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Acta Pharmacologica Sinica Jul 2004Sphingosine-1-phosphate (S1P) has diverse biological functions acting inside cells as a second messenger to regulate cell proliferation and survival, and... (Review)
Review
Sphingosine-1-phosphate (S1P) has diverse biological functions acting inside cells as a second messenger to regulate cell proliferation and survival, and extracellularly, as a ligand for a group of G protein-coupled receptors (GPCRs) named the endothelial differentiation gene (EDG) family. Five closely related GPCRs of EDG family (EDG1, EDG3, EDG5, EDG6, and EDG8) have recently been identified as high-affinity S1P receptors. These receptors are coupled via Gi, Gq, G12/13, and Rho. The signaling pathways are linked to vascular cell migration, proliferation, apoptosis, intracellular Ca2+ mobilization, and expression of adhesion molecules. The formation of an atherosclerotic lesion occurs through activation of cellular events that include monocyte adhesion to the endothelium and vascular smooth muscle cell (VSMC) migration and proliferation. Thus, S1P signaling may play an important role in the pathogenesis of atherosclerotic vascular disease. This review highlights S1P signalling in vascular cells and its involvement in the formation of atherosclerotic lesions.
Topics: Animals; Apoptosis; Arteriosclerosis; Cell Division; Cell Movement; Cytokines; Humans; Lysophospholipids; Muscle, Smooth, Vascular; Phosphotransferases (Alcohol Group Acceptor); Receptors, G-Protein-Coupled; Signal Transduction; Sphingosine
PubMed: 15210056
DOI: No ID Found -
Biochimica Et Biophysica Acta.... Nov 2017Lysophospholipids (LPLs) are metabolic intermediates in bacterial phospholipid turnover. Distinct from their diacyl counterparts, these inverted cone-shaped molecules... (Review)
Review
Lysophospholipids (LPLs) are metabolic intermediates in bacterial phospholipid turnover. Distinct from their diacyl counterparts, these inverted cone-shaped molecules share physical characteristics of detergents, enabling modification of local membrane properties such as curvature. The functions of LPLs as cellular growth factors or potent lipid mediators have been extensively demonstrated in eukaryotic cells but are still undefined in bacteria. In the envelope of Gram-negative bacteria, LPLs are derived from multiple endogenous and exogenous sources. Although several flippases that move non-glycerophospholipids across the bacterial inner membrane were characterized, lysophospholipid transporter LplT appears to be the first example of a bacterial protein capable of facilitating rapid retrograde translocation of lyso forms of glycerophospholipids across the cytoplasmic membrane in Gram-negative bacteria. LplT transports lyso forms of the three bacterial membrane phospholipids with comparable efficiency, but excludes other lysolipid species. Once a LPL is flipped by LplT to the cytoplasmic side of the inner membrane, its diacyl form is effectively regenerated by the action of a peripheral enzyme, acyl-ACP synthetase/LPL acyltransferase (Aas). LplT-Aas also mediates a novel cardiolipin remodeling by converting its two lyso derivatives, diacyl or deacylated cardiolipin, to a triacyl form. This coupled remodeling system provides a unique bacterial membrane phospholipid repair mechanism. Strict selectivity of LplT for lyso lipids allows this system to fulfill efficient lipid repair in an environment containing mostly diacyl phospholipids. A rocker-switch model engaged by a pair of symmetric ion-locks may facilitate alternating substrate access to drive LPL flipping into bacterial cells. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop.
Topics: Bacterial Proteins; Biological Transport; Carbon-Sulfur Ligases; Cell Wall; Gram-Negative Bacteria; Lipogenesis; Lysophospholipids; Phospholipid Transfer Proteins; Signal Transduction; Substrate Specificity
PubMed: 27956138
DOI: 10.1016/j.bbalip.2016.11.015 -
Scientific Reports Nov 2023Nonalcoholic fatty liver disease (NAFLD) is characterized by an increase in hepatic lipid accumulation due to impaired lipid metabolism. Although a correlation was found...
Nonalcoholic fatty liver disease (NAFLD) is characterized by an increase in hepatic lipid accumulation due to impaired lipid metabolism. Although a correlation was found between NAFLD and sphingosine-1-phosphate (S1P), the role of the sphingolipid remains controversial. The aim of this study was to investigate any involvement of S1P in steatosis using its analog FTY720P and HepG2 cells. Lipid accumulation was induced by incubating the cells in a mixture of oleic and palmitic acid, and was quantified using Oil Red O. The involvement of signaling mediators was studied using pharmacological inhibitors and western blot analysis. FTY720P increased lipid accumulation, but this increase wasn't maintained in the presence of inhibitors of S1PR3, Gq, SREBP, mTOR, PI3K, and PPARγ indicating their involvement in the process. The results revealed that FTY720P binds to S1PR3 which activates sequentially Gq, PI3K, and mTOR leading to an increase in SREBP expression and PPARγ activation. It was concluded that in presence of a high level of fatty acids, lipid accumulation is increased in hepatocytes by the exogenously added FTY720P.
Topics: Humans; Hep G2 Cells; Non-alcoholic Fatty Liver Disease; Sterol Regulatory Element Binding Protein 1; PPAR gamma; Liver; TOR Serine-Threonine Kinases; Lipid Metabolism; Lysophospholipids; Phosphatidylinositol 3-Kinases
PubMed: 37953311
DOI: 10.1038/s41598-023-46011-4 -
TheScientificWorldJournal Jul 2001The First International Conference on “Lysophospholipids and Related Bioactive Lipids in Biology and Diseases” was held in Tucson, AZ on June 10–14, 2001, under...
First international conference on lysophospholipids and related bioactive lipids in biology and disease sponsored by the Federation of American Societies of Experimental Biology.
The First International Conference on “Lysophospholipids and Related Bioactive Lipids in Biology and Diseases” was held in Tucson, AZ on June 10–14, 2001, under the sponsorship of the Federation of American Societies of Experimental Biology (FASEB). More than 100 scientists from 11 countries discussed the recent results of basic and clinical research in the broad biology of this emerging field. Immense progress was reported in defining the biochemistry of generation and biology of cellular effects of the bioactive lysophospholipids (LPLs). These aspects of LPLs described at the conference parallel in many ways those of the eicosanoid mediators, such as prostaglandins and leukotrienes. As for eicosanoids, the LPLs termed lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are produced enzymatically from phospholipid precursors in cell membranes and act on cells at nanomolar concentrations through subfamilies of receptors of the G protein–coupled superfamily. The rate-limiting steps in production of LPLs were reported to be controlled by specific phospholipases for LPA and sphingosine kinases for S1P. The receptor subfamilies formerly were designated endothelial differentiation gene-encoded receptors or Edg Rs for their original discovery in endothelial cells. A currently active nomenclature committee at this conference suggested the ligand-based names: S1P = Edg-1, S1P = Edg-5, S1P = Edg-3, S1P = Edg-6, and S1P = Edg-8; LPA = Edg-2, LPA = Edg-4, and LPA = Edg-7 receptors. Several families of lysophospholipid phosphatases (LPPs) have been characterized, which biodegrade LPA, whereas S1P is inactivated with similar rapidity by both a lyase and S1P phosphatases.
Topics: Animals; Biology; Disease; Lysophospholipids
PubMed: 12806083
DOI: 10.1100/tsw.2001.65 -
Journal of Lipid Research Oct 2014It is now accepted that lysophospholipids (LysoGPs) have a wide variety of functions as lipid mediators that are exerted through G protein-coupled receptors (GPCRs)... (Review)
Review
It is now accepted that lysophospholipids (LysoGPs) have a wide variety of functions as lipid mediators that are exerted through G protein-coupled receptors (GPCRs) specific to each lysophospholipid. While the roles of some LysoGPs, such as lysophosphatidic acid and sphingosine 1-phosphate, have been thoroughly examined, little is known about the roles of several other LysoGPs, such as lysophosphatidylserine (LysoPS), lysophosphatidylthreonine, lysophosphatidylethanolamine, lysophosphatidylinositol (LPI), and lysophosphatidylglycerol. Recently, a GPCR was found for LPI (GPR55) and three GPCRs (GPR34/LPS1, P2Y10/LPS2, and GPR174/LPS3) were found for LysoPS. In this review, we focus on these newly identified GPCRs and summarize the actions of LysoPS and LPI as lipid mediators.
Topics: Animals; Humans; Lysophospholipids; Receptors, Lysophospholipid; Structure-Activity Relationship
PubMed: 24891334
DOI: 10.1194/jlr.R046920 -
Journal of Lipid Research Jul 2014Lysophosphatidic acid (LPA) is a small ubiquitous lipid found in vertebrate and nonvertebrate organisms that mediates diverse biological actions and demonstrates... (Review)
Review
Lysophosphatidic acid (LPA) is a small ubiquitous lipid found in vertebrate and nonvertebrate organisms that mediates diverse biological actions and demonstrates medicinal relevance. LPA's functional roles are driven by extracellular signaling through at least six 7-transmembrane G protein-coupled receptors. These receptors are named LPA1-6 and signal through numerous effector pathways activated by heterotrimeric G proteins, including Gi/o, G12/13, Gq, and Gs LPA receptor-mediated effects have been described in numerous cell types and model systems, both in vitro and in vivo, through gain- and loss-of-function studies. These studies have revealed physiological and pathophysiological influences on virtually every organ system and developmental stage of an organism. These include the nervous, cardiovascular, reproductive, and pulmonary systems. Disturbances in normal LPA signaling may contribute to a range of diseases, including neurodevelopmental and neuropsychiatric disorders, pain, cardiovascular disease, bone disorders, fibrosis, cancer, infertility, and obesity. These studies underscore the potential of LPA receptor subtypes and related signaling mechanisms to provide novel therapeutic targets.
Topics: Animals; Heterotrimeric GTP-Binding Proteins; Humans; Lysophospholipids; Models, Biological; Receptors, Lysophosphatidic Acid; Signal Transduction
PubMed: 24643338
DOI: 10.1194/jlr.R046458 -
Current Opinion in Lipidology Oct 2016Phospholipids are major constituents in the intestinal lumen after meal consumption. This article highlights current literature suggesting the contributory role of... (Review)
Review
PURPOSE OF REVIEW
Phospholipids are major constituents in the intestinal lumen after meal consumption. This article highlights current literature suggesting the contributory role of intestinal phospholipid metabolism toward cardiometabolic disease manifestation.
RECENT FINDINGS
Group 1b phospholipase A2 (PLA2g1b) catalyzes phospholipid hydrolysis in the intestinal lumen. The digestive product lysophospholipid, particularly lysophosphatidylcholine (LPC), has a direct role in mediating chylomicron assembly and secretion. The LPC in the digestive tract is further catabolized into lysophosphatidic acid and choline via autotaxin-mediated and autotaxin-independent mechanisms. The LPC and lysophosphatidic acid absorbed through the digestive tract and transported to the plasma directly promote systemic inflammation and cell dysfunction, leading to increased risk of cardiovascular disease and obesity/diabetes. The choline moiety generated in the digestive tract can also be used by gut bacteria to generate trimethylamine, which is subsequently transported to the liver and oxidized into trimethylamine-N-oxide that also enhances atherosclerosis and cardiovascular abnormalities.
SUMMARY
Products of phospholipid metabolism in the intestine through PLA2g1b and autotaxin-mediated pathways directly contribute to cardiometabolic diseases through multiple mechanisms. The implication of these studies is that therapeutic inhibition of PLA2g1b and autotaxin in the digestive tract may be a viable approach for cardiovascular and metabolic disease intervention.
Topics: Animals; Choline; Humans; Intestinal Mucosa; Lysophospholipids; Metabolic Diseases; Myocardium
PubMed: 27438680
DOI: 10.1097/MOL.0000000000000334 -
Journal of Cellular and Molecular... Sep 2020There are many different types of cardiovascular diseases, which impose a huge economic burden due to their extremely high mortality rates, so it is necessary to explore... (Review)
Review
There are many different types of cardiovascular diseases, which impose a huge economic burden due to their extremely high mortality rates, so it is necessary to explore the underlying mechanisms to achieve better supportive and curative care outcomes. Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator with paracrine and autocrine activities that acts through its cell surface S1P receptors (S1PRs) and intracellular signals. In the circulatory system, S1P is indispensable for both normal and disease conditions; however, there are very different views on its diverse roles, and its specific relevance to cardiovascular pathogenesis remains elusive. Here, we review the synthesis, release and functions of S1P, specifically detail the roles of S1P and S1PRs in some common cardiovascular diseases, and then address several controversial points, finally, we focus on the development of S1P-based therapeutic approaches in cardiovascular diseases, such as the selective S1PR1 modulator amiselimod (MT-1303) and the non-selective S1PR1 and S1PR3 agonist fingolimod, which may provide valuable insights into potential therapeutic strategies for cardiovascular diseases.
Topics: Animals; Cardiovascular Diseases; Humans; Lysophospholipids; Models, Biological; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors
PubMed: 32803879
DOI: 10.1111/jcmm.15744 -
Development (Cambridge, England) Apr 2015Lysophosphatidic acid (LPA) is a bioactive phospholipid that is present in all tissues examined to date. LPA signals extracellularly via cognate G protein-coupled... (Review)
Review
Lysophosphatidic acid (LPA) is a bioactive phospholipid that is present in all tissues examined to date. LPA signals extracellularly via cognate G protein-coupled receptors to mediate cellular processes such as survival, proliferation, differentiation, migration, adhesion and morphology. These LPA-influenced processes impact many aspects of organismal development. In particular, LPA signalling has been shown to affect fertility and reproduction, formation of the nervous system, and development of the vasculature. Here and in the accompanying poster, we review the developmentally related features of LPA signalling.
Topics: Animals; Cell Movement; Humans; Lysophospholipids; Nervous System; Receptors, G-Protein-Coupled; Reproduction; Signal Transduction
PubMed: 25852197
DOI: 10.1242/dev.121723 -
The Journal of Experimental Medicine Nov 2012Recent work has highlighted the multitude of biological functions of sphingosine 1-phosphate (S1P), which include roles in hematopoietic cell trafficking, organization... (Review)
Review
Recent work has highlighted the multitude of biological functions of sphingosine 1-phosphate (S1P), which include roles in hematopoietic cell trafficking, organization of immune organs, vascular development, and neuroinflammation. Indeed, a functional antagonist of S1P(1) receptor, FTY720/Gilenya, has entered the clinic as a novel therapeutic for multiple sclerosis. In this issue of the JEM, Zhang et al. highlight yet another function of this lipid mediator: thrombopoiesis. The S1P(1) receptor is required for the growth of proplatelet strings in the bloodstream and the shedding of platelets into the circulation. Notably, the sharp gradient of S1P between blood and the interstitial fluids seems to be essential to ensure the production of platelets, and S1P appears to cooperate with the CXCL12-CXCR4 axis. Pharmacologic modulation of the S1P(1) receptor altered circulating platelet numbers acutely, suggesting a potential therapeutic strategy for controlling thrombocytopenic states. However, the S1P(4) receptor may also regulate thrombopoiesis during stress-induced accelerated platelet production. This work reveals a novel physiological action of the S1P/S1P(1) duet that could potentially be harnessed for clinical translation.
Topics: Blood Platelets; Cell Movement; Chemokine CXCL12; Extracellular Fluid; Lysophospholipids; Models, Biological; Receptors, CXCR4; Receptors, Lysosphingolipid; Sphingosine; Thrombopoiesis
PubMed: 23166370
DOI: 10.1084/jem.20122284