Review articleThe mechanisms of lysophosphatidylcholine in the development of diseases
Graphical abstract
The effect of LPC on cells
LPC can exert its biological function by activating ion channels, increasing the release of inflammatory factors and the expression of adhesion molecule, inducing apoptosis and oxidative stress. LPC can induce intracellular calcium mobilization via increasing external Ca(2+) influx and Ca(2+) release from endoplasmic reticulum Ca(2+) stores. Besides, LPC can affect the concentration of intracellular Na(+) and K(+), affecting the normal physiological function of cells. Importantly, LPC can bind to G protein coupled receptors (GPCRs) and Toll-like receptors (TLRs), activate transcription factors, stable mRNA and then increase the expression of target genes through Ca(2+)-mediated second messenger or directly inducing downstream inflammatory signalling pathways, which could increase the release of inflammatory factors, or induce the expression of adhesion molecules. In addition, there are many mechanisms by which LPC induces apoptosis, such as caspase activation, calcium influx, the release of cytochrome C, and the mitochondrial pathway. LPC increases ROS generation and enhances oxidative stress. Therefore, LPC plays a variety of biological functions in cells, so targeting LPC may be a potential method for the treatment of inflammation-related diseases.
Introduction
Lysophosphatidylcholine (LPC) is the main component of oxidatively damaged low-density lipoprotein (oxLDL) [1]. A high level of LPC, up to 100 μM, has been found in healthy subjects [2]. However, the concentration of LPC varies in different diseases. Researchers have found increased levels of LPC in atherosclerosis [3], inflammatory disease [4], diabetes [5], adrenoleukodystrophy [[6], [7], [8]], and squamous cervical cancer [9], while lower concentrations of LPC have been reported in infectious diseases [10,11], ovarian cancer [12], and colorectal cancer [13]. LPC can exert its biological function by inducing cell division, the release of inflammatory factors and oxidative stress. Our paper reviews the mechanism by which LPC affects different cells and its important role in the development of several diseases.
The source of saturated LPC, palmitoyl (16:0) LPC, is phosphatidylcholine (PC) [[14], [15], [16]], the major component of the cell membrane, and is produced by the cleavage of PC by phospholipase A2 (PLA2) [17]. In addition, the transfer of fatty acids to free cholesterol by lecithin-cholesterol acyltransferase (LCAT) can also generate saturated LPC. Importantly, LPC can be converted to PC via lysophosphatidylcholine acyltransferase (LPCAT) in the presence of Acyl-CoA. LPC can be catalysed by lysophospholipases A1, C and D (Fig. 1) [18]. Autotaxin (ATX) has lysophospholipase D activity, which could degrade LPC and produce lysophosphatidic acid (LPA),a mediator that is highly related with skin diseases and cancers [19]. Another sources of LPC are endothelial lipase (EL) and hepatic lipase (HL), and are generated by the cleavage of HDL-PC, which could produce amounts of unsaturated LPC, like oleoyl-lysophosphatidylcholine (LPC 18:1), linoleoyl-lysophosphatidylcholine (LPC 18:2), arachidonoyl-lysophosphatidylcholine (LPC 20:4), and so on (Fig. 2) [20].
The reported LPC receptors are mainly G protein coupled receptors (GPCRs) and Toll-like receptors (TLRs) (Graphical abstract). LPC is the ligand of GPR132 (G2A) and GPR4, and its affinity for G2A is remarkably higher than that for GPR4. G2A is mainly expressed on lymphocytes and macrophages, and G2A deficiency results in the hyperproliferation of T cells and induces advanced autoimmune diseases. LPC can bind to G2A and then activate ERK mitogen-activated protein kinase, inducing the migration of T lymphocytes [2,21]. LPC plays a key role in the development of atherosclerosis and inflammatory diseases through the role of the G2A receptor. The role of LPC mediated by GPR4 is described in detail below.
TLR2 and TLR4 are major Toll-like receptors that mediate LPC function. LPC can activate the NF-kB, p38 MAPK, and JUN signalling pathways by combining the TLR2 and TLR4 receptors [22,23]. The activation of these pathways can induce the production of pro-inflammatory factors, regulating inflammatory and infectious diseases.
The change in intracellular ion concentration by LPC can regulate many physiological functions (Graphical abstract). LPC can induce intracellular calcium mobilization [[24], [25], [26]]. The increased level of calcium mainly originates from external Ca(2+) influx and Ca(2+) release from endoplasmic reticulum Ca(2+) stores [27]. At the same time, intracellular calcium can be used as a second messenger to activate downstream signalling pathways, such as the p38 MAPK pathway [28]. The concentration of Na(+) and K(+) affect the membrane potential of myocardial cells and ensure normal heart function. LPC can affect the concentration of Na(+) in myocardial cells and induce arrhythmogenesis [29]. Na(+)-H+ exchange inhibition can protect the myocardium from injury induced by LPC [30]. In addition, LPC can also affect K(+) currents through the PKC and Rho-kinase pathways [31].
LPC has many biological functions in organisms, such as pro-inflammatory, oxidative stress, apoptosis induction and anti-infective effects (Graphical abstract). Caspase-1, belonging to the family of pro-inflammatory caspases, can activate biologically inactive pro-cytokines, such as IL-1β and IL-18, and plays an important role in inflammation. Researchers have found that LPC can activate caspase-1 and the production of ROS, which is Na(+)-dependent [[32], [33], [34]]. In addition, LPC can increase the generation of chemokines to attract inflammatory cells and increase the release of inflammatory factors, such as IL-1β, IL-8, IFN-γ, IL-6 and IL-5 [35]. This pro-inflammatory effect of LPC plays a critical role in the pathogenesis of diseases. We will introduce this effect in the following sections.
There are many mechanisms by which LPC induces apoptosis, such as caspase activation, calcium influx, the release of cytochrome C, and the mitochondrial pathway [36,37]. In addition, LPC can also induce apoptosis by increasing the expression of FasL by activating the NF-κB signalling pathway [38].
LPC plays a protective role in infectious diseases. One of the mechanisms is that LPC decreases the release of LPS-induced high mobility group box 1 (HMGB1) via the G2A/Ca(2+)/AMPK signalling pathway [39,40] and then plays an anti-infective role. LPC acts on a variety of immune cells and plays an important role in the process of disease. Next, we will elaborate.
Section snippets
Lymphocyte and neutrophils
The effects of LPC on immune cells include the induction of chemotaxis and alterations in immune function. LPC has a strong chemotaxic effect on thymic lymphoma lymphocytes from the mouse spleen and NK T cells (Table 1) [41,42]. Jurkat cells (a human CD4 T-cell line) exposed to LPC exhibit significantly increased expression of the chemokine receptors CXCR4 and CCR5 [43]. The main mechanism of this chemotaxis is dependent on a signalling pathway mediated by G2A, a receptor that is widely
Cardiovascular diseases (atherosclerosis)
LPC, the main component of oxLDL, has a variety of biological functions in cardiovascular diseases and can be used as a biomarker in some diseases [3]. LPC induces remarkable pro-inflammatory effects and vascular dysfunction in atherosclerosis and other cardiovascular diseases. Researchers have found that the concentration of LPC in plasma correlates with vascular damage and heart rate [99] and that the level of LPC in atherosclerotic plaques is markedly related to inflammatory factors, such as
Conclusion
LPC activates a variety of downstream signalling pathways, such as the MAPK and NF-κB pathways, through G protein coupled receptors and Toll-like receptors and mediates multiple biological functions, including the induction of chemotaxis, the release of inflammatory factors, oxidative stress, and apoptosis. The biological function of LPC in different cells promotes the formation of atherosclerotic plaques, aggravates inflammation, enhances anti-infective responses, regulates blood glucose, and
Acknowledgements
This work was supported by 81830096 from the key project of the National Science Foundation and supported Grant No.81773341 by National Natural Science Foundation of China.
Declaration of competing interest
The authors declare no conflict of interest.
References (184)
- et al.
Lipoprotein-derived lysophosphatidic acid promotes atherosclerosis by releasing CXCL1 from the endothelium
Cell Metab.
(2011) - et al.
Lysophosphatidylcholine contents in plasma LDL in patients with type 2 diabetes mellitus: relation with lipoprotein-associated phospholipase A2 and effects of simvastatin treatment
Atherosclerosis
(2008) - et al.
Comparison of C26:0-carnitine and C26:0-lysophosphatidylcholine as diagnostic markers in dried blood spots from newborns and patients with adrenoleukodystrophy
Mol. Genet. Metab.
(2017) - et al.
Flow injection ionization-tandem mass spectrometry-based estimation of a panel of lysophosphatidylcholines in dried blood spots for screening of X-linked adrenoleukodystrophy
Clin. Chim. Acta
(2019) - et al.
Application of a diagnostic methodology by quantification of 26:0 lysophosphatidylcholine in dried blood spots for Japanese newborn screening of X-linked adrenoleukodystrophy
Mol Genet Metab Rep
(2017) - et al.
The role of lysophosphatidic acid in the physiology and pathology of the skin
Life Sci.
(2019) - et al.
Acyl chain-dependent effect of lysophosphatidylcholine on cyclooxygenase (COX)-2 expression in endothelial cells
Atherosclerosis
(2012) - et al.
Lysophosphatidylcholine induces Ca(2+) mobilization in Jurkat human T lymphocytes and CTLL-2 mouse T lymphocytes by different pathways
Eur. J. Pharm. Sci.
(2011) - et al.
Lysophosphatidylcholine elicits intracellular calcium signaling in a GPR55-dependent manner
Biochem. Biophys. Res. Commun.
(2017) - et al.
Characteristics of lysophosphatidylcholine-induced Ca2+ response in human neuroblastoma SH-SY5Y cells
Life Sci.
(2007)
TRPM2 contributes to LPC-induced intracellular Ca(2+) influx and microglial activation
Biochem. Biophys. Res. Commun.
Lysophosphatidylcholine enhances I(Ks) currents in cardiac myocytes through activation of G protein, PKC and Rho signaling pathways
J. Mol. Cell. Cardiol.
Sodium dependence of lysophosphatidylcholine-induced caspase-1 activity and reactive oxygen species generation
Immunobiology
Importance of lipid rafts for lysophosphatidylcholine-induced caspase-1 activation and reactive oxygen species generation
Cell. Immunol.
Lysophosphatidylcholine-induced apoptosis in H19-7 hippocampal progenitor cells is enhanced by the upregulation of Fas Ligand
Biochim. Biophys. Acta
Stearoyl lysophosphatidylcholine inhibits LPS-induced extracellular release of HMGB1 through the G2A/calcium/CaMKKbeta/AMPK pathway
Eur. J. Pharmacol.
Stearoyl lysophosphatidylcholine prevents lipopolysaccharide-induced extracellular release of high mobility group box-1 through AMP-activated protein kinase activation
Int. Immunopharmacol.
Oxidized lipids and lysophosphatidylcholine induce the chemotaxis and intracellular calcium influx in natural killer cells
Immunobiology
Lysophosphatidylcholine enhances the suppressive function of human naturally occurring regulatory T cells through TGF-beta production
Biochem. Biophys. Res. Commun.
Inflammation-associated lysophospholipids as ligands for CD1d-restricted T cells in human cancer
Blood
Gi-independent macrophage chemotaxis to lysophosphatidylcholine via the immunoregulatory GPCR G2A
Blood
Stearoyl lysophosphatidylcholine enhances the phagocytic ability of macrophages through the AMP-activated protein kinase/p38 mitogen activated protein kinase pathway
Int. Immunopharmacol.
Lysophosphatidylcholine perpetuates macrophage polarization toward classically activated phenotype in inflammation
Cell. Immunol.
Gene transfer of dimethylarginine dimethylaminohydrolase-2 improves the impairments of DDAH/ADMA/NOS/NO pathway in endothelial cells induced by lysophosphatidylcholine
Eur. J. Pharmacol.
Role of ERK1/2 activation and nNOS uncoupling on endothelial dysfunction induced by lysophosphatidylcholine
Atherosclerosis
Lysophosphatidylcholine activates the Akt pathway to upregulate extracellular matrix protein production in human aortic valve cells
J. Surg. Res.
Microglia colonization of developing zebrafish midbrain is promoted by apoptotic neuron and lysophosphatidylcholine
Dev. Cell
Lysophosphatidylcholine activates caspase-1 in microglia via a novel pathway involving two inflammasomes
J. Neuroimmunol.
LOX-1 augments oxLDL uptake by lysoPC-stimulated murine macrophages but is not required for oxLDL clearance from plasma
J. Lipid Res.
Nanomolar concentrations of lysophosphatidylcholine recruit monocytes and induce pro-inflammatory cytokine production in macrophages
Biochem. Biophys. Res. Commun.
Inverse relations of serum phosphatidylcholines and lysophosphatidylcholines with vascular damage and heart rate in patients with atherosclerosis
Nutr. Metab. Cardiovasc. Dis.
Xu, Y. Lysophosphatidylcholine as a ligand for the immunoregulatory receptor G2A
Science
Prevention of 1-palmitoyl lysophosphatidylcholine-induced inflammation by polyunsaturated acyl lysophosphatidylcholine
Inflamm. Res.
Identification of phosphatidylcholine and lysophosphatidylcholine as novel biomarkers for cervical cancers in a prospective cohort study
Tumour Biol.
Alteration of lysophosphatidylcholine-related metabolic parameters in the plasma of mice with experimental Sepsis
Inflammation
Clinical significance of enzymatic lysophosphatidylcholine (LPC) assay data in patients with sepsis
Eur. J. Clin. Microbiol. Infect. Dis.
Differential levels of L-homocysteic acid and lysophosphatidylcholine (16:0) in sera of patients with ovarian cancer
Oncol. Lett.
Plasma lysophosphatidylcholine levels: potential biomarkers for colorectal cancer
J. Clin. Oncol.
Higher plasma levels of lysophosphatidylcholine 18:0 are related to a lower risk of common cancers in a prospective metabolomics study
BMC Med.
greasing the cholesterol transport machinery
Lipid Insights
From yeast to humans - roles of the Kennedy pathway for phosphatidylcholine synthesis
FEBS Lett.
Enhanced expression of Lp-PLA2 and lysophosphatidylcholine in symptomatic carotid atherosclerotic plaques
Stroke
The identification of a phospholipase B precursor in human neutrophils
FEBS J.
T cell chemotaxis to lysophosphatidylcholine through the G2A receptor
Proc. Natl. Acad. Sci. U. S. A.
Lysophosphatidylcholine triggers TLR2- and TLR4-mediated signaling pathways but counteracts LPS-induced NO synthesis in peritoneal macrophages by inhibiting NF-kappaB translocation and MAPK/ERK phosphorylation
PLoS One
Schistosomal-derived lysophosphatidylcholine are involved in eosinophil activation and recruitment through Toll-like receptor-2-dependent mechanisms
J. Infect. Dis.
Regulation of eosinophil adhesion by lysophosphatidylcholine via a non-store-operated Ca2+ channel
Am. J. Respir. Cell Mol. Biol.
Lysophosphatidylcholine modulates cardiac I(Na) via multiple protein kinase pathways
Circ. Res.
Na(+)-H+ exchange inhibition protects against mechanical, ultrastructural, and biochemical impairment induced by low concentrations of lysophosphatidylcholine in isolated rat hearts
Circ. Res.
Cited by (227)
Synergistic antifungal mechanism of eugenol and citral against Aspergillus niger: Molecular Level
2024, Industrial Crops and ProductsRegulation of sexual commitment in malaria parasites — a complex affair
2024, Current Opinion in Microbiology