissue)

                PNPLA6           Ubiquitous

                PNPLA7           Ubiquitous

                PNPLA8           Ubiquitous

                PNPLA9           Ubiquitous

PAF-AH          PLA2G7           Plasma

                PAFAH2           Liver, Kidney

                PAFAH1B2         Ubiquitous

                PAFAH1B3         Ubiquitous

LPLA2           PLA2G15          Ubiquitous

PLAAT           PLA2G16          Adipocytes

ABHD            ABHD2            Ubiquitous

                ABHD3            Ubiquitous

                ABHD4            Ubiquitous

                ABHD5            Ubiquitous

                ABHD6            Ubiquitous

                ABHD12           Ubiquitous

                ABHD16A          Ubiquitous

s[PLA.sub.2]    PLA2G1B          Pancreatic acinar
                                 cells

                PLA2G2A          Small intestinal
                                 Paneth cells,
                                 Leukocytes,
                                 Platelets,
                                 Epithelial cells

                PLA2G2D          Lymphoid DCs

                PLA2G2E          Hypertrophic
                                 adipocytes,

                                 Hair follicles

                PLA2G2F          Epidermal
                                 keratinocytes

                PLA2G5           Hypertrophic
                                 adipocytes,

                                 Bronchial epithelial
                                 cells,

                                 Macrophages, Smooth
                                 muscle cells,

                                 Cardiomyocytes

                PLA2G10          Colorectal
                                 epithelial and
                                 goblet cells, Sperm

                PLA2G3           Epididymal
                                 epithelial cells,
                                 Mast cells

                PLA2G12B         Hepatocytes

Family          Nomenclature     Enzymatic functions

c[PLA.sub.2]    PLA2G4A          AA-specific [PLA.sub.2]

i[PLA.sub.2]    PNPLA1           [omega]-O-acylcer
                                 amide transacylase

                PNPLA2           TG lipase

                PMPLA3           TG lipase
                                 retinyl-palmitate
                                 lipase

                PNPLA6           Lyso phospholipase

                PNPLA7           Lysophospholipase

                PNPLA8           [PLA.sub.1] or
                                 [PLA.sub.2]

                PNPLA9           pla2

PAF-AH          PLA2G7           PAF acetylhydrolase,
                                 oxidized
                                 phospholipid-
                                 specific [PLA.sub.2]

                PAFAH2           PAF acetylhydrolase,
                                 oxidized
                                 phospholipid-
                                 specific [PLA.sub.2]

                PAFAH1B2         PAF acetylhydrolase

                PAFAH1B3         PAF acetylhydrolase

LPLA2           PLA2G15          [PLA.sub.1] or
                                 [PLA.sub.2]

PLAAT           PLA2G16          [PLA.sub.1] or
                                 [PLA.sub.2], N-acyl
                                 PE acyltransferase

ABHD            ABHD2            Hydratase

                ABHD3            Medium-chain and
                                 oxidatively
                                 truncated
                                 phospholipid-
                                 selective
                                 [PLA.sub.1] or
                                 [PLA.sub.2]

                ABHD4            JV-acyl-
                                 phospholipid-
                                 selective
                                 [PLA.sub.1] or
                                 [PLA.sub.2]

                ABHD5            Catalytically
                                 inactive

                ABHD6            Lysophospholipase or
                                 monoacylglycerol
                                 lipase

                ABHD12           LysoPS lipase

                ABHD16A          PS lipase

s[PLA.sub.2]    PLA2G1B          [PLA.sub.2]

                PLA2G2A          [PLA.sub.2]

                PLA2G2D          [PLA.sub.2]

                PLA2G2E          [PLA.sub.2]

                PLA2G2F          [PLA.sub.2]

                PLA2G5           [PLA.sub.2]

                PLA2G10          [PLA.sub.2]

                PLA2G3           [PLA.sub.2]

                PLA2G12B         Catalytically
                                 inactive

Family          Nomenclature     Lipid mobilization

c[PLA.sub.2]    PLA2G4A          Production of AA
                                 metabolites or PAF

i[PLA.sub.2]    PNPLA1           Production of
                                 [omega]-O-
                                 acylceramide for
                                 skin barrier
                                 formation

                PNPLA2           Hydrolysis of TG in
                                 lipid droplets for
                                 fatty acid [beta]-
                                 oxidation

                PMPLA3           Hepatic TG
                                 remodeling for
                                 neutral lipid
                                 accumulation

                PNPLA6           Hydrolysis of LPC

                PNPLA7           Hydrolysis of LPC

                PNPLA8           Membrane
                                 (caldiolipin?)
                                 remodeling
                                 Production of
                                 arachidonate
                                 metabolites or PUFA-
                                 containing
                                 lysophospholipids

                PNPLA9           Membrane remodeling
                                 Production of AA
                                 metabolites or PAF

PAF-AH          PLA2G7           Hydrolysis of
                                 extracellular PAF,
                                 Degradation of
                                 oxidized
                                 phospholipids in
                                 lipoproteins

                PAFAH2           Degradation of
                                 oxidized
                                 phospholipids in
                                 cell membranes

                PAFAH1B2         Hydrolysis of
                                 intracellular PAF

                PAFAH1B3         Hydrolysis of
                                 intracellular PAF

LPLA2           PLA2G15          Lysosomal
                                 degradation of
                                 phospholipids

PLAAT           PLA2G16          Production of
                                 eicosanoids? JV-
                                 acyl-PE metabolism?

ABHD            ABHD2            PC metabolism?

                ABHD3            Hydrolysis of
                                 phospholipids with
                                 medium-chain fatty
                                 acids

                ABHD4            Hydrolysis of N-
                                 acyl-phospholipids

                ABHD5            Acting as a cofactor
                                 for PNPLA2-mediated
                                 lipolysis

                ABHD6            Hydrolysis of
                                 lysophospholipids
                                 and 2-AG

                ABHD12           Hydrolysis of
                                 LysoPS

                ABHD16A          Hydrolysis of PS

s[PLA.sub.2]    PLA2G1B          Dietary and biliary
                                 phospholipid
                                 digestion

                PLA2G2A          Degradation of
                                 bacterial membrane
                                 phospholipids,
                                 Hydrolysis of
                                 microparticular
                                 phospholipids to
                                 yield eicosanoids
                                 and
                                 lysophospholipids

                PLA2G2D          Preferential
                                 production of
                                 [omega]3 PUFA-
                                 derived pro-
                                 resolving lipid
                                 mediators

                PLA2G2E          Hydrolysis of PE and
                                 PS in lipoproteins

                                 Uncertain

                PLA2G2F          Production of
                                 lysoplasmalogen

                PLA2G5           Hydrolysis of PC in
                                 LDL to yield OA

                                 Hydrolysis of lung
                                 surfactant

                                 Production of
                                 eicosanoids?

                                 Production of LPE or
                                 cys-LTs?

                                 Uncertain

                PLA2G10          Mobilization of
                                 [omega]3 PUF As

                                 Production of
                                 eicosanoids and LPC

                                 Hydrolysis of sperm
                                 membrane
                                 phospholipids to
                                 yield DPA and LPC

                                 Production of
                                 [PGE.sub.2]?

                                 Production of PUFAs
                                 that attenuate
                                 nuclear receptor
                                 signaling?

                                 Uncertain

                PLA2G3           Sperm membrane
                                 phospholipid
                                 remodeling

                                 Production of
                                 microenvironmental
                                 [PGD.sub.2]

                PLA2G12B         Uncertain

Family          Nomenclature     Phenotipic outcomes
                                 in knockout (KO)
                                 mice

c[PLA.sub.2]    PLA2G4A          Attenuations of
                                 airway inflammation
                                 (acute lung injury,
                                 bronchial asthma,
                                 and plumonary
                                 fibrosis), cerebral
                                 infarction,
                                 neurodegeneration
                                 (Alzheimer's
                                 disease),
                                 experimental
                                 autoimmune
                                 encephalomyelitis,
                                 collagen-induced
                                 arthritis, metabolic
                                 syndrome
                                 (atherosclerosis,
                                 obesity, and hepatic
                                 steatosis), and
                                 intestinal cancer.
                                 Exacerbations of
                                 ulcerative colitis,
                                 spinal cord injury,
                                 stress-induced
                                 cardiac hypertrophy,
                                 hemorrhage, female
                                 infertility, and
                                 renal function.

i[PLA.sub.2]    PNPLA1           Lethal ichthyosis

                PNPLA2           TG accumulation in
                                 multiple tissues,
                                 Defective lipolysis
                                 and alterd energy
                                 metabolism, Cardiac
                                 dysfunction,
                                 Protection from
                                 cancer-associated
                                 cachexia by
                                 preventing fat loss

                                 Impaired
                                 phagocytosis of
                                 macrophages and
                                 resistance to
                                 atherosclerosis
                                 (macrophage-
                                 specific KO)

                                 Hyperglycemia due to
                                 impaired insulin
                                 secretion ([beta]-
                                 cell-specific KO)

                PMPLA3           Perturbed hepatic
                                 fatty acid
                                 metabolism and TG
                                 accumulation under
                                 ER stress

                                 Exacerbation of
                                 nonalcoholic fatty
                                 liver disease (loss-
                                 of-function
                                 mutation)

                PNPLA6           Embryonic lethality
                                 due to placental
                                 defect

                                 Neurodegeneration
                                 (neuron-specific KO)

                PNPLA7           Aberrant hepatic
                                 metabolism
                                 (unpublished data)

                PNPLA8           Skeletal muscular
                                 weakness, heart
                                 failure, and
                                 impaired adaptive
                                 thermogenesis due to
                                 mitochondorial
                                 dysfunction and
                                 reduced [beta]-
                                 oxidation, Resistant
                                 to diet-induced
                                 metabolic syndrome,
                                 Neurodegeneration,
                                 Susceptibility to
                                 parasitic infection,
                                 Platelet dysfunction

                PNPLA9           Male infertility,
                                 Impaired glucose-
                                 induced insulin
                                 secreteion,
                                 Neurodegeneration,
                                 Aged-related bone
                                 loss, Reduction of
                                 pancreatic [beta]-
                                 cell apoptosis,
                                 migration and
                                 contraction of
                                 vascular cells, and
                                 tumorigenesis of
                                 ovarian and breast
                                 cancers

PAF-AH          PLA2G7           Protection from
                                 atherosclerosis
                                 (human mutations)

                                 Resistance to colon
                                 tumorigenesis

                PAFAH2           Protection from
                                 oxidative stress-
                                 induced liver damage

                PAFAH1B2         Male infertility due
                                 to impaired
                                 testicular
                                 spermatogenesis,
                                 Reduced A[beta]
                                 production

                PAFAH1B3         Enlargement of
                                 ganglionic eminences
                                 in [Pafah1b2.sup.-/
                                 -][Pafah1b3.sup.-/
                                 -] mice

LPLA2           PLA2G15          Abberant
                                 accumulation of non-
                                 degraded surfactant
                                 phospholipids in
                                 lysosomes of
                                 alveolar macrophages
                                 (phospholipidosis),
                                 Impaired selection
                                 and maturation of
                                 iNKT cells, Impaired
                                 adaptive T cell
                                 immunity against
                                 mycobacterium

PLAAT           PLA2G16          Resistance to diet-
                                 induced obesity and
                                 metabolic syndrome

ABHD            ABHD2            Increase of smooth
                                 muscle cell
                                 migration and
                                 intimai hyperplasia,
                                 Pulmonary emphysema
                                 in aged mice due to
                                 altered surfactant
                                 phospholipid
                                 metabolism

                ABHD3            Impaired hydrolysis
                                 of myristoyl-
                                 phospholipids

                ABHD4            Impaired hydrolysis
                                 of N-acyl-PE

                ABHD5            Impaired hydrolysis
                                 of TG, Lethal
                                 ichthyosis

                ABHD6            Impaired hydrolysis
                                 of 2-AG for
                                 microglia migration,
                                 Enhanced adipose
                                 browning, Attenuated
                                 diet-induced obesity
                                 and metabolic
                                 syndrome

                ABHD12           Massive accumulation
                                 of LysoPS in brain
                                 leading to age-
                                 dependent increases
                                 in microglial
                                 activation, auditory
                                 and motor defects

                ABHD16A          Lower lysoPS content
                                 in the CNS, Reduced
                                 body size, Decreased
                                 cytokine production
                                 by peritoneal
                                 macrophages

s[PLA.sub.2]    PLA2G1B          Resistance to diet-
                                 induced obesity,
                                 insulin resistance,
                                 and atherosclerosis

                PLA2G2A          Resistance to
                                 bacterial infection
                                 (transgenic mice)

                                 Resistance to
                                 arthritis

                                 Increased
                                 susceptibility to
                                 colorectal cancer
                                 (natural mutation)

                PLA2G2D          Exacervation of
                                 contact
                                 hypersensitivity and
                                 psoriasis,
                                 Protection from skin
                                 cancer and viral
                                 infection

                PLA2G2E          Protection from
                                 diet-induced obesity
                                 and hyperlipidemia

                                 Modest abnormalities
                                 in hair follicles

                PLA2G2F          Protection from
                                 psoriasis and skin
                                 cancer

                PLA2G5           Exacerbation of
                                 diet-induced obesity
                                 and associated
                                 metabolic phenotypes

                                 Neonatal death due
                                 to a respiratory
                                 defect (transgenic
                                 mice)

                                 Resistance to LPS-
                                 induced airway
                                 injury

                                 Reduced Th2 response
                                 and asthma

                                 Defective
                                 phagocytosis of
                                 harmful materials
                                 leading to increased
                                 susceptibility to
                                 infection and
                                 arthritis

                                 Protection from
                                 atherosclerosis
                                 (hematopoietic cell-
                                 specific KO), aortic
                                 rupture, and
                                 myocardial
                                 infarction

                PLA2G10          Exacerbation of
                                 colitis and
                                 colorectal cancer

                                 Attenuation of
                                 asthma and
                                 influenza-induced
                                 pneumonia

                                 Reduced male
                                 fertility

                                 Reduced insulin
                                 secretion

                                 Hypercorticosteronemia,
                                 Reduced TLR4
                                 signaling

                                 Exacerbation of
                                 atherosclerosis with
                                 increased Thl
                                 immunity
                                 (hematopoietic cell-
                                 specific KO),
                                 Reduced nociception,
                                 Attenuation of
                                 aneurysm and
                                 myocardial
                                 infarction

                PLA2G3           Impaired epididymal
                                 sperm maturation and
                                 male infertility

                                 Impaired mast cell
                                 maturation and
                                 associated
                                 anaphylaxis

                PLA2G12B         Steatohepatitis due
                                 to impaired hepatic
                                 VLDL secretion

Family          Nomenclature     References

c[PLA.sub.2]    PLA2G4A          14-24

i[PLA.sub.2]    PNPLA1           68

                PNPLA2           57, 58,
                                 60

                                 144

                                 145

                PMPLA3           146, 147

                                 64

                PNPLA6           48

                                 148

                PNPLA7

                PNPLA8           46,
                                 149-153

                PNPLA9           54, 55,
                                 154-158

PAF-AH          PLA2G7           78

                PAFAH2           74

                PAFAH1B2         73, 159,
                                 160

                PAFAH1B3         161

LPLA2           PLA2G15          80-82

PLAAT           PLA2G16          84

ABHD            ABHD2            161, 162

                ABHD3            90

                ABHD4            91

                ABHD5            163, 164

                ABHD6            92, 93,
                                 165

                ABHD12           96, 97

                ABHD16A          96

s[PLA.sub.2]    PLA2G1B          105, 106,
                                 108

                PLA2G2A          113, 114

                                 115, 126,
                                 166

                                 167

                PLA2G2D          7, 116,
                                 117

                PLA2G2E          119

                                 118

                PLA2G2F          6

                PLA2G5           119

                                 123

                                 168

                                 124, 131

                                 125-127

                                 169-171

                PLA2G10          24, 167

                                 130-132

                                 24, 129

                                 172

                                 173

                                 174-176

                PLA2G3           135

                                 136

                PLA2G12B         139

Enzymes whose in vivo functions have been analyzed using
knockout mice are summarized.

Table 2. Representative PLA2 mutations in human diseases

Families           [PLA.sub.2] genes          Human diseases

c[PLA.sub.2]     PLA2G4A                  Platelet
                                          dysfunction,
                                          Intestinal
                                          ulceration

i[PLA.sub.2]     PNPLA1                   Ichthyosis

                 PNPLA2                   Chanarin-Dorfman
                                          syndrome (neutral
                                          lipid strage disease
                                          with myopathy)

                 PNPLA3                   Non-alchoholic fatty
                                          liver disease (NASH,
                                          NAFLD)

                 PNPLA6                   Ataxia, Hereditary
                                          spastic paraplegia,
                                          Boucher-Neuhauser
                                          and Gordon Holmes
                                          syndromes

                                          Photoreceptor
                                          degeneration

                 PNPLA7                   Psychophysiological
                                          endophenotype

                 PNPLA8                   Myopathy

                 PNPLA9/ PLA2G6           Parkinson's disease,
                                          Infantile
                                          neuroaxonal
                                          dystrophy (INAD)

                                          Familial melanoma

PAFAH            PAFAH/PLA2G7A            Cardiovascular
                                          disease

ABHD             ABHD5                    Chanarin-Dorfman
                                          Syndrome with
                                          ichtyosis

                 ABHD12                   PHARC syndrome
                                          (polyneuropathy,
                                          hearing loss,
                                          ataxia, retinitis
                                          pigmentosa, and
                                          cataract)

s[PLA.sub.2]     PLA2G1B                  Obesity

                 PLA2G2A                  Cardiovascular
                                          disease

                                          Gastric cancer

                 PLA2G2D                  Body weight loss in
                                          COPD (chronic
                                          obstructive
                                          pulmonary disease)

                 PLA2G2E                  Ulcerative colitis

                 PLA2G3                   Colorectal cancer

                                          Alzheimer's disease

                 PLA2G5                   Hyperlipidemia in
                                          type II diabetes

                                          Benign fleck retina

Families             Human diseases       References

c[PLA.sub.2]     Platelet                 35
                 dysfunction,
                 Intestinal
                 ulceration

i[PLA.sub.2]     Ichthyosis               177

                 Chanarin-Dorfman         178
                 syndrome (neutral
                 lipid strage disease
                 with myopathy)

                 Non-alchoholic fatty     63
                 liver disease (NASH,
                 NAFLD)

                 Ataxia, Hereditary       179
                 spastic paraplegia,
                 Boucher-Neuhauser
                 and Gordon Holmes
                 syndromes

                 Photoreceptor            53
                 degeneration

                 Psychophysiological      180
                 endophenotype

                 Myopathy                 51

                 Parkinson's disease,     49
                 Infantile
                 neuroaxonal
                 dystrophy (INAD)

                 Familial melanoma        181

PAFAH            Cardiovascular           182
                 disease

ABHD             Chanarin-Dorfman         98
                 Syndrome with
                 ichtyosis

                 PHARC syndrome           97
                 (polyneuropathy,
                 hearing loss,
                 ataxia, retinitis
                 pigmentosa, and
                 cataract)

s[PLA.sub.2]     Obesity                  109

                 Cardiovascular           142, 183
                 disease

                 Gastric cancer           184

                 Body weight loss in      185
                 COPD (chronic
                 obstructive
                 pulmonary disease)

                 Ulcerative colitis       186

                 Colorectal cancer        187, 188

                 Alzheimer's disease      189

                 Hyperlipidemia in        114, 190
                 type II diabetes

                 Benign fleck retina      191
COPYRIGHT 2017 The Japan Academy
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2017 Gale, Cengage Learning. All rights reserved.

 
Article Details
Printer friendly Cite/link Email Feedback
Author:Murakami, Makoto
Publication:Japan Academy Proceedings Series B: Physical and Biological Sciences
Article Type:Report
Geographic Code:9JAPA
Date:Sep 1, 2017
Words:18034
Previous Article:Significance of functional disease-causal/susceptible variants identified by whole-genome analyses for the understanding of human diseases.
Next Article:Prostaglandin terminal synthases as novel therapeutic targets.
Topics:

Terms of use | Privacy policy | Copyright © 2018 Farlex, Inc. | Feedback | For webmasters