Special Issue "Phospholipids: Dynamic Lipid Signaling in Health and Diseases"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 December 2019).

Special Issue Editor

Prof. Laura Riboni
E-Mail Website
Guest Editor
Universita degli Studi di Milano, Department of Medical Biotechnology and Translational Medicine, Milan, Italy
Interests: lipid signalling; lipid metabolism; sphingolipids; oncology; neuropathology
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Special Issue Information

Dear Colleagues,

It is now amply recognised that phospholipid signalling is one of the most important signal transduction pathways used by cell-surface receptors to control intracellular events, and functions as a key homeostatic regulator, orchestrating cell activities.

Phospholipid signalling is able to actively influence their resident cells’ physiology, integrating complex signals in space and time, and plays key roles in development and tissue homeostasis by controlling a variety of cellular processes, such us proliferation, differentiation, adhesion and movement, metabolism, pluripotency, stemness, and death. The wide range of biological processes in which the specific involvement of phospholipid signalling is involved explains the need for phospholipid structural diversity. Indeed, phospholipids, with their glycero- and sphingo-phospholipid classes, constitute a large superfamily of membrane lipids, exhibiting an extraordinary structural heterogeneity, mainly derived from their diversity in the hydrophobic acyl/sphingoid tails, which adds a high level of complexity to that conferred by the polar head group.

Many advances have been made over the last decade in signal sensing centred on phospholipids. Many research studies have revealed that phospholipids maintain homeostasis through a complex and dynamic network of metabolic events, regulated by multiple enzymes, whose activities are highly responsive to extracellular and intracellular factors. This multitude of phospholipid metabolic pathways is responsible for the formation of a large and structurally complex group of signalling molecules. The number of effectors that exist, even within a single cell, creates an extremely complex signalling web downstream of phospholipid signalling activation. Recent studies revealed important aspects of phospholipid signalling, and the relevance of their spatiotemporally diverse and dynamic molecular profile, including their multiple locations in either specific membrane microdomains, or distinct intramembrane pools, or different subcellular sites and compartments, as well as different extracellular fluids. Along with their metabolic products, phospholipids play a crucial role in signalling events implicated in a wide range of biological processes, regulating survival, growth, differentiation, shape, motility, activation, and death. An intriguing aspect of phospholipid signalling recently emerged from the evidence that several phospholipids and their derivatives play a critical role as transcriptional regulators of complex nuclear signalling pathways. Indeed, some phospholipid species can act as non-membrane associated lipids to specifically bind and functionally regulate the activity of certain nuclear receptors. Moreover, some nuclear receptors can bind a phospholipid head group to key phospholipid signalling enzymes, which can then modify the phospholipid head group with unique kinetic properties. Thus, phospholipid signalling represents a complex, highly controlled network of metabolic pathways that is essential for effective cellular responses, intercellular communication, and the regulation of homeostasis.

A further strength of phospholipid signalling resides in the generation of lysophospholipids, small lipid signals that can be secreted by some cell types to act as extracellular autocrine/paracrine signals through binding to specific receptors. The relevance of this extracellular signalling is underscored by multiple evidence demonstrating the roles of lysophospholipids in the regulation of different key processes ranging from embryo development to neurogenesis, vasculogenesis and immune response, as well as their implication in multiple human diseases.

Recent studies also revealed an additional complexity to the multifaceted mechanisms of phospholipid signalling, that is its involvement in the regulation of extracellular vesicles. These small, secreted vesicular structures are emerging as a new frontier of signal transduction, involved in intercellular communication, and the maintenance of physiological homeostasis. These vesicles appear to transport specific phospholipid enzymes/signals to provide a mean of their efficient delivering at great distances, without dilution or degradation, to different cells.

Given the key role and the wide array of cell regulatory functions of phospholipid signalling, its dysregulation is, as expected, the cause of many diseases. Evidence has recently accumulated showing that defects in phospholipid signalling occur in, and contribute to, driving the onset of a range of human diseases. Numerous findings indicate that alterations of phospholipid signalling can promote the progression of several disorders, being involved in developmental and degenerative diseases, and having an intricate role in complex diseases such as cancer, cardiovascular and neurodegenerative disorders. A relevant, active area of research focuses on the understanding of the factors that induce the signalling switch to a pathological role, and on the development of novel therapeutic modalities

This Special Issue seeks reviews and original papers covering a wide range of topics related to phospholipid signalling, with the aim of providing recent advances, new concepts and new ideas on the mechanisms underlying phospholipid signalling in health and disease. The objective is to highlight the current state of the art regarding phospholipid signalling, its biological relevance in physiological contexts, and to provide us with an understanding of its impact on human diseases, and how it can be modulated in disease to gain a therapeutic benefit. The field needs input from biophysicists, biochemists, molecular and cell biologists, physiologists, pathologists, and clinicians.

Prof. Laura Riboni
Guest Editor

Manuscript Submission Information

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Keywords

  • phospholipid signalling
  • lysophospholipids
  • phospholipases
  • lipid kinases
  • lipid phosphatases

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Published Papers (8 papers)

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Research

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Article
Impairment of Membrane Lipid Homeostasis by Bichalcone Analog TSWU-BR4 Attenuates Function of GRP78 in Regulation of the Oxidative Balance and Invasion of Cancer Cells
Cells 2020, 9(2), 371; https://doi.org/10.3390/cells9020371 - 05 Feb 2020
Cited by 5 | Viewed by 1086
Abstract
The specialized cholesterol/sphingolipid-rich membrane domains termed lipid rafts are highly dynamic in the cancer cells, which rapidly assemble effector molecules to form a sorting platform essential for oncogenic signaling transduction in response to extra- or intracellular stimuli. Density-based membrane flotation, subcellular fractionation, cell [...] Read more.
The specialized cholesterol/sphingolipid-rich membrane domains termed lipid rafts are highly dynamic in the cancer cells, which rapidly assemble effector molecules to form a sorting platform essential for oncogenic signaling transduction in response to extra- or intracellular stimuli. Density-based membrane flotation, subcellular fractionation, cell surface biotinylation, and co-immunoprecipitation analyses of bichalcone analog ((E)-1-(4-Hydroxy-3-((4-(4-((E)-3-(pyridin-3-yl)acryloyl)phenyl)piperazin-1-yl)methyl)phenyl)-3-(pyridin-3-yl)prop-2-en-1-one (TSWU-BR4)-treated cancer cells showed dissociation between GRP78 and p85α conferring the recruitment of PTEN to lipid raft membranes associated with p85α. Ectopic expression of GRP78 could overcome induction of lipid raft membrane-associated p85α–unphosphorylated PTEN complex formation and suppression of GRP78−PI3K−Akt−GTP-Rac1-mediated and GRP78-regulated PERK−Nrf2 antioxidant pathway and cancer cell invasion by TSWU-BR4. Using specific inducer, inhibitor, or short hairpin RNA for ASM demonstrated that induction of the lipid raft membrane localization and activation of ASM by TSWU-BR4 is responsible for perturbing homeostasis of cholesterol and ceramide levels in the lipid raft and ER membranes, leading to alteration of GRP78 membrane trafficking and subsequently inducing p85α–unphosphorylated PTEN complex formation, causing disruption of GRP78−PI3K−Akt−GTP-Rac1-mediated signal and ER membrane-associated GRP78-regulated oxidative stress balance, thus inhibiting cancer cell invasion. The involvement of the enrichment of ceramide to lipid raft membranes in inhibition of NF-κB-mediated MMP-2 expression was confirmed through attenuation of NF-κB activation using C2-ceramide, NF-κB specific inhibitors, ectopic expression of NF-κB p65, MMP-2 promoter-driven luciferase, and NF-κB-dependent reporter genes. In conclusion, localization of ASM in the lipid raft membranes by TSWU-BR4 is a key event for initiating formation of ceramide-enriched lipid raft membrane platforms, which causes delocalization of GRP78 from the lipid raft and ER membranes to the cytosol and formation of p85α–unphosphorylated PTEN complexes to attenuate the GRP78-regulated oxidative stress balance and GRP78−p85α−Akt−GTP-Rac1−NF-κB−MMP-2-mediated cancer cell invasion. Full article
(This article belongs to the Special Issue Phospholipids: Dynamic Lipid Signaling in Health and Diseases)
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Article
Neutral Lipids Are Not a Source of Arachidonic Acid for Lipid Mediator Signaling in Human Foamy Monocytes
Cells 2019, 8(8), 941; https://doi.org/10.3390/cells8080941 - 20 Aug 2019
Cited by 6 | Viewed by 1918
Abstract
Human monocytes exposed to free arachidonic acid (AA), a secretory product of endothelial cells, acquire a foamy phenotype which is due to the accumulation of cytoplasmic lipid droplets with high AA content. Recruitment of foamy monocytes to the inflamed endothelium contributes to the [...] Read more.
Human monocytes exposed to free arachidonic acid (AA), a secretory product of endothelial cells, acquire a foamy phenotype which is due to the accumulation of cytoplasmic lipid droplets with high AA content. Recruitment of foamy monocytes to the inflamed endothelium contributes to the development of atherosclerotic lesions. In this work, we investigated the potential role of AA stored in the neutral lipids of foamy monocytes to be cleaved by lipases and contribute to lipid mediator signaling. To this end, we used mass spectrometry-based lipidomic approaches combined with strategies to generate monocytes with different concentrations of AA. Results from our experiments indicate that the phospholipid AA pool in monocytes is stable and does not change upon exposure of the cells to the external AA. On the contrary, the AA pool in triacylglycerol is expandable and can accommodate relatively large amounts of fatty acid. Stimulation of the cells with opsonized zymosan results in the expected decreases of cellular AA. Under all conditions examined, all of the AA decreases observed in stimulated cells were accounted for by decreases in the phospholipid pool; we failed to detect any contribution of the triacylglycerol pool to the response. Experiments utilizing selective inhibitors of phospholipid or triacylglyerol hydrolysis confirmed that the phospholipid pool is the sole contributor of the AA liberated by stimulated cells. Thus, the AA in the triacylglycerol is not a source of free AA for the lipid mediator signaling during stimulation of human foamy monocytes and may be used for other cellular functions. Full article
(This article belongs to the Special Issue Phospholipids: Dynamic Lipid Signaling in Health and Diseases)
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Article
Cellular Plasmalogen Content Does Not Influence Arachidonic Acid Levels or Distribution in Macrophages: A Role for Cytosolic Phospholipase A2γ in Phospholipid Remodeling
Cells 2019, 8(8), 799; https://doi.org/10.3390/cells8080799 - 31 Jul 2019
Cited by 15 | Viewed by 1648
Abstract
Availability of free arachidonic acid (AA) constitutes a rate limiting factor for cellular eicosanoid synthesis. AA distributes differentially across membrane phospholipids, which is largely due to the action of coenzyme A-independent transacylase (CoA-IT), an enzyme that moves the fatty acid primarily from diacyl [...] Read more.
Availability of free arachidonic acid (AA) constitutes a rate limiting factor for cellular eicosanoid synthesis. AA distributes differentially across membrane phospholipids, which is largely due to the action of coenzyme A-independent transacylase (CoA-IT), an enzyme that moves the fatty acid primarily from diacyl phospholipid species to ether-containing species, particularly the ethanolamine plasmalogens. In this work, we examined the dependence of AA remodeling on plasmalogen content using the murine macrophage cell line RAW264.7 and its plasmalogen-deficient variants RAW.12 and RAW.108. All three strains remodeled AA between phospholipids with similar magnitude and kinetics, thus demonstrating that cellular plasmalogen content does not influence the process. Cell stimulation with yeast-derived zymosan also had no effect on AA remodeling, but incubating the cells in AA-rich media markedly slowed down the process. Further, knockdown of cytosolic-group IVC phospholipase A2γ (cPLA2γ) by RNA silencing significantly reduced AA remodeling, while inhibition of other major phospholipase A2 forms such as cytosolic phospholipase A2α, calcium-independent phospholipase A2β, or secreted phospholipase A2 had no effect. These results uncover new regulatory features of CoA-IT-mediated transacylation reactions in cellular AA homeostasis and suggest a hitherto unrecognized role for cPLA2γ in maintaining membrane phospholipid composition via regulation of AA remodeling. Full article
(This article belongs to the Special Issue Phospholipids: Dynamic Lipid Signaling in Health and Diseases)
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Article
Arachidonic Acid Evokes an Increase in Intracellular Ca2+ Concentration and Nitric Oxide Production in Endothelial Cells from Human Brain Microcirculation
Cells 2019, 8(7), 689; https://doi.org/10.3390/cells8070689 - 09 Jul 2019
Cited by 17 | Viewed by 1457
Abstract
It has long been known that the conditionally essential polyunsaturated arachidonic acid (AA) regulates cerebral blood flow (CBF) through its metabolites prostaglandin E2 and epoxyeicosatrienoic acid, which act on vascular smooth muscle cells and pericytes to vasorelax cerebral microvessels. However, AA may also [...] Read more.
It has long been known that the conditionally essential polyunsaturated arachidonic acid (AA) regulates cerebral blood flow (CBF) through its metabolites prostaglandin E2 and epoxyeicosatrienoic acid, which act on vascular smooth muscle cells and pericytes to vasorelax cerebral microvessels. However, AA may also elicit endothelial nitric oxide (NO) release through an increase in intracellular Ca2+ concentration ([Ca2+]i). Herein, we adopted Ca2+ and NO imaging, combined with immunoblotting, to assess whether AA induces intracellular Ca2+ signals and NO release in the human brain microvascular endothelial cell line hCMEC/D3. AA caused a dose-dependent increase in [Ca2+]i that was mimicked by the not-metabolizable analogue, eicosatetraynoic acid. The Ca2+ response to AA was patterned by endoplasmic reticulum Ca2+ release through type 3 inositol-1,4,5-trisphosphate receptors, lysosomal Ca2+ mobilization through two-pore channels 1 and 2 (TPC1-2), and extracellular Ca2+ influx through transient receptor potential vanilloid 4 (TRPV4). In addition, AA-evoked Ca2+ signals resulted in robust NO release, but this signal was considerably delayed as compared to the accompanying Ca2+ wave and was essentially mediated by TPC1-2 and TRPV4. Overall, these data provide the first evidence that AA elicits Ca2+-dependent NO release from a human cerebrovascular endothelial cell line, but they seemingly rule out the possibility that this NO signal could acutely modulate neurovascular coupling. Full article
(This article belongs to the Special Issue Phospholipids: Dynamic Lipid Signaling in Health and Diseases)
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Review

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Review
Oxidized Phospholipids in Healthy and Diseased Lung Endothelium
Cells 2020, 9(4), 981; https://doi.org/10.3390/cells9040981 - 15 Apr 2020
Cited by 11 | Viewed by 1443
Abstract
Circulating and cell membrane phospholipids undergo oxidation caused by enzymatic and non-enzymatic mechanisms. As a result, a diverse group of bioactive oxidized phospholipids generated in these conditions have both beneficial and harmful effects on the human body. Increased production of oxidized phospholipid products [...] Read more.
Circulating and cell membrane phospholipids undergo oxidation caused by enzymatic and non-enzymatic mechanisms. As a result, a diverse group of bioactive oxidized phospholipids generated in these conditions have both beneficial and harmful effects on the human body. Increased production of oxidized phospholipid products with deleterious effects is linked to the pathogenesis of various cardiopulmonary disorders such as atherosclerosis, thrombosis, acute lung injury (ALI), and inflammation. It has been determined that the contrasting biological effects of lipid oxidation products are governed by their structural variations. For example, full-length products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine oxidation (OxPAPC) have prominent endothelial barrier protective and anti-inflammatory activities while most of the truncated oxidized phospholipids induce vascular leak and exacerbate inflammation. The extensive studies from our group and other groups have demonstrated a strong potential of OxPAPC in mitigating a wide range of agonist-induced lung injuries and inflammation in pulmonary endothelial cell culture and rodent models of ALI. Concurrently, elevated levels of truncated oxidized phospholipids are present in aged mice lungs that potentiate the inflammatory agents-induced lung injury. On the other hand, increased levels of full length OxPAPC products accelerate ALI recovery by facilitating production of anti-inflammatory lipid mediator, lipoxin A4, and other molecules with anti-inflammatory properties. These findings suggest that OxPAPC-assisted lipid program switch may be a promising therapeutic strategy for treatment of acute inflammatory syndromes. In this review, we will summarize the vascular-protective and deleterious aspects of oxidized phospholipids and discuss their therapeutic potential including engineering of stable analogs of oxidized phospholipids with improved anti-inflammatory and barrier-protective properties. Full article
(This article belongs to the Special Issue Phospholipids: Dynamic Lipid Signaling in Health and Diseases)
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Review
Regulation of Necroptosis by Phospholipids and Sphingolipids
Cells 2020, 9(3), 627; https://doi.org/10.3390/cells9030627 - 05 Mar 2020
Cited by 5 | Viewed by 1175
Abstract
Several non-apoptotic regulated cell death pathways have been recently reported. Necroptosis, a form of necrotic-regulated cell death, is characterized by the involvement of receptor-interacting protein kinases and/or the pore-forming mixed lineage kinase domain-like protein. Recent evidence suggests a key role for lipidic molecules [...] Read more.
Several non-apoptotic regulated cell death pathways have been recently reported. Necroptosis, a form of necrotic-regulated cell death, is characterized by the involvement of receptor-interacting protein kinases and/or the pore-forming mixed lineage kinase domain-like protein. Recent evidence suggests a key role for lipidic molecules in the regulation of necroptosis. The purpose of this mini-review is to outline the regulation of necroptosis by sphingolipids and phospholipids. Full article
(This article belongs to the Special Issue Phospholipids: Dynamic Lipid Signaling in Health and Diseases)
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Review
Sphingosine-1-Phosphate in the Tumor Microenvironment: A Signaling Hub Regulating Cancer Hallmarks
Cells 2020, 9(2), 337; https://doi.org/10.3390/cells9020337 - 01 Feb 2020
Cited by 9 | Viewed by 1811
Abstract
As a key hub of malignant properties, the cancer microenvironment plays a crucial role intimately connected to tumor properties. Accumulating evidence supports that the lysophospholipid sphingosine-1-phosphate acts as a key signal in the cancer extracellular milieu. In this review, we have a particular [...] Read more.
As a key hub of malignant properties, the cancer microenvironment plays a crucial role intimately connected to tumor properties. Accumulating evidence supports that the lysophospholipid sphingosine-1-phosphate acts as a key signal in the cancer extracellular milieu. In this review, we have a particular focus on glioblastoma, representative of a highly aggressive and deleterious neoplasm in humans. First, we highlight recent advances and emerging concepts for how tumor cells and different recruited normal cells contribute to the sphingosine-1-phosphate enrichment in the cancer microenvironment. Then, we describe and discuss how sphingosine-1-phosphate signaling contributes to favor cancer hallmarks including enhancement of proliferation, stemness, invasion, death resistance, angiogenesis, immune evasion and, possibly, aberrant metabolism. We also discuss the potential of how sphingosine-1-phosphate control mechanisms are coordinated across distinct cancer microenvironments. Further progress in understanding the role of S1P signaling in cancer will depend crucially on increasing knowledge of its participation in the tumor microenvironment. Full article
(This article belongs to the Special Issue Phospholipids: Dynamic Lipid Signaling in Health and Diseases)
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Review
Role of Cardiolipin in Mitochondrial Function and Dynamics in Health and Disease: Molecular and Pharmacological Aspects
Cells 2019, 8(7), 728; https://doi.org/10.3390/cells8070728 - 16 Jul 2019
Cited by 64 | Viewed by 4068
Abstract
In eukaryotic cells, mitochondria are involved in a large array of metabolic and bioenergetic processes that are vital for cell survival. Phospholipids are the main building blocks of mitochondrial membranes. Cardiolipin (CL) is a unique phospholipid which is localized and synthesized in the [...] Read more.
In eukaryotic cells, mitochondria are involved in a large array of metabolic and bioenergetic processes that are vital for cell survival. Phospholipids are the main building blocks of mitochondrial membranes. Cardiolipin (CL) is a unique phospholipid which is localized and synthesized in the inner mitochondrial membrane (IMM). It is now widely accepted that CL plays a central role in many reactions and processes involved in mitochondrial function and dynamics. Cardiolipin interacts with and is required for optimal activity of several IMM proteins, including the enzyme complexes of the electron transport chain (ETC) and ATP production and for their organization into supercomplexes. Moreover, CL plays an important role in mitochondrial membrane morphology, stability and dynamics, in mitochondrial biogenesis and protein import, in mitophagy, and in different mitochondrial steps of the apoptotic process. It is conceivable that abnormalities in CL content, composition and level of oxidation may negatively impact mitochondrial function and dynamics, with important implications in a variety of pathophysiological situations and diseases. In this review, we focus on the role played by CL in mitochondrial function and dynamics in health and diseases and on the potential of pharmacological modulation of CL through several agents in attenuating mitochondrial dysfunction. Full article
(This article belongs to the Special Issue Phospholipids: Dynamic Lipid Signaling in Health and Diseases)
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