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Phospholipases: From Structure to Biological Function
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Phospholipases: From Structure to Biological Function

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biological Factors".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 68243

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. María A. Balboa

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Guest Editor
1. Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Valladolid, 47003 Valladolid, Spain
2. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
Interests: inflammation; innate immunity; lipid mediators; phospholipases; lipins
Prof. Dr. Jesús Balsinde

E-Mail Website
Guest Editor
1. Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), 47003 Valladolid, Spain
2. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
Interests: inflammation; innate immunity; lipid mediators; phospholipases; lipins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is now widely recognized that, in addition to their roles as membrane building blocks and energy sources, lipids play key roles in intracellular signalling and extracellular cell communication. When deregulated, lipid signalling contributes to a wide range of diseases, including cardiovascular and degenerative diseases, and cancer. Many bioactive lipids are generated by phospholipases, which are enzymes that hydrolyze the esther bonds present in phospholipids. As there are four different ester bonds in phospholipids, four major classes of phospholipases enzymes exist, termed A, B, C, and D, which are distinguished by the type of reaction that they catalyse.

Phospholipases of the A-type, which include A1 and A2 forms, are acyl hydrolases, which release fatty acids such as arachidonic acid, and lysophospholipids. Each of these products is implicated in the signal transduction process itself, but also serve as a precursor for eicosanoids, including prostaglandins, leukotrienes, and lipoxins or platelet activating factor. These compounds are implicated in numerous inflammatory diseases, such as rheumatoid arthritis, sepsis, intestinal bowel disease, and asthma, as well as playing a role in cancer, atherosclerosis, and premature parturition. Other important phospholipases include phospholipase C, which controls the production of inositol-1,4,5-trisphosphate, which induces cytosolic Ca2+ release, and diacylglycerol, which activates a myriad of intracellular effectors. Phospholipase D generates phosphatidic acid, which subsequently can either be metabolized to lysophosphophatidic acid, a potent cellular mitogen, or by phosphatidate phosphohydrolase, yielding diacylglycerol. The family of type-2 phosphatidate phosphatases, collectively called lipins, are Mg2+-dependent phospholipase C-type enzymes that act specifically on phosphatidic acid, and have recently gained much attention because of their involvement in a number of pathologies, including rhadomyolisis, atherosclerosis, and colon cancer. Sphingomyelinase, another phospholipase C-type enzyme, and related enzymes of the sphingolipid metabolism are implicated in apoptosis and other signalling processes.

In summary, the phospholipases generate numerous lipid products, which control much of cellular signalling. The aim of this Special Issue aims to bring together international experts to provide a comprehensive view of the recent advances related to the subject of "phospholipases". Both original research articles or focused reviews are acceptable. Articles with mechanistic and functional insights at a cellular or molecular level, as well as animal models of disease are particularly welcome.

Prof. María A. Balboa
Prof. Jesús Balsinde
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Bioactive lipids and lipid signaling
  • Membrane remodeling
  • Phospholipase A2
  • Phospholipase C
  • Phospholipase D
  • Sphingomyelinase
  • Lipins and lipinopathies
  • Animal models of disease

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Published Papers (17 papers)

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Editorial

Jump to: Research, Review

4 pages, 211 KiB  
Editorial
Phospholipases: From Structure to Biological Function
by María A. Balboa and Jesús Balsinde
Biomolecules 2021, 11(3), 428; https://doi.org/10.3390/biom11030428 - 15 Mar 2021
Cited by 17 | Viewed by 1901
Abstract
Phospholipases are enzymes that cleave ester bonds within phospholipids [...] Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)

Research

Jump to: Editorial, Review

16 pages, 5191 KiB  
Article
Lipid Profile of Activated Macrophages and Contribution of Group V Phospholipase A2
by Masaya Koganesawa, Munehiro Yamaguchi, Sachin K. Samuchiwal and Barbara Balestrieri
Biomolecules 2021, 11(1), 25; https://doi.org/10.3390/biom11010025 - 29 Dec 2020
Cited by 14 | Viewed by 2649
Abstract
Macrophages activated by Interleukin (IL)-4 (M2) or LPS+ Interferon (IFN)γ (M1) perform specific functions respectively in type 2 inflammation and killing of pathogens. Group V phospholipase A2 (Pla2g5) is required for the development and functions of IL-4-activated macrophages and phagocytosis of pathogens. [...] Read more.
Macrophages activated by Interleukin (IL)-4 (M2) or LPS+ Interferon (IFN)γ (M1) perform specific functions respectively in type 2 inflammation and killing of pathogens. Group V phospholipase A2 (Pla2g5) is required for the development and functions of IL-4-activated macrophages and phagocytosis of pathogens. Pla2g5-generated bioactive lipids, including lysophospholipids (LysoPLs), fatty acids (FAs), and eicosanoids, have a role in many diseases. However, little is known about their production by differentially activated macrophages. We performed an unbiased mass-spectrometry analysis of phospholipids (PLs), LysoPLs, FAs, and eicosanoids produced by Wild Type (WT) and Pla2g5-null IL-4-activated bone marrow-derived macrophages (IL-4)BM-Macs (M2) and (LPS+IFNγ)BM-Macs (M1). Phosphatidylcholine (PC) was preferentially metabolized in (LPS+IFNγ)BM-Macs and Phosphatidylethanolamine (PE) in (IL-4)BM-Macs, with Pla2g5 contributing mostly to metabolization of selected PE molecules. While Pla2g5 produced palmitic acid (PA) in (LPS+IFNγ)BM-Macs, the absence of Pla2g5 increased myristic acid (MA) in (IL-4)BM-Macs. Among eicosanoids, Prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2) were significantly reduced in (IL-4)BM-Macs and (LPS+IFNγ)BM-Macs lacking Pla2g5. Instead, the IL-4-induced increase in 20-carboxy arachidonic acid (20CooH AA) was dependent on Pla2g5, as was the production of 12-hydroxy-heptadecatrienoic acid (12-HHTrE) in (LPS+IFNγ)BM-Macs. Thus, Pla2g5 contributes to PE metabolization, PGE2 and PGD2 production independently of the type of activation, while in (IL-4)BM-Macs, Pla2g5 regulates selective lipid pathways and likely novel functions. Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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19 pages, 3020 KiB  
Article
A Representative GIIA Phospholipase A2 Activates Preadipocytes to Produce Inflammatory Mediators Implicated in Obesity Development
by Elbio Leiguez, Priscila Motta, Rodrigo Maia Marques, Bruno Lomonte, Suely Vilela Sampaio and Catarina Teixeira
Biomolecules 2020, 10(12), 1593; https://doi.org/10.3390/biom10121593 - 24 Nov 2020
Cited by 15 | Viewed by 2236
Abstract
Adipose tissue secretes proinflammatory mediators which promote systemic and adipose tissue inflammation seen in obesity. Group IIA (GIIA)-secreted phospholipase A2 (sPLA2) enzymes are found to be elevated in plasma and adipose tissue from obese patients and are active during inflammation, [...] Read more.
Adipose tissue secretes proinflammatory mediators which promote systemic and adipose tissue inflammation seen in obesity. Group IIA (GIIA)-secreted phospholipase A2 (sPLA2) enzymes are found to be elevated in plasma and adipose tissue from obese patients and are active during inflammation, generating proinflammatory mediators, including prostaglandin E2 (PGE2). PGE2 exerts anti-lipolytic actions and increases triacylglycerol levels in adipose tissue. However, the inflammatory actions of GIIA sPLA2s in adipose tissue cells and mechanisms leading to increased PGE2 levels in these cells are unclear. This study investigates the ability of a representative GIIA sPLA2, MT-III, to activate proinflammatory responses in preadipocytes, focusing on the biosynthesis of prostaglandins, adipocytokines and mechanisms involved in these effects. Our results showed that MT-III induced biosynthesis of PGE2, PGI2, MCP-1, IL-6 and gene expression of leptin and adiponectin in preadipocytes. The MT-III-induced PGE2 biosynthesis was dependent on cytosolic PLA2 (cPLA2)-α, cyclooxygenases (COX)-1 and COX-2 pathways and regulated by a positive loop via the EP4 receptor. Moreover, MT-III upregulated COX-2 and microsomal prostaglandin synthase (mPGES)-1 protein expression. MCP-1 biosynthesis induced by MT-III was dependent on the EP4 receptor, while IL-6 biosynthesis was dependent on EP3 receptor engagement by PGE2. These data highlight preadipocytes as targets for GIIA sPLA2s and provide insight into the roles played by this group of sPLA2s in obesity. Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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23 pages, 4405 KiB  
Article
Metabolic Effects of Selective Deletion of Group VIA Phospholipase A2 from Macrophages or Pancreatic Islet Beta-Cells
by John Turk, Haowei Song, Mary Wohltmann, Cheryl Frankfater, Xiaoyong Lei and Sasanka Ramanadham
Biomolecules 2020, 10(10), 1455; https://doi.org/10.3390/biom10101455 - 17 Oct 2020
Cited by 8 | Viewed by 2417
Abstract
To examine the role of group VIA phospholipase A2 (iPLA2β) in specific cell lineages in insulin secretion and insulin action, we prepared mice with a selective iPLA2β deficiency in cells of myelomonocytic lineage, including macrophages (MØ-iPLA2β-KO), [...] Read more.
To examine the role of group VIA phospholipase A2 (iPLA2β) in specific cell lineages in insulin secretion and insulin action, we prepared mice with a selective iPLA2β deficiency in cells of myelomonocytic lineage, including macrophages (MØ-iPLA2β-KO), or in insulin-secreting β-cells (β-Cell-iPLA2β-KO), respectively. MØ-iPLA2β-KO mice exhibited normal glucose tolerance when fed standard chow and better glucose tolerance than floxed-iPLA2β control mice after consuming a high-fat diet (HFD). MØ-iPLA2β-KO mice exhibited normal glucose-stimulated insulin secretion (GSIS) in vivo and from isolated islets ex vivo compared to controls. Male MØ-iPLA2β-KO mice exhibited enhanced insulin responsivity vs. controls after a prolonged HFD. In contrast, β-cell-iPLA2β-KO mice exhibited impaired glucose tolerance when fed standard chow, and glucose tolerance deteriorated further when introduced to a HFD. β-Cell-iPLA2β-KO mice exhibited impaired GSIS in vivo and from isolated islets ex vivo vs. controls. β-Cell-iPLA2β-KO mice also exhibited an enhanced insulin responsivity compared to controls. These findings suggest that MØ iPLA2β participates in HFD-induced deterioration in glucose tolerance and that this mainly reflects an effect on insulin responsivity rather than on insulin secretion. In contrast, β-cell iPLA2β plays a role in GSIS and also appears to confer some protection against deterioration in β-cell functions induced by a HFD. Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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18 pages, 2205 KiB  
Article
cPLA2α Enzyme Inhibition Attenuates Inflammation and Keratinocyte Proliferation
by Felicity J. Ashcroft, Nur Mahammad, Helene Midtun Flatekvål, Astrid J. Feuerherm and Berit Johansen
Biomolecules 2020, 10(10), 1402; https://doi.org/10.3390/biom10101402 - 02 Oct 2020
Cited by 18 | Viewed by 3071
Abstract
As a regulator of cellular inflammation and proliferation, cytosolic phospholipase A2 α (cPLA2α) is a promising therapeutic target for psoriasis; indeed, the cPLA2α inhibitor AVX001 has shown efficacy against plaque psoriasis in a phase I/IIa clinical trial. To [...] Read more.
As a regulator of cellular inflammation and proliferation, cytosolic phospholipase A2 α (cPLA2α) is a promising therapeutic target for psoriasis; indeed, the cPLA2α inhibitor AVX001 has shown efficacy against plaque psoriasis in a phase I/IIa clinical trial. To improve our understanding of the anti-psoriatic properties of AVX001, we sought to determine how the compound modulates inflammation and keratinocyte hyperproliferation, key characteristics of the psoriatic epidermis. We measured eicosanoid release from human peripheral blood mononuclear cells (PBMC) and immortalized keratinocytes (HaCaT) and studied proliferation in HaCaT grown as monolayers and stratified cultures. We demonstrated that inhibition of cPLA2α using AVX001 produced a balanced reduction of prostaglandins and leukotrienes; significantly limited prostaglandin E2 (PGE2) release from both PBMC and HaCaT in response to pro-inflammatory stimuli; attenuated growth factor-induced arachidonic acid and PGE2 release from HaCaT; and inhibited keratinocyte proliferation in the absence and presence of exogenous growth factors, as well as in stratified cultures. These data suggest that the anti-psoriatic properties of AVX001 could result from a combination of anti-inflammatory and anti-proliferative effects, probably due to reduced local eicosanoid availability. Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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20 pages, 4404 KiB  
Article
A Lipidomic Perspective of the Action of Group IIA Secreted Phospholipase A2 on Human Monocytes: Lipid Droplet Biogenesis and Activation of Cytosolic Phospholipase A2α
by Juan P. Rodríguez, Elbio Leiguez, Carlos Guijas, Bruno Lomonte, José M. Gutiérrez, Catarina Teixeira, María A. Balboa and Jesús Balsinde
Biomolecules 2020, 10(6), 891; https://doi.org/10.3390/biom10060891 - 10 Jun 2020
Cited by 11 | Viewed by 3788
Abstract
Phospholipase A2s constitute a wide group of lipid-modifying enzymes which display a variety of functions in innate immune responses. In this work, we utilized mass spectrometry-based lipidomic approaches to investigate the action of Asp-49 Ca2+-dependent secreted phospholipase A2 [...] Read more.
Phospholipase A2s constitute a wide group of lipid-modifying enzymes which display a variety of functions in innate immune responses. In this work, we utilized mass spectrometry-based lipidomic approaches to investigate the action of Asp-49 Ca2+-dependent secreted phospholipase A2 (sPLA2) (MT-III) and Lys-49 sPLA2 (MT-II), two group IIA phospholipase A2s isolated from the venom of the snake Bothrops asper, on human peripheral blood monocytes. MT-III is catalytically active, whereas MT-II lacks enzyme activity. A large decrease in the fatty acid content of membrane phospholipids was detected in MT III-treated monocytes. The significant diminution of the cellular content of phospholipid-bound arachidonic acid seemed to be mediated, in part, by the activation of the endogenous group IVA cytosolic phospholipase A2α. MT-III triggered the formation of triacylglycerol and cholesterol enriched in palmitic, stearic, and oleic acids, but not arachidonic acid, along with an increase in lipid droplet synthesis. Additionally, it was shown that the increased availability of arachidonic acid arising from phospholipid hydrolysis promoted abundant eicosanoid synthesis. The inactive form, MT-II, failed to produce any of the effects described above. These studies provide a complete lipidomic characterization of the monocyte response to snake venom group IIA phospholipase A2, and reveal significant connections among lipid droplet biogenesis, cell signaling and biochemical pathways that contribute to initiating the inflammatory response. Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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25 pages, 5798 KiB  
Article
Crotoxin-Induced Mice Lung Impairment: Role of Nicotinic Acetylcholine Receptors and COX-Derived Prostanoids
by Marco Aurelio Sartim, Camila O. S. Souza, Cassiano Ricardo A. F. Diniz, Vanessa M. B. da Fonseca, Lucas O. Sousa, Ana Paula F. Peti, Tassia Rafaella Costa, Alan G. Lourenço, Marcos C. Borges, Carlos A. Sorgi, Lucia Helena Faccioli and Suely Vilela Sampaio
Biomolecules 2020, 10(5), 794; https://doi.org/10.3390/biom10050794 - 20 May 2020
Cited by 8 | Viewed by 2995
Abstract
Respiratory compromise in Crotalus durissus terrificus (C.d.t.) snakebite is an important pathological condition. Considering that crotoxin (CTX), a phospholipase A2 from C.d.t. venom, is the main component of the venom, the present work investigated the toxin effects on respiratory failure. Lung mechanics, [...] Read more.
Respiratory compromise in Crotalus durissus terrificus (C.d.t.) snakebite is an important pathological condition. Considering that crotoxin (CTX), a phospholipase A2 from C.d.t. venom, is the main component of the venom, the present work investigated the toxin effects on respiratory failure. Lung mechanics, morphology and soluble markers were evaluated from Swiss male mice, and mechanism determined using drugs/inhibitors of eicosanoids biosynthesis pathway and autonomic nervous system. Acute respiratory failure was observed, with an early phase (within 2 h) characterized by enhanced presence of eicosanoids, including prostaglandin E2, that accounted for the increased vascular permeability in the lung. The alterations of early phase were inhibited by indomethacin. The late phase (peaked 12 h) was marked by neutrophil infiltration, presence of pro-inflammatory cytokines/chemokines, and morphological alterations characterized by alveolar septal thickening and bronchoconstriction. In addition, lung mechanical function was impaired, with decreased lung compliance and inspiratory capacity. Hexamethonium, a nicotinic acetylcholine receptor antagonist, hampered late phase damages indicating that CTX-induced lung impairment could be associated with cholinergic transmission. The findings reported herein highlight the impact of CTX on respiratory compromise, and introduce the use of nicotinic blockers and prostanoids biosynthesis inhibitors as possible symptomatic therapy to Crotalus durissus terrificus snakebite. Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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16 pages, 1812 KiB  
Article
The Contribution of Cytosolic Group IVA and Calcium-Independent Group VIA Phospholipase A2s to Adrenic Acid Mobilization in Murine Macrophages
by Patricia Monge, Alvaro Garrido, Julio M. Rubio, Victoria Magrioti, George Kokotos, María A. Balboa and Jesús Balsinde
Biomolecules 2020, 10(4), 542; https://doi.org/10.3390/biom10040542 - 03 Apr 2020
Cited by 18 | Viewed by 2899
Abstract
Adrenic acid (AA), the 2-carbon elongation product of arachidonic acid, is present at significant levels in membrane phospholipids of mouse peritoneal macrophages. Despite its abundance and structural similarity to arachidonic acid, very little is known about the molecular mechanisms governing adrenic acid mobilization [...] Read more.
Adrenic acid (AA), the 2-carbon elongation product of arachidonic acid, is present at significant levels in membrane phospholipids of mouse peritoneal macrophages. Despite its abundance and structural similarity to arachidonic acid, very little is known about the molecular mechanisms governing adrenic acid mobilization in cells of the innate immune system. This contrasts with the wide availability of data on arachidonic acid mobilization. In this work, we used mass-spectrometry-based lipidomic procedures to define the profiles of macrophage phospholipids that contain adrenic acid and their behavior during receptor activation. We identified the phospholipid sources from which adrenic acid is mobilized, and compared the data with arachidonic acid mobilization. Taking advantage of the use of selective inhibitors, we also showed that cytosolic group IVA phospholipase A2 is involved in the release of both adrenic and arachidonic acids. Importantly, calcium independent group VIA phospholipase A2 spared arachidonate-containing phospholipids and hydrolyzed only those that contain adrenic acid. These results identify separate mechanisms for regulating the utilization of adrenic and arachidonic acids, and suggest that the two fatty acids may serve non-redundant functions in cells. Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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12 pages, 2005 KiB  
Article
2-Oxoester Phospholipase A2 Inhibitors with Enhanced Metabolic Stability
by Giorgos S. Koutoulogenis, Maroula G. Kokotou, Daiki Hayashi, Varnavas D. Mouchlis, Edward A. Dennis and George Kokotos
Biomolecules 2020, 10(3), 491; https://doi.org/10.3390/biom10030491 - 24 Mar 2020
Cited by 5 | Viewed by 2904
Abstract
2-Oxoesters constitute an important class of potent and selective inhibitors of human cytosolic phospholipase A2 (GIVA cPLA2) combining an aromatic scaffold or a long aliphatic chain with a short aliphatic chain containing a free carboxylic acid. Although highly potent 2-oxoester [...] Read more.
2-Oxoesters constitute an important class of potent and selective inhibitors of human cytosolic phospholipase A2 (GIVA cPLA2) combining an aromatic scaffold or a long aliphatic chain with a short aliphatic chain containing a free carboxylic acid. Although highly potent 2-oxoester inhibitors of GIVA cPLA2 have been developed, their rapid degradation in human plasma limits their pharmaceutical utility. In an effort to address this problem, we designed and synthesized two new 2-oxoesters introducing a methyl group either on the α-carbon to the oxoester functionality or on the carbon carrying the ester oxygen. We studied the in vitro plasma stability of both derivatives and their in vitro inhibitory activity on GIVA cPLA2. Both derivatives exhibited higher plasma stability in comparison with the unsubstituted compound and both derivatives inhibited GIVA cPLA2, however to different degrees. The 2-oxoester containing a methyl group on the α-carbon atom to the oxoester functionality exhibits enhancement of the metabolic stability and retains considerable inhibitory potency. Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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Review

Jump to: Editorial, Research

16 pages, 596 KiB  
Review
Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features
by Polly J. Ferguson and Hatem El-Shanti
Biomolecules 2021, 11(3), 367; https://doi.org/10.3390/biom11030367 - 28 Feb 2021
Cited by 18 | Viewed by 4043
Abstract
Majeed syndrome is a multi-system inflammatory disorder affecting humans that presents with chronic multifocal osteomyelitis, congenital dyserythropoietic anemia, with or without a neutrophilic dermatosis. The disease is an autosomal recessive disorder caused by mutations in LPIN2, the gene encoding the phosphatidic acid [...] Read more.
Majeed syndrome is a multi-system inflammatory disorder affecting humans that presents with chronic multifocal osteomyelitis, congenital dyserythropoietic anemia, with or without a neutrophilic dermatosis. The disease is an autosomal recessive disorder caused by mutations in LPIN2, the gene encoding the phosphatidic acid phosphatase LIPIN2. It is exceedingly rare. There are only 24 individuals from 10 families with genetically confirmed Majeed syndrome reported in the literature. The early descriptions of Majeed syndrome reported severely affected children with recurrent fevers, severe multifocal osteomyelitis, failure to thrive, and marked elevations of blood inflammatory markers. As more affected families have been identified, it has become clear that there is significant phenotypic variability. Data supports that disruption of the phosphatidic acid phosphatase activity in LIPIN2 results in immune dysregulation due to aberrant activation of the NLRP3 inflammasome and overproduction of proinflammatory cytokines including IL-1β, however, these findings did not explain the bone phenotype. Recent studies demonstrate that LPIN2 deficiency drives pro-inflammatory M2-macrophages and enhances osteoclastogenesis which suggest a critical role of lipin-2 in controlling homeostasis at the growth plate in an inflammasome-independent manner. While there are no approved medications for Majeed syndrome, pharmacologic blockade of the interleukin-1 pathway has been associated with rapid clinical improvement. Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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25 pages, 1503 KiB  
Review
Sphingomyelinases and Liver Diseases
by Naroa Insausti-Urkia, Estel Solsona-Vilarrasa, Carmen Garcia-Ruiz and Jose C. Fernandez-Checa
Biomolecules 2020, 10(11), 1497; https://doi.org/10.3390/biom10111497 - 30 Oct 2020
Cited by 31 | Viewed by 3238
Abstract
Sphingolipids (SLs) are critical components of membrane bilayers that play a crucial role in their physico-chemical properties. Ceramide is the prototype and most studied SL due to its role as a second messenger in the regulation of multiple signaling pathways and cellular processes. [...] Read more.
Sphingolipids (SLs) are critical components of membrane bilayers that play a crucial role in their physico-chemical properties. Ceramide is the prototype and most studied SL due to its role as a second messenger in the regulation of multiple signaling pathways and cellular processes. Ceramide is a heterogeneous lipid entity determined by the length of the fatty acyl chain linked to its carbon backbone sphingosine, which can be generated either by de novo synthesis from serine and palmitoyl-CoA in the endoplasmic reticulum or via sphingomyelin (SM) hydrolysis by sphingomyelinases (SMases). Unlike de novo synthesis, SMase-induced SM hydrolysis represents a rapid and transient mechanism of ceramide generation in specific intracellular sites that accounts for the diverse biological effects of ceramide. Several SMases have been described at the molecular level, which exhibit different pH requirements for activity: neutral, acid or alkaline. Among the SMases, the neutral (NSMase) and acid (ASMase) are the best characterized for their contribution to signaling pathways and role in diverse pathologies, including liver diseases. As part of a Special Issue (Phospholipases: From Structure to Biological Function), the present invited review summarizes the physiological functions of NSMase and ASMase and their role in chronic and metabolic liver diseases, of which the most relevant is nonalcoholic steatohepatitis and its progression to hepatocellular carcinoma, due to the association with the obesity and type 2 diabetes epidemic. A better understanding of the regulation and role of SMases in liver pathology may offer the opportunity for novel treatments of liver diseases. Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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32 pages, 2420 KiB  
Review
Updating Phospholipase A2 Biology
by Makoto Murakami, Hiroyasu Sato and Yoshitaka Taketomi
Biomolecules 2020, 10(10), 1457; https://doi.org/10.3390/biom10101457 - 19 Oct 2020
Cited by 112 | Viewed by 10394
Abstract
The phospholipase A2 (PLA2) superfamily contains more than 50 enzymes in mammals that are subdivided into several distinct families on a structural and biochemical basis. In principle, PLA2 has the capacity to hydrolyze the sn-2 position of glycerophospholipids [...] Read more.
The phospholipase A2 (PLA2) superfamily contains more than 50 enzymes in mammals that are subdivided into several distinct families on a structural and biochemical basis. In principle, PLA2 has the capacity to hydrolyze the sn-2 position of glycerophospholipids to release fatty acids and lysophospholipids, yet several enzymes in this superfamily catalyze other reactions rather than or in addition to the PLA2 reaction. PLA2 enzymes play crucial roles in not only the production of lipid mediators, but also membrane remodeling, bioenergetics, and body surface barrier, thereby participating in a number of biological events. Accordingly, disturbance of PLA2-regulated lipid metabolism is often associated with various diseases. This review updates the current state of understanding of the classification, enzymatic properties, and biological functions of various enzymes belonging to the PLA2 superfamily, focusing particularly on the novel roles of PLA2s in vivo. Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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18 pages, 700 KiB  
Review
Interface of Phospholipase Activity, Immune Cell Function, and Atherosclerosis
by Robert M. Schilke, Cassidy M. R. Blackburn, Temitayo T. Bamgbose and Matthew D. Woolard
Biomolecules 2020, 10(10), 1449; https://doi.org/10.3390/biom10101449 - 15 Oct 2020
Cited by 10 | Viewed by 4974
Abstract
Phospholipases are a family of lipid-altering enzymes that can either reduce or increase bioactive lipid levels. Bioactive lipids elicit signaling responses, activate transcription factors, promote G-coupled-protein activity, and modulate membrane fluidity, which mediates cellular function. Phospholipases and the bioactive lipids they produce are [...] Read more.
Phospholipases are a family of lipid-altering enzymes that can either reduce or increase bioactive lipid levels. Bioactive lipids elicit signaling responses, activate transcription factors, promote G-coupled-protein activity, and modulate membrane fluidity, which mediates cellular function. Phospholipases and the bioactive lipids they produce are important regulators of immune cell activity, dictating both pro-inflammatory and pro-resolving activity. During atherosclerosis, pro-inflammatory and pro-resolving activities govern atherosclerosis progression and regression, respectively. This review will look at the interface of phospholipase activity, immune cell function, and atherosclerosis. Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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14 pages, 868 KiB  
Review
Regulation of Signaling and Metabolism by Lipin-mediated Phosphatidic Acid Phosphohydrolase Activity
by Andrew J. Lutkewitte and Brian N. Finck
Biomolecules 2020, 10(10), 1386; https://doi.org/10.3390/biom10101386 - 29 Sep 2020
Cited by 24 | Viewed by 4699
Abstract
Phosphatidic acid (PA) is a glycerophospholipid intermediate in the triglyceride synthesis pathway that has incredibly important structural functions as a component of cell membranes and dynamic effects on intracellular and intercellular signaling pathways. Although there are many pathways to synthesize and degrade PA, [...] Read more.
Phosphatidic acid (PA) is a glycerophospholipid intermediate in the triglyceride synthesis pathway that has incredibly important structural functions as a component of cell membranes and dynamic effects on intracellular and intercellular signaling pathways. Although there are many pathways to synthesize and degrade PA, a family of PA phosphohydrolases (lipin family proteins) that generate diacylglycerol constitute the primary pathway for PA incorporation into triglycerides. Previously, it was believed that the pool of PA used to synthesize triglyceride was distinct, compartmentalized, and did not widely intersect with signaling pathways. However, we now know that modulating the activity of lipin 1 has profound effects on signaling in a variety of cell types. Indeed, in most tissues except adipose tissue, lipin-mediated PA phosphohydrolase activity is far from limiting for normal rates of triglyceride synthesis, but rather impacts critical signaling cascades that control cellular homeostasis. In this review, we will discuss how lipin-mediated control of PA concentrations regulates metabolism and signaling in mammalian organisms. Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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23 pages, 1782 KiB  
Review
Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate
by Cyntanna C. Hawkins, Tomader Ali, Sasanka Ramanadham and Anita B. Hjelmeland
Biomolecules 2020, 10(10), 1357; https://doi.org/10.3390/biom10101357 - 23 Sep 2020
Cited by 29 | Viewed by 4116
Abstract
Glioblastoma (GBM) is a primary malignant brain tumor with a dismal prognosis, partially due to our inability to completely remove and kill all GBM cells. Rapid tumor recurrence contributes to a median survival of only 15 months with the current standard of care [...] Read more.
Glioblastoma (GBM) is a primary malignant brain tumor with a dismal prognosis, partially due to our inability to completely remove and kill all GBM cells. Rapid tumor recurrence contributes to a median survival of only 15 months with the current standard of care which includes maximal surgical resection, radiation, and temozolomide (TMZ), a blood–brain barrier (BBB) penetrant chemotherapy. Radiation and TMZ cause sphingomyelinases (SMase) to hydrolyze sphingomyelins to generate ceramides, which induce apoptosis. However, cells can evade apoptosis by converting ceramides to sphingosine-1-phosphate (S1P). S1P has been implicated in a wide range of cancers including GBM. Upregulation of S1P has been linked to the proliferation and invasion of GBM and other cancers that display a propensity for brain metastasis. To mediate their biological effects, SMases and S1P modulate signaling via phospholipase C (PLC) and phospholipase D (PLD). In addition, both SMase and S1P may alter the integrity of the BBB leading to infiltration of tumor-promoting immune populations. SMase activity has been associated with tumor evasion of the immune system, while S1P creates a gradient for trafficking of innate and adaptive immune cells. This review will explore the role of sphingolipid metabolism and pharmacological interventions in GBM and metastatic brain tumors with a focus on SMase and S1P. Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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25 pages, 3302 KiB  
Review
Rescue of Hepatic Phospholipid Remodeling Defect in iPLA2β-Null Mice Attenuates Obese but Not Non-Obese Fatty Liver
by Walee Chamulitrat, Chutima Jansakun, Huili Li and Gerhard Liebisch
Biomolecules 2020, 10(9), 1332; https://doi.org/10.3390/biom10091332 - 17 Sep 2020
Cited by 8 | Viewed by 3564
Abstract
Polymorphisms of group VIA calcium-independent phospholipase A2 (iPLA2β or PLA2G6) are positively associated with adiposity, blood lipids, and Type-2 diabetes. The ubiquitously expressed iPLA2β catalyzes the hydrolysis of phospholipids (PLs) to generate a fatty acid and a lysoPL. We [...] Read more.
Polymorphisms of group VIA calcium-independent phospholipase A2 (iPLA2β or PLA2G6) are positively associated with adiposity, blood lipids, and Type-2 diabetes. The ubiquitously expressed iPLA2β catalyzes the hydrolysis of phospholipids (PLs) to generate a fatty acid and a lysoPL. We studied the role of iPLA2β on PL metabolism in non-alcoholic fatty liver disease (NAFLD). By using global deletion iPLA2β-null mice, we investigated three NAFLD mouse models; genetic Ob/Ob and long-term high-fat-diet (HFD) feeding (representing obese NAFLD) as well as feeding with methionine- and choline-deficient (MCD) diet (representing non-obese NAFLD). A decrease of hepatic PLs containing monounsaturated- and polyunsaturated fatty acids and a decrease of the ratio between PLs and cholesterol esters were observed in all three NAFLD models. iPLA2β deficiency rescued these decreases in obese, but not in non-obese, NAFLD models. iPLA2β deficiency elicited protection against fatty liver and obesity in the order of Ob/Ob › HFD » MCD. Liver inflammation was not protected in HFD NAFLD, and that liver fibrosis was even exaggerated in non-obese MCD model. Thus, the rescue of hepatic PL remodeling defect observed in iPLA2β-null mice was critical for the protection against NAFLD and obesity. However, iPLA2β deletion in specific cell types such as macrophages may render liver inflammation and fibrosis, independent of steatosis protection. Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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Graphical abstract

24 pages, 1158 KiB  
Review
Lipid Phosphate Phosphatases and Cancer
by Xiaoyun Tang and David N. Brindley
Biomolecules 2020, 10(9), 1263; https://doi.org/10.3390/biom10091263 - 02 Sep 2020
Cited by 27 | Viewed by 6614
Abstract
Lipid phosphate phosphatases (LPPs) are a group of three enzymes (LPP1–3) that belong to a phospholipid phosphatase (PLPP) family. The LPPs dephosphorylate a wide spectrum of bioactive lipid phosphates, among which lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) are two important extracellular signaling molecules. [...] Read more.
Lipid phosphate phosphatases (LPPs) are a group of three enzymes (LPP1–3) that belong to a phospholipid phosphatase (PLPP) family. The LPPs dephosphorylate a wide spectrum of bioactive lipid phosphates, among which lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) are two important extracellular signaling molecules. The LPPs are integral membrane proteins, which are localized on plasma membranes and intracellular membranes, including the endoplasmic reticulum and Golgi network. LPPs regulate signaling transduction in cancer cells and demonstrate different effects in cancer progression through the breakdown of extracellular LPA and S1P and other intracellular substrates. This review is intended to summarize an up-to-date understanding about the functions of LPPs in cancers. Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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