The mechanisms of lysophosphatidylcholine in the development of diseases

Abstract

Lysophosphatidylcholine (LPC) is the main component of oxidatively damaged low-density lipoprotein (oxLDL). LPC originates from the cleavage of phosphatidylcholine by phospholipase A2 (PLA2). LPC plays a biological role by binding to G protein-coupled receptors and Toll-like receptors. LPC can induce the migration of lymphocytes and macrophages, increase the production of pro-inflammatory cytokines, induce oxidative stress, and promote apoptosis, which can aggregate inflammation and promote the development of diseases. The effects of LPC on endothelial cells, vascular smooth muscle cells and arteries play a vital role in the progression of atherosclerosis and other cardiovascular diseases. In addition, the regulation of inflammation by LPC plays different roles in inflammatory and infectious diseases. In diabetes, LPC can induce insulin resistance. On the other hand, it can decrease blood glucose. The concentration of LPC varies in different tumours. LPC plays an important role in the invasion, metastasis and prognosis of tumours. Therefore, targeting LPC and lipid metabolism might be a potential therapeutic method for 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.