Lipoquality control by phospholipase [A.sub.2] enzymes.
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.
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.
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(Received May 9, 2017; accepted July 19, 2017)
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 * , * , * , ([dagger])
(Communicated by Kunihiko SUZUKI, M.J.A.)
*  Laboratory of Environmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
*  Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
*  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: email@example.com).
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
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|Publication:||Japan Academy Proceedings Series B: Physical and Biological Sciences|
|Date:||Sep 1, 2017|
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