ReviewNovel bioactive glycerol-based lysophospholipids: New data – New insight into their function
Graphical abstract
Multiple activities of bioactive lysophospholipids. LPLs act mainly through direct interaction with a specific GPCR or/and ion channel or through modulation of lipid rafts organization. Incorporation of LPLs into the cell membrane also leads to dimerisation/oligomerisation of receptors and triggering downstream signaling pathways. Besides, micelles composed of LPLs are able to disrupt cell membrane integrity and lysis of whole cells.
Highlights
► The review is devoted to novel bioactive lysophospholipids: LPI, LPE, LPS, LPG, LPC. ► We summarize their in vivo distribution and biosynthesis pathways. ► Those LPLs regulate fundamental cellular functions by modulating multiple targets. ► They alter the structure and fluidity of lipid rafts. ► We comprehend the progress in deorphanizing GPCRs for LPC, LPS, LPI, LPG and LPE.
Introduction
For many years lysophospholipids (LPLs) have shied away from the limelight. However, the rapidly expanding field of bioactive LPLs has recently shown that they are not only intermediates in the pathways for the synthesis of various phospholipids – the main constituents of biological membranes, but are also important signaling mediators in their own right, with wide-ranging biological effects. In particular, LPLs with glycerol (lysophosphatidic acid, LPA) or sphingoid (sphingosine-1-phosphate, S1P) backbones are attracting attention in this area. While LPA and S1P have been studied in detail, the actions of other LPLs such as lysophosphatidylglycerol (LPG), lysophosphatidylserine (LPS), lysophosphatidylinositol (LPI), lysophosphatidylethanolamine (LPE) or even lysophosphatidylcholine (LPC) have not been elucidated to such a high degree. Although very little is known about their endogenous receptors, recent in vitro studies suggest that they can induce various and unique cellular responses.
In spite of their simple structure, LPLs were found to be very important biologically active compounds. Glycerol derivatives of lysophospholipids share a few structural features: they possess a glycerol backbone, a phosphate head group at the sn-3 position, a hydroxyl group at the sn-2 (or sn-1) position and a single fatty acid chain at the sn-1 (or sn-2) position (Fig. 1). There are no more properties that characterize the whole family, as the linkage between the phosphate head group and fatty acid tail, the level of unsaturation and substituents vary within different molecules. It is also well known that the acyl chain at the sn-2 position of the 2-acyl-lysophospholipid has a tendency to migrate to the sn-1 position, thus resulting in the creation of the 1-acyl-lysophospholipid [1].
The relative simplicity and diversity of lysophospholipid structures lead to interactions of those compounds with various biomolecular targets. The hydrophobic tail of fatty acid residue and the hydrophilic head group determine the specific chemical construction of LPL molecules and consequently affect their unique biological activities: detergent-like action, an ability to alter mechanical properties of lipid membranes, and interaction with G-protein coupled receptors and ion channels. A broad range of LPL's biological properties has prompted many synthetic efforts to construct new lysophospholipid analogs. Special attention has been paid to a class of ether-linked LPL analogs (Fig. 1) due to their antitumor activities [2]. Another example comes from studies by Iwashita et al. who synthesized 2-deoxy derivatives of LPS and replaced its serine with threonine residue (Fig. 1) [3]. These modifications led to changes in activities of the new compounds both in vitro and in vivo.
Since biological activities of LPA and S1P have been amply reviewed elsewhere [4], [5], this paper will focus on other aforementioned LPLs, and in particular glycerol-based lysophospholipids. Those molecules have been shown to be involved in such diseases as cancer, diabetes, obesity, atherosclerosis, and inflammation. Within the last couple of years much progress has been made in deorphanizing novel GPCRs for LPC, LPS, LPI, LPG and LPE as well as in identifying other targets responsible for their biological activity. Therefore, the present review is devoted to novel glycerol-based lysophospholipids and recent findings concerning their functions and possible signaling pathways regulating physiological and pathological processes.
Section snippets
In vivo distribution, biosynthesis, and activities of LPC, LPS, LPI, LPG, and LPE
LPLs have been observed to be produced by various pathways: by enzymes mediated de novo synthesis from glycerol-3-phosphate and fatty acyl-CoA, and through hydrolysis of one acyl group of phospholipids (PLs). In enzymatic biosynthesis of LPLs from PLs mainly phospholipases and acyltransferases are involved [1], [6], [7] (Table 1).
Lysophospholipids interfere with lipid membrane structure and ion channel activities
Based on the results of several studies, lysophospholipids were observed to be inducing a wide array of effects in a cell-specific manner. Besides, the diverse activities induced by LPLs appeared to be attributed, mainly, to an interaction with specific receptors. However, a number of receptor-independent effects were also noticed, e.g., partitioning into the lipid bilayer and altering the properties of cell membranes, or directly binding to the non-receptor protein partners, such as ion
GPCR-mediated effects of LPC, LPS, LPI, LPG and LPE
Evolutionary conservatism indicates that LPLs as molecules involved in intercellular communication have ancient nature [104]. The signal transduction mechanism of bioactive lipids is rather complex and cannot be always defined by one pathway. LPLs may exert regulatory activities in cells for example by changing properties of lipid rafts into which they are incorporated or/and directly via G-protein coupled receptors. Accumulated data have now demonstrated that most of the biological effects of
Conclusions
The last two decades have shown that lysophospholipids regulate fundamental cellular mechanisms and might reveal therapeutic targets for drug development. The development of analytical methods such as mass spectrometry has demonstrated the existence in vivo not only LPA and S1P, but also other bioactive LPLs. However, the more we know about their biology the more questions arise. Present discoveries show that this area of cellular biology is more surprising than one could expect, especially
Acknowledgments
This work was supported by a Grant (2011/01/B/ST5/06383) from the National Science Centre.
References (161)
- et al.
Phosphatidylserine-specific phospholipase A1 stimulates histamine release from rat peritoneal mast cells through production of 2-acyl-1-lysophosphatidylserine
J. Biol. Chem.
(2001) - et al.
Acyl chain and headgroup specificity of human plasma lecithin:cholesterol acyltransferase. Separation of matrix and molecular specificities
J. Biol. Chem.
(1985) - et al.
Serum lysophosphatidic acid is produced through diverse phospholipase pathways
J. Biol. Chem.
(2002) - et al.
Metabolism and atherogenic disease association of lysophosphatidylcholine
Atherosclerosis
(2010) - et al.
Improved method for the quantification of lysophospholipids including enol ether species by liquid chromatography-tandem mass spectrometry
J. Lipid Res.
(2010) - et al.
Headgroup specificity of lecithin cholesterol acyltransferase for monomeric and vesicular phospholipids
Biochim. Biophys. Acta
(2000) - et al.
Phospholipase A2 subclasses in acute respiratory distress syndrome
Biochim. Biophys. Acta
(2009) - et al.
The highly selective production of 2-arachidonoyl lysophosphatidylcholine catalyzed by purified calcium-independent phospholipase A2gamma: identification of a novel enzymatic mediator for the generation of a key branch point intermediate in eicosanoid signaling
J. Biol. Chem.
(2005) - et al.
Recent progress in phospholipase A research: from cells to animals to humans
Prog. Lipid Res.
(2011) Sphingosylphosphorylcholine and lysophosphatidylcholine: G protein-coupled receptors and receptor-mediated signal transduction
Biochim. Biophys. Acta
(2002)
Lysophosphatidylcholine enhances the suppressive function of human naturally occurring regulatory T cells through TGF-beta production
Biochem. Biophys. Res. Commun.
Importance of lipid rafts for lysophosphatidylcholine-induced caspase-1 activation and reactive oxygen species generation
Cell. Immunol.
Acyl chain-dependent effect of lysophosphatidylcholine on endothelial prostacyclin production
J. Lipid Res.
Lysophosphatidylcholine induces apoptosis in human endothelial cells through a p38-mitogen-activated protein kinase-dependent mechanism
Atherosclerosis
Lysophosphatidylcholine induces apoptotic and non-apoptotic death in vascular smooth muscle cells: in comparison with oxidized LDL
Atherosclerosis
Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptor
Biochem. Biophys. Res. Commun.
NADPH oxidase-dependent generation of lysophosphatidylserine enhances clearance of activated and dying neutrophils via G2A
J. Biol. Chem.
Serine phospholipid-specific phospholipase A that is secreted from activated platelets. A new member of the lipase family
J. Biol. Chem.
Pathophysiologic implications of membrane phospholipid asymmetry in blood cells
Blood
Surface loops of extracellular phospholipase A(1) determine both substrate specificity and preference for lysophospholipids
J. Lipid Res.
The exogenous lipid requirement for histamine release from rat peritoneal mast cells stimulated by concanavalin A
FEBS Lett.
Lysophosphatidylserine potentiates nerve growth factor-induced differentiation of PC12 cells
Neurosci. Lett.
Lysophosphatidylserine regulates blood glucose by enhancing glucose transport in myotubes and adipocytes
Biochem. Biophys. Res. Commun.
Lysophosphatidylcholine activates adipocyte glucose uptake and lowers blood glucose levels in murine models of diabetes
J. Biol. Chem.
Lysophosphatidylserine stimulates leukemic cells but not normal leukocytes
Biochem. Biophys. Res. Commun.
Lysophosphatidylserine stimulates chemotactic migration in U87 human glioma cells
Biochem. Biophys. Res. Commun.
Phosphatidylserine prevents UV-induced decrease of type I procollagen and increase of MMP-1 in dermal fibroblasts and human skin in vivo
J. Lipid Res.
A novel host-parasite lipid cross-talk. Schistosomal lyso-phosphatidylserine activates toll-like receptor 2 and affects immune polarization
J. Biol. Chem.
Formation of lysophosphatidylinositol in platelets stimulated with thrombin or ionophore A23187
J. Biol. Chem.
Lysophosphatidylinositol signalling: new wine from an old bottle
Biochim. Biophys. Acta
Interfacial kinetic and binding properties of mammalian group IVB phospholipase A2 (cPLA2beta) and comparison with the other cPLA2 isoforms
J. Biol. Chem.
Generation of lysophosphatidylinositol by DDHD domain containing 1 (DDHD1): possible involvement of phospholipase D/phosphatidic acid in the activation of DDHD1
Biochim. Biophys. Acta
L-alpha-lysophosphatidylinositol meets GPR55: a deadly relationship
Trends Pharmacol. Sci.
Lysophospholipids stimulate prostate cancer cell migration via TRPV2 channel activation
Biochim. Biophys. Acta
Lysophosphatidylglycerol stimulates chemotactic migration and tube formation in human umbilical vein endothelial cells
Biochem. Biophys. Res. Commun.
Lysophosphatidylglycerol stimulates chemotactic migration in human natural killer cells
Biochem. Biophys. Res. Commun.
Lysophosphatidylinositol, but not lysophosphatidic acid, stimulates insulin release. A possible role for phospholipase A2 but not de novo synthesis of lysophospholipid in pancreatic islet function
Biochem. Biophys. Res. Commun.
Isolation of lysophosphatidylethanolamine from human serum
Biochim. Biophys. Acta
Lysophosphatidylethanolamine is - in contrast to - choline - generated under in vivo conditions exclusively by phospholipase A2 but not by hypochlorous acid
Bioorg. Chem.
Phospholipid and fatty acid specificity of endothelial lipase: potential role of the enzyme in the delivery of docosahexaenoic acid (DHA) to tissues
Biochim. Biophys. Acta
Lysophosphatidylethanolamine stimulates chemotactic migration and cellular invasion in SK-OV3 human ovarian cancer cells: involvement of pertussis toxin-sensitive G-protein coupled receptor
FEBS Lett.
Lysophosphatidylethanolamine in Grifola frondosa as a neurotrophic activator via activation of MAPK
J. Lipid Res.
Lysophospholipid regulates release and activation of latent TGF-beta1 from chondrocyte extracellular matrix
Biochim. Biophys. Acta
Lipid translocation across the human erythrocyte membrane. Regulatory factors
J. Biol. Chem.
Molecular aggregation in aqueous dispersions of phosphatidyl and lysophosphatidyl cholines
Biochim. Biophys. Acta
The enthalpy of acyl chain packing and the apparent water-accessible apolar surface area of phospholipids
Biophys. J.
Lysophospholipids modulate voltage-gated calcium channel currents in pituitary cells; effects of lipid stress
Cell Calcium
Sensing of lysophospholipids by TRPC5 calcium channel
J. Biol. Chem.
Lysophospholipids open the two-pore domain mechano-gated K(+) channels TREK-1 and TRAAK
J. Biol. Chem.
Albumin inhibits cytotoxic activity of lysophosphatidylcholine by direct binding
Prostaglandins Other Lipid Mediat.
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