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Arteriosclerosis, Thrombosis, and... Feb 2021Membrane phospholipid metabolism forms lysophospholipids, which possess unique biochemical and biophysical properties that influence membrane structure and dynamics.... (Review)
Review
Membrane phospholipid metabolism forms lysophospholipids, which possess unique biochemical and biophysical properties that influence membrane structure and dynamics. However, lysophospholipids also function as ligands for G-protein-coupled receptors that influence embryonic development, postnatal physiology, and disease. The 2 most well-studied species-lysophosphatidic acid and S1P (sphingosine 1-phosphate)-are particularly relevant to vascular development, physiology, and cardiovascular diseases. This review summarizes the role of lysophosphatidic acid and S1P in vascular developmental processes, endothelial cell biology, and their roles in cardiovascular disease processes. In addition, we also point out the apparent connections between lysophospholipid biology and the Wnt (int/wingless family) pathway, an evolutionarily conserved fundamental developmental signaling system. The discovery that components of the lysophospholipid signaling system are key genetic determinants of cardiovascular disease has warranted current and future research in this field. As pharmacological approaches to modulate lysophospholipid signaling have entered the clinical sphere, new findings in this field promise to influence novel therapeutic strategies in cardiovascular diseases.
Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Endothelial Cells; Humans; Ligands; Lysophospholipids; Morphogenesis; Receptors, Lysophosphatidic Acid; Receptors, Lysophospholipid; Sphingosine; Sphingosine-1-Phosphate Receptors; Wnt Signaling Pathway
PubMed: 33327749
DOI: 10.1161/ATVBAHA.120.305565 -
Proceedings of the National Academy of... Oct 2022The lysosome is central to the degradation of proteins, carbohydrates, and lipids and their salvage back to the cytosol for reutilization. Lysosomal transporters for...
The lysosome is central to the degradation of proteins, carbohydrates, and lipids and their salvage back to the cytosol for reutilization. Lysosomal transporters for amino acids, sugars, and cholesterol have been identified, and the metabolic fates of these molecules in the cytoplasm have been elucidated. Remarkably, it is not known whether lysosomal salvage exists for glycerophospholipids, the major constituents of cellular membranes. By using a transport assay screen against orphan lysosomal transporters, we identified the major facilitator superfamily protein Spns1 that is ubiquitously expressed in all tissues as a proton-dependent lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) transporter, with LPC and LPE being the lysosomal breakdown products of the most abundant eukaryotic phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively. Spns1 deficiency in cells, zebrafish embryos, and mouse liver resulted in lysosomal accumulation of LPC and LPE species with pathological consequences on lysosomal function. Flux analysis using stable isotope-labeled phospholipid apolipoprotein E nanodiscs targeted to lysosomes showed that LPC was transported out of lysosomes in an Spns1-dependent manner and re-esterified back into the cytoplasmic pools of phosphatidylcholine. Our findings identify a phospholipid salvage pathway from lysosomes to the cytosol that is dependent on Spns1 and critical for maintaining normal lysosomal function.
Topics: Animals; Lysophosphatidylcholines; Lysophospholipids; Lysosomes; Membrane Proteins; Membrane Transport Proteins; Mice; Phosphatidylcholines; Phosphatidylethanolamines; Protons; Zebrafish; Zebrafish Proteins
PubMed: 36161949
DOI: 10.1073/pnas.2210353119 -
International Journal of Molecular... Dec 2017The nuclear receptor superfamily includes ligand-inducible transcription factors that play diverse roles in cell metabolism and are associated with pathologies such as... (Review)
Review
The nuclear receptor superfamily includes ligand-inducible transcription factors that play diverse roles in cell metabolism and are associated with pathologies such as cardiovascular diseases. Lysophosphatidic acid (LPA) belongs to a family of lipid mediators. LPA and its naturally occurring analogues interact with G protein-coupled receptors on the cell surface and an intracellular nuclear hormone receptor. In addition, several enzymes that utilize LPA as a substrate or generate it as a product are under its regulatory control. Recent studies have demonstrated that the endogenously produced peroxisome proliferator-activated receptor gamma (PPARγ) antagonist cyclic phosphatidic acid (cPA), which is structurally similar to LPA, inhibits cancer cell invasion and metastasis in vitro and in vivo. We recently observed that cPA negatively regulates PPARγ function by stabilizing the binding of the co-repressor protein, a silencing mediator of retinoic acid, and the thyroid hormone receptor. We also showed that cPA prevents neointima formation, adipocyte differentiation, lipid accumulation, and upregulation of PPARγ target gene transcription. The present review discusses the arbitrary aspects of the physiological and pathophysiological actions of lysophospholipids in vascular and nervous system biology.
Topics: Animals; Dementia; Humans; Lysophospholipids; PPAR gamma; Signal Transduction; Spinal Cord Injuries; Vascular Diseases
PubMed: 29258184
DOI: 10.3390/ijms18122730 -
Journal of Neurochemistry Sep 2022Sphingosine-1-phosphate (S1P) is a bioactive lysophospholipid that can influence a broad range of biological processes through its binding to five distinct... (Review)
Review
Sphingosine-1-phosphate (S1P) is a bioactive lysophospholipid that can influence a broad range of biological processes through its binding to five distinct G-protein-coupled receptors. S1P receptor modulators are a new group of immunosuppressive agents currently used in the immunotherapy of multiple sclerosis. Inflammation following stroke can exacerbate neuronal injury. Given that S1P signaling is linked to multiple immune processes, therapies targeting the S1P axis may be suitable for treating stroke. In this review, we outline S1P metabolism and S1P receptors, discuss the mechanisms of action of S1P receptor modulators in lymphocyte migration and their direct action on cells of the central nervous system, and provide a concise summary of the efficacy of S1P receptor modulators in animal studies and clinical trials on treatments for stroke.
Topics: Animals; Fingolimod Hydrochloride; Immunosuppressive Agents; Lysophospholipids; Multiple Sclerosis; Receptors, Lysosphingolipid; Sphingosine 1 Phosphate Receptor Modulators; Sphingosine-1-Phosphate Receptors; Stroke
PubMed: 35943290
DOI: 10.1111/jnc.15685 -
Biochimica Et Biophysica Acta Jan 2013Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), two of the best-studied lysophospholipids, are known to influence diverse biological events, including... (Review)
Review
Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), two of the best-studied lysophospholipids, are known to influence diverse biological events, including organismal development as well as function and pathogenesis within multiple organ systems. These functional roles are due to a family of at least 11 G protein-coupled receptors (GPCRs), named LPA(1-6) and S1P(1-5), which are widely distributed throughout the body and that activate multiple effector pathways initiated by a range of heterotrimeric G proteins including G(i/o), G(12/13), G(q) and G(s), with actual activation dependent on receptor subtypes. In the central nervous system (CNS), a major locus for these signaling pathways, LPA and S1P have been shown to influence myriad responses in neurons and glial cell types through their cognate receptors. These receptor-mediated activities can contribute to disease pathogenesis and have therapeutic relevance to human CNS disorders as demonstrated for multiple sclerosis (MS) and possibly others that include congenital hydrocephalus, ischemic stroke, neurotrauma, neuropsychiatric disorders, developmental disorders, seizures, hearing loss, and Sandhoff disease, based upon the experimental literature. In particular, FTY720 (fingolimod, Gilenya, Novartis Pharma, AG) that becomes an analog of S1P upon phosphorylation, was approved by the FDA in 2010 as a first oral treatment for MS, validating this class of receptors as medicinal targets. This review will provide an overview and update on the biological functions of LPA and S1P signaling in the CNS, with a focus on results from studies using genetic null mutants for LPA and S1P receptors. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.
Topics: Central Nervous System; Humans; Lysophospholipids; Nervous System Diseases; Receptors, Lysophospholipid; Receptors, Lysosphingolipid
PubMed: 22884303
DOI: 10.1016/j.bbalip.2012.07.015 -
Pharmacology & Therapeutics Jun 2023Lysophosphatidic acid (LPA) is a simple phospholipid consisting of a phosphate group, glycerol moiety, and only one hydrocarbon chain. Despite its simple chemical... (Review)
Review
Lysophosphatidic acid (LPA) is a simple phospholipid consisting of a phosphate group, glycerol moiety, and only one hydrocarbon chain. Despite its simple chemical structure, LPA plays an important role as an essential bioactive signaling molecule via its specific six G protein-coupled receptors, LPA. Recent studies, especially those using genetic tools, have revealed diverse physiological and pathological roles of LPA and LPA receptors in almost every organ system. Furthermore, many studies are illuminating detailed mechanisms to orchestrate multiple LPA receptor signaling pathways and to facilitate their coordinated function. Importantly, these extensive "bench" works are now translated into the "bedside" as exemplified by approaches targeting LPA signaling to combat fibrotic diseases. In this review, we discuss the physiological and pathological roles of LPA signaling and their implications for clinical application by focusing on findings revealed by in vivo studies utilizing genetic tools targeting LPA receptors.
Topics: Humans; Receptors, Lysophosphatidic Acid; Lysophospholipids; Signal Transduction; Glycerol
PubMed: 37080433
DOI: 10.1016/j.pharmthera.2023.108421 -
Free Radical Biology & Medicine Aug 2022Studies in the last decade have established the roles of oxidized phospholipids as modulators of various cellular processes, from inflammation and immunity to cell... (Review)
Review
Studies in the last decade have established the roles of oxidized phospholipids as modulators of various cellular processes, from inflammation and immunity to cell death. Oxidized lysophospholipids, formed through the activity of phospholipases and oxidative enzymes and lacking an acyl chain in comparison with parent phospholipids, are now emerging as novel bioactive lipid mediators. Their detection and structural characterization have been limited in the past due to low amounts and the complexity of their biosynthetic and removal pathways, but recent studies have unequivocally demonstrated their formation under inflammatory conditions. The involvement of oxidized lysophospholipids in immune regulation classifies them as damage-associated molecular patterns (DAMPs), which can promote sterile inflammation and contribute to autoimmune and chronic diseases as well as aging-related diseases. Their signaling pathways are just beginning to be revealed. As the first publications indicate that oxidized lysophospholipids use the same receptors as pathogen-associated molecular patterns (PAMPs), it is likely that the inhibition of signaling pathways activated by oxidized lysophospholipids would affect innate immunity per se. On the other hand, inhibition or modulation of their enzymatic formation, which would not interfere with the response to pathogens, might be beneficial and is potentially a promising new field of research.
Topics: Humans; Immunity, Innate; Inflammation; Lysophospholipids; Oxidation-Reduction; Phospholipases
PubMed: 35779690
DOI: 10.1016/j.freeradbiomed.2022.06.228 -
Cell Chemical Biology Jan 2023Autotaxin (ATX; ENPP2) produces the lipid mediator lysophosphatidic acid (LPA) that signals through disparate EDG (LPA) and P2Y (LPA) G protein-coupled receptors....
Autotaxin (ATX; ENPP2) produces the lipid mediator lysophosphatidic acid (LPA) that signals through disparate EDG (LPA) and P2Y (LPA) G protein-coupled receptors. ATX/LPA promotes several (patho)physiological processes, including in pulmonary fibrosis, thus serving as an attractive drug target. However, it remains unclear if clinical outcome depends on how different types of ATX inhibitors modulate the ATX/LPA signaling axis. Here, we show that the ATX "tunnel" is crucial for conferring key aspects of ATX/LPA signaling and dictates cellular responses independent of ATX catalytic activity, with a preference for activation of P2Y LPA receptors. The efficacy of the ATX/LPA signaling responses are abrogated more efficiently by tunnel-binding inhibitors, such as ziritaxestat (GLPG1690), compared with inhibitors that exclusively target the active site, as shown in primary lung fibroblasts and a murine model of radiation-induced pulmonary fibrosis. Our results uncover a receptor-selective signaling mechanism for ATX, implying clinical benefit for tunnel-targeting ATX inhibitors.
Topics: Mice; Animals; Pulmonary Fibrosis; Receptors, Lysophosphatidic Acid; Signal Transduction; Lysophospholipids; Fibroblasts
PubMed: 36640760
DOI: 10.1016/j.chembiol.2022.12.006 -
Current Opinion in Lipidology Oct 2015The bioactive lysophospholipids, lysophosphatidic acid (LPA) and sphingosine 1 phosphate (S1P), have potent effects on blood and vascular cells. This review focuses... (Review)
Review
PURPOSE OF REVIEW
The bioactive lysophospholipids, lysophosphatidic acid (LPA) and sphingosine 1 phosphate (S1P), have potent effects on blood and vascular cells. This review focuses their potential contributions to the development of atherosclerosis, acute complications such as acute myocardial infarction, and chronic ischemic cardiac damage.
RECENT FINDINGS
Exciting recent developments have provided insight into the molecular underpinnings of LPA and S1P receptor signaling. New lines of evidence suggest roles for these pathways in the development of atherosclerosis. In experimental animal models, the production, signaling, and metabolism of LPA may be influenced by environmental factors in the diet that synergize to promote the progression of atherosclerotic vascular disease. This is supported by observations of human polymorphisms in the lysophospholipid-metabolizing enzyme PPAP2B, which are associated with risk of coronary artery disease and myocardial infarction. S1P signaling protects from myocardial damage that follows acute and chronic ischemia, both by direct effects on cardiomyocytes and through stem cell recruitment to ischemic tissue.
SUMMARY
This review will suggest novel strategies to prevent the complications of coronary artery disease by targeting LPA production and signaling. Additionally, ways in which S1P signaling pathways may be harnessed to attenuate ischemia-induced cardiac dysfunction will be explored.
Topics: Animals; Atherosclerosis; Coronary Artery Disease; Humans; Lysophospholipids; Myocardial Ischemia; Signal Transduction; Sphingosine
PubMed: 26270808
DOI: 10.1097/MOL.0000000000000226 -
The Journal of Membrane Biology Oct 2020Lysophospholipids are potent hormone-like signalling biological lipids that regulate many important biological processes in mammals (including humans). Lysophosphatidic... (Review)
Review
Lysophospholipids are potent hormone-like signalling biological lipids that regulate many important biological processes in mammals (including humans). Lysophosphatidic acid and sphingosine-1-phosphate represent the best studied examples for this lipid class, and their metabolic enzymes and/or cognate receptors are currently under clinical investigation for treatment of various neurological and autoimmune diseases in humans. Over the past two decades, the lysophsophatidylserines (lyso-PSs) have emerged as yet another biologically important lysophospholipid, and deregulation in its metabolism has been linked to various human pathophysiological conditions. Despite its recent emergence, an exhaustive review summarizing recent advances on lyso-PSs and the biological pathways that this bioactive lysophospholipid regulates has been lacking. To address this, here, we summarize studies that led to the discovery of lyso-PS as a potent signalling biomolecule, and discuss the structure, its detection in biological systems, and the biodistribution of this lysophospholipid in various mammalian systems. Further, we describe in detail the enzymatic pathways that are involved in the biosynthesis and degradation of this lipid and the putative lyso-PS receptors reported in the literature. Finally, we discuss the various biological pathways directly regulated by lyso-PSs in mammals and prospect new questions for this still emerging biomedically important signalling lysophospholipid.
Topics: Animals; Biological Transport; Cell Degranulation; Humans; Lipid Metabolism; Lysophospholipids; Macrophages; Mast Cells; Membrane Lipids; Metabolic Networks and Pathways; Oxidation-Reduction; Phagocytosis; Signal Transduction; Structure-Activity Relationship
PubMed: 32767057
DOI: 10.1007/s00232-020-00133-2