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Atherosclerosis
Volume 208, Issue 1, January 2010, Pages 10-18
doi:10.1016/j.atherosclerosis.2009.05.029 | How to Cite or Link Using DOI
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Review
Metabolism and atherogenic disease association of lysophosphatidylcholine
Gerd Schmitz,a, and Katharina Ruebsaamena
a Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, D-93042 Regensburg, Germany
Received 6 October 2008;
revised 27 April 2009;
accepted 25 May 2009.
Available online 9 June 2009.
Abstract
Lysophosphatidylcholine (LPC) is a major plasma lipid that has been recognized as an important cell signalling molecule produced under physiological conditions by the action of phospholipase A2 on phosphatidylcholine. LPC transports glycerophospholipid components such as fatty acids, phosphatidylglycerol and choline between tissues. LPC is a ligand for specific G protein-coupled signalling receptors and activates several second messengers. LPC is also a major phospholipid component of oxidized low-density lipoproteins (Ox-LDL) and is implicated as a critical factor in the atherogenic activity of Ox-LDL. Hence, LPC plays an important role in atherosclerosis and acute and chronic inflammation.
In this review we focus in some detail on LPC function, biochemical pathways, sources and signal-transduction system. Moreover, we outline the detection of LPC by mass spectrometry which is currently the best method for accurate and simultaneous analysis of each individual LPC species and reveal the pathophysiological implication of LPC which makes it an interesting target for biomarker and drug development regarding atherosclerosis and cardiovascular disorders.
Keywords: Lysophospholipids; Lipidomics; Lipid species; Signalling; G protein-coupled receptor; Phospholipase
Abbreviations: AA, arachidonic acid; AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; ESI, electrospray ionization; GPR, G protein-coupled receptor; LC, liquid chromatography; LCAT, lecithin-cholesterol acyltransferase; Lp(a), lipoprotein (a); LPA, lysophosphatidic acid; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; LPG, lysophosphatidylglycerol; LPI, lysophosphatidylinositol; LPS, lysophosphatidylserine; Lp-PLA2, lipoprotein-associated phospholipase A2; MAPK, mitogen-activated protein kinase; MS, mass spectrometry; Ox-LDL, oxidized low-density lipoprotein; PA, phosphatidic acid; PAF, platelet activating factor; PC, phosphatidylcholine; PLA1/2, phospholipase A1/2; PLD, phospholipase D; S1P, spingosine-1-phosphate; SPC, sphingosylphosphorylcholine
Article Outline
1.Lysophospholipids
2.Sources of LPC
2.1.Biochemical pathways 2.2.Occurrence of LPC
3.LPC binding to G protein-coupled receptors
4.LPC signalling and cell specific effects
5.Atherogenic disease association of LPC and pharmacological aspects
5.1.Secretory phospholipases A2 (sPLA2) 5.2.Lipoprotein-associated phospholipase A2 (Lp-PLA2) 5.3.Phospholipase A2 inhibitors
6.Determination of relevant LPC species
7.Future pathophysiological and molecular perspectives towards LPC based biomarker and drug target development
Acknowledgements
Appendix A.Supplementary data
References
1. Lysophospholipids
This phospholipid group includes glycerol- and sphingoid-based lipids which contain just one carbon chain: one fatty acid (in lysoglycerophospholipids) or the long chain of sphingosine alcohol (in lysosphingolipids). The different lysophospholipids are displayed inTable 1. Among them lysophosphatidic acid (LPA) and spingosine-1-phosphate (S1P) are probably the best characterized lysophospholipids and multiple G protein-coupled receptors (GPRs) have been identified so far with varying ligand specificities[1]. The characteristics of the currently identified lysophospholipid GPR are listed inSuppl. Table 1. However, additional as yet unidentified receptors may exist for a number of lysophospholipids which will increase this group of GPR (e.g. for LPG and LPE). Lysophospholipids have been found in a wide range of tissues and cell types, indicating their importance in many physiological and pathophysiological processes, including vascular development, reproduction, myelination, neuronal diseases and cancer[2]. Their role as intracellular signalling molecules beside the function of membrane phospholipid metabolites is increasingly appreciated. They regulate a wide variety of cellular activities including proliferation, wound healing, smooth muscle contraction and tumor cell invasiveness[3]. Lysophospholipids activate several second messengers including extracellular-signal-regulated kinases, mitogen-activated protein kinase (MAPK), phosphoinositide-3-kinase, Ca2+, adenylate cyclase (AC) and Rho[2] (Suppl. Table 1). These signalling pathways have been already covered extensively in reviews[4],[5],[6] and[7].
 
Table 1. Chemical structure of the different lysophospholipids. LIPID MAPS ID Short name Full name Structure
LMGP 01050018 LPC Lysophosphatidylcholine
LMGP 10050006 LPA Lysophosphatidic acid
LMGP 02050002 LPE lysophosphatidylethanolamine
LMGP 04050008 LPG Lysophosphatidylglycerol
LMGP 06050002 LPI Lysophosphatidylinositol
LMGP 03050002 LPS Lysophosphatidylserine
LMGP 01060010 Lyso-PAF Lyso-platelet activating factor
LMSP 01060001 SPC Sphingosylphosphorylcholine
LMSP 01050001 S1P Spingosine-1-phosphate
Full-size table
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2. Sources of LPC
2.1. Biochemical pathways
The biochemical pathway of LPC is shown inFig. 1 and the relevant LPC enzymes are displayed inTable 2. LPC is derived from polar surface phosphatidylcholine (PC) of lipoproteins or from cell membrane-derived PC as a result of phospholipase A2 (PLA2)[8] and[9]. There is also a phospholipase A1 (PLA1), which is able to cleave the sn-1 ester bond[10]. Appreciable amounts of LPC are either formed in plasma by endothelial lipase[10] or by lecithin-cholesterol acyltransferase (LCAT) secreted from the liver to catalyse the transfer of fatty acids, preferentially linoleate which is in sn-2 position of phosphatidylcholine, to free cholesterol in plasma for the formation of cholesteryl esters[11]. Lysophospholipase substrates the reaction of LPC and water to carboxylate and glycerophosphocholine which is further converted to sn-glycerol-3-phosphate and choline by glycerophosphocholine phosphodiesterase. Glycerol-3-phosphate acyltransferase, located in both endoplasmic reticulum and mitochondria, catalyses the formation of the lysoproduct LPA by the acylation of glycerol 3-phosphate. LPA may also be synthesized by PLA2 catalysed deacylation of phosphatidic acid (PA). PA is generated by the hydrolysis of PC by PC-specific phospholipase D (PLD) or the acylation of LPA by LPA acyl transferases. PA is an important metabolite involved in phospholipid biosynthesis and membrane remodeling. PA appears to function in a manner similar to many other lipid second messengers: by promoting the binding of selected targets to specific regions of the cell membrane. Dephosphorylation of PA by phosphatidic acid phosphatase yields diacylglycerol which can be acylated at the sn-3 position to produce triacylglycerol by diacylglycerol acyltransferase. PA and diacylglycerol are both used as precursors for the major membrane glycerolipids. In addition, diacylglycerol is converted to PC by diacylglycerol-choline phosphotransferase.
Full-size image (75K)
Fig. 1.
Biosynthesis pathway of lysophosphatidylcholine (LPC).
View Within Article
Table 2. LPC relevant phospholipases and lysophospholipases. Enzyme Group Source Localization References
PLA1 Liver/bile/kidney/muscle Cytosolic[102] and[103]
PLA2 I B Pancreas/lung/kidney/spleen/liver/ovary/brain Secretory[68] and[104]
II A Synovial fluid/intestinal mucosa/lacrimal gland Secretory
II D Pancreas/spleen/mast cells Secretory
II E Brain/heart/uterus Secretory
II F Testis/placenta Secretory
III Kidney/heart/liver/skeletal muscle/placenta Secretory
IV A–D Ubiquitous Cytosolic
V Heart/lung/macrophages/neutrophils Secretory
VI A1/A2/B–F Ubiquitous Cytosolic
VII A/B Plasma/liver/kidney/macrophages Secretory
VIII A/B Brain Cytosolic
X Spleen/thymus/lung/pancreas/colon/leukocytes Secretory
XII A Heart/skeletal muscle/kidney/pancreas Secretory
XII B Liver/kidney/heart/skeletal muscle Secretory
XV Ubiquitous Lysosomal
PLC Ubiquitous Cytosolic[27] and[52]
PLD 1/2 Ubiquitous Cytosolic[105]
EL Brain/plasma Secretory[106]
HL Liver/plasma Secretory[107] and[108]
LCAT Plasma Secretory[106]
LYPL A1/A2 Ubiquitous Cytosolic[109]
D Liver/plasma/kidney/glandular gastric mucosa/myocytes/intestinal epithelial cells/testes Secretory[110] and[111]
LPCAT Lung/liver/adipose/pancreas/red blood cells/monocytes Cytosolic[112],[113],[114] and[115]
Full-size table
Abbreviations: phospholipase A1–2/C/D (PLA1/2/C/D), endothelial lipase (EL), hepatic lipase (HL), lysophospholipase (LYPL), lecithin-cholesterol acyltransferase (LCAT), and LPC-acyltransferase (LPCAT).
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Direct hepatic secretion is a quantitatively important source of plasma unsaturated LPC[12]. LPC can also be formed when LDL is oxidatively altered in vitro by a number of different mechanisms. These include LDL exposure to different agents such as dissolved oxygen[13], transition metal ions[14], free radical initiators[15], UV radiation[16], specific iron or copper-containing proteins[17], lipoxygenase[18] and myeloperoxidase[19] as well as prolonged storage[20]. Also endothelial cells[14], smooth muscle cells[21] and[22], monocytes/macrophages and neutrophils[18] are capable of oxidizing LDL in vitro. Several cancer cell lines also release significant amounts of LPC into the culture medium which turned out to be a substrate for autotaxin, a tumor cell motility-stimulating factor[23]. The fact that autotaxin and lysophospholipase D are identical suggests that autocrine or paracrine production of LPA contributes to tumor cell motility, survival and proliferation[23].
2.2. Occurrence of LPC
The LPC molecule is wedge-shaped, consisting of one long hydrophobic fatty acyl chain and one large hydrophilic polar choline headgroup, attached to the glycerol backbone (Table 1)[24]. The amphipathic nature of LPC gives it surfactant- and detergent-like properties and LPC may lyse cells at high concentration[25]. Unlike other lipid signalling molecules, such as S1P, SPC and LPA, the physiological concentrations of LPC in body fluids are relatively high[26],[27],[28] and[29]. Independent analytical methods revealed normal blood levels of LPC between 140 and 150 μM[30] and[31], which increase to millimolar levels in hyperlipidemic subjects[32]. LPC, with one mole of fatty acid per mole of lipid in position sn-1, is also found in small amounts in most tissues. The functionally available concentrations of LPC in vivo and the activation of LPC receptors may be controlled by a balance between different physical forms of LPC, free, micellar or bound to LDL and hydrophobic serum proteins such as albumin, anti-phospholipid-immune complexes, or incorporated into plasma membranes[26] and[33]. Unlike LPA and S1P, which are active in the albumin-bound form for many of their biological effects, LPC signalling is strongly influenced by its physical form (free versus bound)[7]. In plasma most of the circulating LPC is likely bound to albumin, representing 5–20% of total phospholipids[26], but some is associated with lipoprotein particles, where it comprises 1–5% of the total PC content of LDL particles[34]. Another minor source of circulating LPC is represented by exosomes (2 nmol in 300 ml blood)[35] as well as microparticles, shedded from cells that are in contact to plasma, which contain about 2% LPC of all phospholipids[36] and[37]. Oxidation and fragmentation of the polyunsaturated sn-2 fatty acyl residues of PC, followed by the hydrolysis of the shortened fatty acyl residues by LDL-associated platelet activating factor (PAF) acetylhydrolase[38], also increase the content of LPC during oxidative modification of LDL that accompanies their conversion to atherogenic particles[39].
3. LPC binding to G protein-coupled receptors
LPC activates GRPs that are widely expressed and regulate distinct cellular functions. LPC activate two receptors of the OGR1 cluster GPR4 and G2A[5] as well as the orphan GPR119[40]. These can be regulated by both, specific lipid agonists and protons. However, the precise molecular mechanisms, by which dual regulation of these receptors takes place, remain to be determined. G2A receptors appear to play a functional role in migration and apoptosis of immune cells (lymphoid tissues, lymphocytes and macrophages)[41] and[42]. Mice in which G2A was genetically deleted suffered from a late-onset autoimmune syndrome that was attributed to insufficient T-cell apoptosis[43]. The GPR4 receptor is widely distributed, e.g. endothelial cells, overexpressed in cancer cells and contribute to osteoclastogenesis and angiogenesis, respectively. GRP4 is also involved in migration and impairment of endothelial barrier function[44] and[45]. GPR119 is predominantly expressed in the pancreas and involved in insulin secretion from β-cells[40]. LPC activates another receptor for phospholipids, the PAF receptor[46] and[47] which is involved in calcium signalling[48] and[49]. However, Marathe et al.[34] could not confirm that LPC is a PAF receptor agonist, therefore LPC may not be a direct ligand of orphan GPR119.Suppl. Table 1 provides a synopsis of the different GPR for LPC.
4. LPC signalling and cell specific effects
Interestingly, there are many indications of specific cell signalling mediated by LPC in accordance with the hypothesis of a specific receptor for LPC. However, because of its amphipathic character it is possible that LPC also induces non-specific cell responses. The biological effects and the signalling properties of LPC have been most extensively studied in vitro in cells related to atherosclerosis (for details see review articles in Refs.[24],[39],[50] and[51]). LPC has been demonstrated to be both atherogenic and antiatherogenic[50]. These effects are outlined inTable 3. One major signalling effect of LPC is the increase of [Ca2+][27] and[28] which is believed to be mediated mainly through PAF receptors[49]. LPC also inhibits or activates MAPK[52] such as p42/44 and p38[53], and activates protein kinase C[51] and PC-specific phospholipase C[27]. In addition LPC affects AC signalling to produce cyclic adenosine monophosphate (cAMP) as an intracellular signalling molecule in the monocytic cell line THP-1[54]. LPC activates a wide range of cell types and events in the vascular system, and therefore understanding its actions is relevant for multiple immunologic and inflammatory events. The cell specific effects are summarized inTable 4.
Table 3. Pro- and antiatherogenic effects of LPC. Proatherogenic Antiatherogenic
Arterial wall and smooth muscle cells Attenuation of cellular uptake of oxidized LDL[132]
Upregulation of adhesive molecules (VCAM-1/ICAM-1) and MCP-1[116],[117] and[118] Increase of extracellular superoxide dismutase expression in monocytes/macrophages[133]
Increase of cellular permeability and apoptosis[119],[120],[121] and[122] Stimulation of HDL-mediated cholesterol efflux from cells[134] and[135]
Release of arachidonic acid[123]
Inhibition of endothelial relaxation[124]
Cell proliferation, migration and overexpression of growth factor gene[125] and[126]
Macrophages
Production of IL-1β[127]
Cell activation[128]
Upregulation of scavenger receptor expression[129]
Increased expression of urokinase-type plasminogen activator and its receptor[130]
Tissue
Arachidonic acid formation leading to eicosanoid generation and signalling[131]
Full-size table
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Table 4. Cell specific effects of LPC. Cell type Effect of LPC References
Immune cells Chemotaxis[131] and[136]
Monocytes Cell adhesion[137]
Macrophages Migration[130]
T-lymphocytes Growth[138]
Neutrophils Proinflammatory activity[131]
Lymphoid cells Cytokine synthesis[47] and[139]
Migration[140]
Smooth muscle cells Chemoattraction[126]
Proliferation[39]
Endothelial cells Growth factor expression[116] and[141]
Apoptotic cells Chemotactic attraction of phagocytes[142] and[143]
Pancreatic β-cells Induction of insulin secretion[40] and[144]
Full-size table
View Within Article
5. Atherogenic disease association of LPC and pharmacological aspects
In vivo, LPC is claimed to be an important component of Ox-LDL[55] and[56] which is increased 5-fold in Ox-LDL compared to normal LDL and 7-fold in oxidized lipoprotein (a) (Lp(a)) compared to normal Lp(a). Ox-LDL and oxidized Lp(a) induce apoptosis via oxidative stress which promotes atherogenesis[57]. LPC can be detected in atherosclerotic lesions[58] and[59] and exerts both pro- and anti-atherogenic roles (Table 3), depending on the arterial cell type and oxidation/inflammation status. Due to the elevation of LPC concentrations in atherogenic diseases, various attempts were undertaken to decrease LPC levels which are linked to PLA2 activity.
5.1. Secretory phospholipases A2 (sPLA2)
The sPLA2 family displayed inTable 2 is calcium-dependent and responsible for phospholipid hydrolysis at the sn-2 position to produce two potentially bioactive lipids that include non-esterified fatty acids (principally AA) and lysophospholipids such as LPC[60]. Among the sPLA2 enzymes groups IIa, V and X are highly expressed in human atherosclerotic lesions where the various groups have overlapping and dissimilar potential roles in atherosclerosis and lipoprotein metabolism[61]. The development of genetically manipulated mouse models lacking or overexpressing each of the three enzymes improved the understanding of the unique and shared functions of sPLA2-IIa, V and X in atherosclerosis. Two reviews about this topic including a detailed overview of group specific sPLA2 tissue and cell distribution were recently published[62] and[63] beside well-documented summaries of various clinical studies dealing with the questions of the potential role of sPLA2 in cardiovascular disorders[62],[63] and[64]. Concerning the role of lipoproteins as physiologic substrates of these three enzymes, sPLA2-V and X are considerably more active than sPLA2-IIA, an acute phase protein[65], to hydrolyze PC in HDL with no oxidation or modification of apolipoprotein A–I[66]. Thus, the reverse cholesterol efflux from lipid-loaded macrophages promoted by HDL is impaired. However, the potential in vivo consequences of HDL hydrolysis by sPLA2-V and X deserve further investigation. Furthermore, the interaction of apolipoprotein B containing lipoproteins with arterial proteoglycans in the intima is believed to be an important component of their atherogenicity[67]. In the extracellular intima sPLA2-V and X in contrast to sPLA2-IIa can be better suited for acting on apoliporotein B lipoproteins entrapped in this space[62] and LDL modified by sPLA2-V and X induce both foam cell formation[68]. sPLA2-IIa and V activity lead to fusion and enhanced binding of modified lipoproteins to extracellular proteoglycans that increase extracellular deposition of cholesterol-rich modified lipoproteins[69]. All these characteristics lead to the fact that sPLA2 enzymes have become a promising therapeutic target.
5.2. Lipoprotein-associated phospholipase A2 (Lp-PLA2)
Lp-PLA2, also known as platelet activating factor acetylhydrolase or type VIIA PLA2, is a calcium-independent phospholipase predominantly synthesized by macrophages. The biology of Lp-PLA2 is discussed in detail in a review article by Stafforini et al.[70]. In plasma Lp-PLA2 is bound to LDL and HDL lipoproteins with a greater affinity for the polar surface of LDL particles, particularly electronegative small LDL particles that have been minimally oxidatively modified[61]. Through hydrolysis of Ox-LDL particles, Lp-PLA2 generates two proinflammatory mediators, LPC and oxidized fatty acids, which activate redox-sensitive inflammatory pathways[71]. The products of Lp-PLA2 activity have been identified in human atherosclerotic vessel wall[72]. In preclinical animal studies, inhibition of the enzyme attenuates the inflammatory process and slows atherosclerotic disease progression, suggesting that it is not only a risk marker but also a candidate risk factor because it is intimately involved in the causal pathway of the intimal inflammatory cascade[73]. An overview of more than 25 published prospective epidemiologic studies showing an association of elevated Lp-PLA2 and higher cardiovascular risk is presented by recent reviews[64],[73] and[74]. Lp-PLA2 appears to be highly specific for vascular inflammation such that it appears to be unaffected by common infections or arthritis, and it has low biologic variability, similar to lipids[74]. The low biologic fluctuation makes it possible to use a single measurement for clinical decisions and also permits clinicians to follow serial assessment over time[74]. The level of Lp-PLA2 is independent of traditional risk factors, BMI and insulin resistance because Lp-PLA2 is produced by macrophages and foam cells in atherosclerotic plaques unlike systemic inflammatory markers, which may be produced by the liver in response to cytokines produced in mesenteric adipose tissue[74]. Lp-PLA2 is also incremental to high sensitivity C-reactive protein in risk assessment[73]. However, Lp-PLA2, unlike C-reactive protein and other biomarkers, is not recommended for general population screening. But, once a patient is determined to be at intermediate or high cardiovascular risk, elevated Lp-PLA2 might be used to move the patient to the next higher risk category, and low Lp-PLA2 might increase confidence that the patient is optimally treated or at lower risk[73]. Thus, the basic principle of preventive therapies is fulfilled to match the intensity of treatment to individual patient risk.
5.3. Phospholipase A2 inhibitors
To decrease LPC levels in the future a single drug molecule would be useful with a dual function, PLA2 inhibition and antioxidant activity, because PLA2 activation also results in AA-derived free radical intermediates. That could lead to PLA2 activity inhibition; scavenge free radicals released during AA metabolism and reduce pro-inflammatory molecules. Many secondary metabolites from plants and marine sponges like flavonoids, terpenes and alkaloids exhibit both anti-inflammatory and antioxidant properties. But in term of PLA2 inhibition and antioxidant activity, the structural aspects of flavonoids are well studied rather than terpenes and alkaloids[75]. Further selective PLA2 inhibitors have to be analyzed in randomized clinical trials and currently two specific inhibitors for Lp-PLA2 and sPLA2 are under evaluation[61]. Recently a review about PLA2 inhibitors was published by Rosenson et al.[61] showing that sPLA2 inhibition reduces LDL cholesterol levels, and both Lp-PLA2 and sPLA2 inhibitors mitigate inflammatory processes. The questions remain how much these enzymes should be inhibited to reduce cardiovascular events and how specific the inhibition should be to achieve efficiency. In relation to atherosclerosis treatment the inhibitor varespladib methyl emerged as a potential drug, especially in combination with statin therapy (pravastatin)[76].
6. Determination of relevant LPC species
The determination of LPC is often related to the determination of PLA2 activities[77]. However, potential effects of the detergent moiety on the enzyme activity cannot be excluded and the phospholipid bilayer structure is neglected. Beside mass spectrometry (MS) there exist other methods based on chromatography[78] and[79], UV- and fluorescence spectroscopy[80], NMR spectroscopy[81] and radioactivity[82] for analysis of lysophospholipids. The most common methods published for LPC analysis involve separation by thin-layer chromatography[83] and[84] or HPLC[85] and[86]. Studies analyzing LPC fatty acid composition used either TLC separation followed by gas chromatographic analysis[26] and[28] or HPLC coupled to electrospray ionization (ESI) MS[87]. The application of these methodologies in the routine laboratory, however, is limited because they are complicated, time-consuming procedures that are partly insensitive, lack specificity and accuracy. Within the last decade the analytical possibilities for detection of LPC species considerably improved. The detection and identification of phospholipids including LPC was made possible by further development of MS and meanwhile it is also possible to analyze all major lysophospholipids simultaneously[88] and[89]. Applying MALDI-TOF it was shown that the PC/LPC ratio was easily determined[90]. However most studies used liquid chromatography (LC) tandem MS[91],[92],[93] and[94] preferring ESI as the ion source of choice to couple LC with MS[95],[96] and[97]. It is concluded that ESI-MS/MS is the best and perhaps the only way to accurately determine the levels of each individual LPC species simultaneously in minimal amounts of body fluids such as blood. The “soft” ionization during usage of ESI-MS/MS does not cause extensive fragmentation, is highly sensitive, accurate, and reproducible without elaborate chromatographic separation.Suppl. Table 2 shows a protocol of an ESI-MS/MS methodology, developed by Liebisch et al.[97], which allows high-throughput quantification of distinct lysophosphatidylcholine (LPC) species from plasma and cell samples with an analysis time of 2 min/sample, simple sample preparation, and automated data analysis.
7. Future pathophysiological and molecular perspectives towards LPC based biomarker and drug target development
Research of the past decades has demonstrated that many important physiological and pathophysiological processes are regulated by lysophospholipids. However, there are still numerous open questions which require a better answer for the role of LPC in defined organs and diseases. Identification of enzymes controlling abnormal LPC levels in atherogenic disease and their relation to individual LPC species will be an initial step towards the development of novel therapeutics for treatment. LPC receptors need to be further characterized concerning ligand specificity and response, and attempts for pharmacological inhibition should be carried out. The fact that minor alterations of acyl chain length abolish LPC binding to GPR suggests that other structural modifications may uncover ligand mimetics with higher receptor binding affinities sufficient to effectively compete LPC binding[98]. The details of LPC contribution under conditions of atherogenic diseases have to be clarified after finding a lot of intriguing in vitro results for the important biological functions of LPC in cellular signalling and the development of different pathologies. It is also important to take into consideration that different LPC species, concerning fatty acid chain length and degree of saturation, could have different biological functions[99]. There are only a few studies related to inflammation which address this issue[100] and[101]. Many scientific and technical challenges need to be resolved to determine whether lysophospholipids or the enzymes producing lysophospholipids alone or in combination with other markers have the potential to contribute to early diagnosis. An emerging field of LPC based drug target development in atherosclerosis will certainly be inhibitors of the phospholipase A2 superfamily which serve as potential targets of therapy to reduce cardiovascular events as they are involved in lipoprotein modification, retention and oxidation; and activation of vascular and systemic inflammatory responses[61]. Together with Lp-PLA2 as a biomarker the final aim of preventive therapies might be fulfilled to match the intensity of treatment to individual patient risk.
Acknowledgements
This work was supported by Deutsche Forschungsgemeinschaft (SFB-TR 13/A3) (proposal number 013032) and by SSA – Danubian Biobank (WP4: enabling technologies) (proposal number 018822). This work was also supported by the seventh framework program of the EU-funded “LipidomicNet” (proposal number 202272). For more information see alsowww.lipidomicnet.org.
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Copyright © 2009 Published by Elsevier Ltd.
Atherosclerosis
Volume 208, Issue 1, January 2010, Pages 10-18


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