Novel bioactive glycerol-based lysophospholipids: New data – New insight into their function

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Biochimie 95 (2013) 667e679

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Biochimie

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Review

Novel bioactive glycerol-based lysophospholipids: New data e Newinsight into their function

Anna Grzelczyk, Edyta Gendaszewska-Darmach*

Institute of Technical Biochemistry, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego 4/10, 90-924 Lodz, Poland

a r t i c l e i n f o

Article history:Received 6 May 2012Accepted 11 October 2012Available online 23 October 2012

Keywords:LysophospholipidsG-protein coupled receptorsMembranes/fluidityPhospholipases

Abbreviations: ALP, alkaline phosphatase; CMC, cFPRL1, formyl peptide receptor like-1; HODE, hydrointestinal alkaline phosphatase; LPA, lysophosphatiddylcholine; LPE, lysophosphatidylethanolamine; LPG, llysophosphatidylinositol; LPL, lysophospholipid; LPS,lysophosphatidylthreonine; OEA, oleoylethanolamide;phosphatidylethanolamine; PL, phospholipid; PLC, phtidylserine; ROS, reactive oxygen species; S1P, spsphingosylphosphorylcholine; TRP, transient receptor* Corresponding author. Tel.: þ48 42 6313432.

E-mail address: [email protected] (E. Gendaszewsk

0300-9084/$ e see front matter � 2012 Elsevier Mashttp://dx.doi.org/10.1016/j.biochi.2012.10.009

a b s t r a c t

Based on the results of research conducted over last two decades, lysophospholipids (LPLs) wereobserved to be not only structural components of cellular membranes but also biologically activemolecules influencing a broad variety of processes such as carcinogenesis, neurogenesis, immunity,vascular development or regulation of metabolic diseases. With a growing interest in the involvement ofextracellular lysophospholipids in both normal physiology and pathology, it has become evident thatthose small molecules may have therapeutic potential. While lysophosphatidic acid (LPA) and sphin-gosine-1-phosphate (S1P) have been studied in detail, other LPLs such as lysophosphatidylglycerol (LPG),lysophosphatidylserine (LPS), lysophosphatidylinositol (LPI), lysophosphatidylethanolamine (LPE) oreven lysophosphatidylcholine (LPC) have not been elucidated to such a high degree. Although infor-mation concerning the latter LPLs is sparse as compared to LPA and S1P, within the last couple of yearsmuch progress has been made. Recently published data suggest that these compounds may regulatefundamental cellular activities by modulating multiple molecular targets, e.g. by binding to specificreceptors and/or altering the structure and fluidity of lipid rafts. Therefore, the present review is devotedto novel bioactive glycerol-based lysophospholipids and recent findings concerning their functions andpossible signaling pathways regulating physiological and pathological processes.

� 2012 Elsevier Masson SAS. All rights reserved.

1. Introduction

For many years lysophospholipids (LPLs) have shied away fromthe limelight. However, the rapidly expanding field of bioactiveLPLs has recently shown that they are not only intermediates in thepathways for the synthesis of various phospholipids e the mainconstituents of biological membranes, but are also importantsignaling mediators in their own right, with wide-ranging biolog-ical effects. In particular, LPLs with glycerol (lysophosphatidic acid,LPA) or sphingoid (sphingosine-1-phosphate, S1P) backbones areattracting attention in this area. While LPA and S1P have been

ritical micelle concentration;xyoctadecadienoic acid; IAP,ic acid; LPC, lysophosphati-ysophosphatidylglycerol; LPI,lysophosphatidylserine; LPT,PC, phosphatidylcholine; PE,ospholipase C; PS, phospha-hingosine-1-phosphate; SPC,potential.

a-Darmach).

son SAS. All rights reserved.

studied in detail, the actions of other LPLs such as lysophosphati-dylglycerol (LPG), lysophosphatidylserine (LPS), lysophosphatidy-linositol (LPI), lysophosphatidylethanolamine (LPE) or evenlysophosphatidylcholine (LPC) have not been elucidated to sucha high degree. Although very little is known about their endoge-nous receptors, recent in vitro studies suggest that they can inducevarious and unique cellular responses.

In spite of their simple structure, LPLs were found to be veryimportant biologically active compounds. Glycerol derivatives oflysophospholipids share a few structural features: they possessa 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 fattyacid chain at the sn-1 (or sn-2) position (Fig. 1). There are no moreproperties that characterize the whole family, as the linkagebetween the phosphate head group and fatty acid tail, the level ofunsaturation and substituents vary within different molecules. It isalso well known that the acyl chain at the sn-2 position of the2-acyl-lysophospholipid has a tendency to migrate to the sn-1position, thus resulting in the creation of the 1-acyl-lysophos-pholipid [1].

The relative simplicity and diversity of lysophospholipid struc-tures lead to interactions of those compounds with various biomo-lecular targets. The hydrophobic tail of fatty acid residue and the

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lysophosphatidyl

lysophosphatidyl

2 deoxylysophosphatidylserine

O

OHOC

O

R PO-

OO NCH3

CH3

CH3

+

O

OHOC

O

R PO-

OO COOH

NH3+

O

OHOC

O

R PO-

OO

O

OHOC

O

R POH

OO

OH OH

O

OHOC

O

R PO-

OO COOH

NH3+

O

OC

O

R PO-

OO COOH

NH3+

lysophosphatidylcholine (LPC) serine (LPS)

edelfosine threonine (LPT)

lysophosphatidylglycerol (LPG) -

lysophosphatidylinositol (LPI) lysophosphatidylethanolamine

O

OCH3OC

O

R PO-

OO NCH3

CH3

CH3

+

O

OHOC

O

R POH

OOOH

OH

OHOHHO

NH3+

Fig. 1. Structures of glycerol-based lysophospholipids; R-fatty acyl chain.

A. Grzelczyk, E. Gendaszewska-Darmach / Biochimie 95 (2013) 667e679668

hydrophilic head group determine the specific chemical construc-tionof LPLmolecules and consequentlyaffect their unique biologicalactivities: detergent-like action, an ability to alter mechanicalproperties of lipid membranes, and interaction with G-proteincoupled receptors and ion channels. A broad range of LPL’s biologicalproperties has prompted many synthetic efforts to construct newlysophospholipid analogs. Special attention has been paid to a classof ether-linked LPL analogs (Fig. 1) due to their antitumor activities[2]. Another example comes from studies by Iwashita et al. whosynthesized 2-deoxy derivatives of LPS and replaced its serine withthreonine residue (Fig. 1) [3]. These modifications led to changes inactivities of the new compounds both in vitro and in vivo.

Since biological activities of LPA and S1P have been amplyreviewed elsewhere [4,5], this paper will focus on other afore-mentioned LPLs, and in particular glycerol-based lysophospholi-pids. Those molecules have been shown to be involved in suchdiseases as cancer, diabetes, obesity, atherosclerosis, and inflam-mation. Within the last couple of years much progress has beenmade in deorphanizing novel GPCRs for LPC, LPS, LPI, LPG and LPEas well as in identifying other targets responsible for their biolog-ical activity. Therefore, the present review is devoted to novelglycerol-based lysophospholipids and recent findings concerningtheir functions and possible signaling pathways regulating physi-ological and pathological processes.

2. In vivo distribution, biosynthesis, and activities of LPC, LPS,LPI, LPG, and LPE

LPLs have been observed to be produced by various pathways: byenzymesmediated de novo synthesis fromglycerol-3-phosphate andfatty acyl-CoA, and through hydrolysis of one acyl group of phos-pholipids (PLs). In enzymatic biosynthesis of LPLs from PLs mainlyphospholipases and acyltransferases are involved [1,6,7] (Table 1).

2.1. Lysophosphatidylcholine

LPC is themost abundant LPLwith relatively high (around150mM)concentration inhumanblood [8].However, theconcentrationof totalLPC inmouse serumhas been recentlyestimated as 66mM[9].Mostofthe circulating LPCmolecules are associatedwith albumin. LPC is alsoa major phospholipid component of oxidized low-density lipopro-teins [8]. Several typesof LPCmoleculeswithvariousacyl chains (16:0,18:0,18:1,18:2, 20:4and22:6)havebeen found inhumanplasma [10].

LPC present in plasma is derived from phosphatidylcholine bylecithin:cholesterol acyltransferase (LCAT) catalyzing the trans-acylation of the sn-2 fatty acid residue of lecithin to free choles-terol, resulting in the formation of cholesterol ester and LPC [7].The rate of ester formation by LCAT depends on the nature of theheadgroup, fatty acid residues, and the macromolecular proper-ties of the lipid [6,11]. It is also generated by the action of phos-pholipases A2 (PLA2) and phospholipases A1 (PLA1), which areable to cleave the sn-2 and sn-1 ester bond, respectively [12,13]and which are subdivided into several classes [14e16]. Appre-ciable amounts of LPC are also formed in plasma by endotheliallipase [8] (Table 1).

LPC was recognized as carriers of fatty acids, phosphatidylgly-cerol and choline between tissues [17]. As a pro-inflammatory LPL,it is involved in modulation of T cell functions and immunity. Inactivated microglia (brain macrophages), LPC has been found totrigger IL-1b processing and release [18]. LPC has been reported toenhance the expression of cytokine-induced IFN-g [19] and TGF-b1[20]. Moreover, LPC-dependent NADPH oxidase stimulation andproduction of reactive oxygen species (ROS) has been demon-strated to activate caspase-1 that converts pro-cytokines to theirmature, biologically active forms (IL-1b, IL-18 and IL-33) [21]. LPC isalso involved in the production of prostacyclin PGI2 in vitro inprimary human aortic endothelial cells and in vivo in mice model.Among LPC species under studies, LPC 18:1 and 20:4 have been

Table 1Classification and characteristics of enzymes involved in LPLs biosynthesis.

Enzyme family Group Substate specifity References

Lecithin:cholesterol cyltransferase (LCAT) PE > PC > PG > PA > PS or PC >>

PE; 18:2 > 18:1 > 20:4[1,6,8,11e16,32,52e54,69]

Intracellular PLA2 Group IV, cytosoliccalcium-dependent (cPLA2)

IVA cPLA2a Lysophospholipase > PLA1/PLA2; PC ¼ PI > PE >

PA ¼ PS sn-2: 20:4 > 18:3 > 18:2 > 18:1 > 16:1IVB cPLA2b Lysophospholipase > PLA1/PLA2; PLA1:PC; PLA2:

PA, PS, PG > PC, PEIVC cPLA2g Lysophospholipase > PLA1/PLA2; PE > PCIVD cPLA2d Lysophospholipase > PLA1/PLA2;

IVE cPLA2 3 Low lysophospholipase and PLA2/PLA1 activitiesIVF cPLA2z PLA1 w PLA2 toward PLs with different head

groups, sn-2: 20:4 > 16:0Group VI, calcium-independent(iPLA2) patatin-like phospholipasedomain-containing lipases

VIA iPLA2b LPLs containing 20:4 at the sn-2 position; sn-1lysophospholipase and transacylase activity

B iPLA2g PLA1for 1-palmitoyl-2-arachidonoyl-PC PLA2 forplasmenylcholine with 20:4 at sn-2 position

C,D,E,F very weak PLA2 activity in vitroPAF-AH PAF and PLs containing short fatty acids

Extracellular PLA2 Secretory (sPLA2) IB PG > PS >> PCIIA PG > PS >> PC; PE > PCIIC PG >> PCIID PG w PCIIE PG > PCIIF PG >> PCIII PG > PC; PE w PCV PE > PC > PS; PE w PCX PC > PS; PE w PC > PAFXIIA PG > PC >> PSXIIB Inactive

Lp-PLA2 (P-AH) PAF, oxidized PLsIntracellular PLA1 iPLA1a (PA-PLA1, DDHD1) PA

iPLA1b (p125)iPLA1g (KIAA0725, DDHD2)

Extracellular PLA1 PS-PLA1 PSPA-PLA1a PAPA-PLA1b PAEndothelial lipase (EL) PE > PC > PSHepatic lipase (HL) PE > PC

A. Grzelczyk, E. Gendaszewska-Darmach / Biochimie 95 (2013) 667e679 669

potent inducers of 6-keto PGF1a, a stable degradation product ofPGI2. Interestingly enough, unsaturated LPCs, possessing 20:4 and22:6 hydrocarbon chains, attenuated inflammation induced bysaturated acyl LPCs (16:0) [22]. The anti-inflammatory effects have

Table 2Characteristics of putative G-protein coupled receptors for novel glycerol-based lysopho

Receptor Putative ligands Tissue distribution G proteincoupled

G2A (GPR132) LPC, SPC, LPS,LPE 9-HODE, protons

Hematopoietic cells,endothelial cells andkeratinocytes

Gai, Gaq/11

Gas, Ga13

GPR119 LPC (18:1, 16:0 > 18:0)> LPE > LPI; OEA

Largely pancreaticislets, insulinomas,less in brain,gastrointestinal tract

Gas

GPR4 LPC, SPC, protons Mainly vascularendothelial andsmooth muscle cellslung, kidney, heart,liver, ovary, placenta

Gai/o ?

GPR34 LPS (14:0 > 16:0> 12:0; 18:0)

Ubiquous, in almostall tissues

Gai/o

GPR55 LPI (20:4) [LPSw LPE w LPC; LPG;cannabinoids sn-2LPI (20:4 > 18:2) >sn-1 LPI (18:1) w sn-2LPI (18:1) w sn-1LPI (18:0 > 16:0)

Central nervous system,adrenal glands, testis,spleen, gastrointestinaltract, breast adiposetissues, endothelium,cancer cells

Ga12 Gaq

been related to down-regulation of leukocyte extravasation, plasmaleakage, and formation of pro-inflammatory mediators (IL-5, IL-6,NO, 12-HETE and PGE2) stimulated by LPC 16:0, and up-regulation of anti-inflammatory mediators (IL-4 and IL-10) [23].

spholipids.

Main signalingpathways

Function References

[Ca2þ]i[, ERK[,p38 MAPK[ JNK[

Migration, apoptosis,suppression ofautoimmunity,efferocytosis

[18,26,82,113,115,118,120]

AC[ PKA[ Regulation of insulinsecretion

[24,55,142e146]

[Ca2þ]i[, ERK[ Migration, angiogenesis,impairment of endothelialbarrier function

[27,123e128,130,132,141]

[Ca2þ]i[ ERK[ Mast cells degranulation,response to immunologicalchallenges, tumorigenesis,neuroinflammation

[3,44,108,134,135]

[Ca2þ]i[ PLC[ ERK[,rhoA[, cdc42[ rac1[

Regulation of cancer cellsproliferation and metastasis,nervous system, bonemorphogenesis

[24,47,57e59,107,110,148,151e160]


LPC was found to be connected to pathological conditions suchas atherosclerosis. It is thought to play a significant role in theatherogenic disease as being found as a component of oxidizedlow-density lipoprotein (LDL) in atherosclerotic lesions. LPC 16:0also induces HUVECs and VSMCs cell apoptosis processes what canbe associated with atherogenesis [24,25]. Recently, much attentionhas been paid to the fact that LPC causes an increase in glucose-stimulated insulin secretion from pancreatic beta-cells [26]. Thisreport is in line with the previous observation of Metz on dose-dependent lysophospholipid-induced insulin secretion [27].

2.2. Lysophosphatidylserine

LPS is the constituent of biological fluids, however, its concen-tration is significantly lower than LPC. Liliom et al. have detectedaround 10 mM of LPS in aqueous humor from rabbits [28]. The totalLPS concentration (16:0, 18:0, 18:1, 18:2, 20:3, 20:4, 22:4, 22:5,22:6) in mouse serum has been estimated to be 0.13 mM [9.Recently, Lee et al. by using LC-ESI-MS/MS analysis in negative ionmode, have demonstrated that LPS 18:0 is also present in humanplasma, however, the concentration has not been evaluated [10]. Itis known that LPS is generated by rat peritoneal cells [1] and byhuman neutrophils where NADPH oxidase is activated [29].

One of the main enzymes responsible for LPS production is PS-specific phospholipase (PS-PLA1). The enzyme is secreted fromactivated platelets [30] and acts on phosphatidylserine (PS) mole-cules in the outer leaflet of cell bilayer [1]. In this case phospho-lipids present in the plasma membrane were found in asymmetricarrangement. The majority of sphingomyelin and phosphatidyl-choline (PC) molecules are present in outer leaflet of themembrane. In contrast, aminophospholipids (PS) and phosphati-dylethanolamine (PE) were found predominantly on the cyto-plasmic face of the membrane [31]. PS is confined to the innerleaflet in normal cells, however in apoptotic or cytokine-activatedcells is exported to the cell surface being hydrolyzed by PS-PLA1to LPS [1]. PS-PLA1 produces LPS with fatty acid residue at the sn-2position of the glycerol backbone (2-acyl-LPS), which is unstableand is readily converted to 1-acyl-LPS by the fast spontaneous acylchain migration. Thus, PS-PLA1 generates as well as eliminates LPS,since 2-acyl-LPS produced by PS-PLA1 is degraded by the sameenzyme after acyl migration. It was also shown that the surfaceloops of PS-PLA1 are not involved in the recognition of thesubstrate. Instead, both amino and carboxyl groups of the serineresidue of PS enter into the catalytic pocket of PS-PLA1 [32].

LPS has been reported to regulate many biological processes.The most characterized activity of LPS is its role in inflammationand this phenomenon has been reviewed very recently [33].Among other LPLs, only LPS was found to have an ability to triggerhistamine release from rat peritoneal mast cells initiated bybinding of antigen-IgE complexes to high affinity receptors for IgE[1,34].

The secretion of histamine from rat mast cell is stimulated byLPS and occurs on activated platelets working collaboratively withnerve growth factor [35]. The collaborative action of NGF and LPSwas also observed in PC-12 rat pheochromocytoma cells. LPS alonewas ineffective, however strongly promoted NGF-induced differ-entiation increasing the number of PC12 cells that developedneurites [36]. Other biological activities of LPS include decreasing ofblood glucose level in both normal and type 1/2 diabetic mice[37,38]. LPS, unlike LPE, LPG, and LPI, stimulates glucose uptake bymyotubes of L6 GLUT4myc myoblasts and 3T3-L1 adipocytes whatis probably connected with enhancement of glucose transporterGLUT4 translocation from cytoplasm to the cell membrane [38].Furthermore, LPS treatment of L2071 mouse fibroblasts, U87human glioma cells or human leukemia THP-1 cells, with the

exception of normal human peripheral blood mononuclear cells,leads to their chemotactic migration [39e41]. However, LPSexhibits markedly different effects on cell proliferation. Despiteinducing transient increase in cytosolic free Ca2þ level in ovarianand breast cancer cell lines, LPS does not substantially alter cellproliferation [42]. In contrast, LPS induces DNA synthesis in freshlyisolated keratinocytes [28], however inhibits human Jurkat T cellsproliferation [43]. Finally, the preventive effect on ultraviolet (UV)-induced decrease of procollagen was demonstrated for LPS due toits inhibitory effect on UV-induced MMP-1 expression andprocollagen-upregulating [44].

LPS was also identified as the Toll-like receptor e activatingmolecule during schistosome infection. This activity appeared to bean unique property of schistosomal LPS, containing a 20:1 fatty acidesterified in the sn-2 position [45]. LPS together with PS had a strongTLR2-mediated TNF-a-inducing capacity in whole blood fromGabonese children living in a schistosomiasis endemic area. The latterstudy indicates that LPS present in schistosomes may possess signif-icant immune modulatory properties acting as TLR2 ligands [46].

2.3. Lysophosphatidylinositol

In rat brain 37.5 nmol of LPI (predominantly 16:0, 18:0, 18:1,20:4) per gram of tissue has been detected [47], whereas in mouseserum the concentration of total LPI (16:0, 18:0, 18:1,18:2, 20:1,20:2, 20:3, 20:4, 20:6, 22:4, 22:5, 22:6) was estimated to be ca2.5 mM [9]. The level of LPI in samples of plasma from healthywomen was found to be around 1.51 mM, however, elevated levelsof LPI were found in samples obtained from patients with ovariancancer thus suggesting that LPI can be a good indicator of poordiagnosis [48].

LPI is mainly generated by the action of PLA2 which catalyzes thehydrolysis of the sn-2 ester bond of phosphatidylinositol (PI). PLA2-like activity generates LPI and free arachidonic acid in thrombin-stimulated platelets [49] and in Ras-transformed thyroid cells[50,51]. The group IV calcium-dependent PLA2 is the main enzymeresponsible for LPI synthesis, although LPI has been described to bea product of iPLA2 as well [52,53]. Recent studies suggest that alsoPLA1 can be involved in the synthesis of LPI. Yamashita et al. havedemonstrated that purified recombinant DDHD1 has PLA activitytoward PI and that HEK293 cells expressing DDHD1 generatearachidonic acid-containing LPI upon stimulation by ionomycin[54] (Table 1).

The physiological role of LPI is not well understood, however, anaccumulation of LPI as a consequence of the malignant cell trans-formation identified LPI as a biomarker for poor prognosis in cancerpatients. In vitro studies demonstrated significantly elevated levelsof LPI in highly proliferative cancer cells overexpressing ras-p21protein encoded by the members of the ras family proto-oncogenes [55].

LPI significantly increases proliferation of Ha-Ras-transformedfibroblasts and thyroid cells [50,51]. Additionally, in the case ofMDA-MB-231 human breast cancer cells and PC-3 human prostatecell line, the compound acts as a chemotactic factor and stimulatesmigration of the cells toward FBS [56,57]. LPI produced by macro-phages under inflammatory conditions also evokes neutrophilmigration [58]. In addition, elevated levels of plasma LPI (16:0, 18:0,20:4) have been observed in obese patients. LPI has been shown toupregulate the expression of lipogenic genes in visceral adiposetissue explants [59].

2.4. Lysophosphatidylglycerol

The presence of LPG (16:0, 18:0) has been detected in humanplasma [10] and increased accumulation of LPG has been found to

Table 3Values for critical micelle concentrations of glycerol-based lysophospholipids.

Lysophospholipid CMC [mM] References

LPC 10:0 7e8 [79,80]LPC 12:0 0.7e0.9 [79,80]LPC 14:0 0.04e0.07 [79,80]LPC 16:0 0.007e0.01 [79,80]LPI 0.03e0.07 [77]LPG 14:0 0.3e0.16 [79]LPG 16:0 0.6e0.018 [79]LPE 12:0 4.4 [79]LPE 14:0 0.33 [79]


be characteristic for crystalline lens [60]. The concentration of LPG(16:0, 16:1, 18:0, 18:1,18:2, 20:1, 20:2, 20:3, 20:4) in mouse serumhas been estimated at 0.05 mM level [9].

Although the biological role of LPG has not been extensivelystudied, LPG was reported to participate in de novo synthesis ofphosphatidylglycerol and act as a bioactive ligand stimulatingsignaling molecules and certain cellular responses. LPG modulatesbiological responses in endothelial cells by increasing tube forma-tion and stimulation of chemotactic migration in HUVECs [61].However, the LPG inhibition of motility of endothelial cells isolatedfrom adult bovine aortas was reported previously [62]. LPG stim-ulates migration of human natural killer cells [63], howeverselectively inhibits a formyl peptide receptor like-1 (FPRL1) agonist(MMK-1)-stimulated chemotactic migration in human phagocytes,such as neutrophils or monocytes. LPG can be regarded as a regu-lator of FPRL1-mediated cellular responses because it was found toinhibit IL-1b production by another FPRL1 agonist serum amyloid Ain human monocytes and neutrophils. LPG stimulates superoxideanion production alone as well as after stimulation with MMK-1.Thus, some authors suggest the putative anti-inflammatory roleof LPG [64]. Furthermore, LPG has similar insulinotropic effects asLPI [65] and similar inhibitory effect on UV-induced MMP-1expression as LPS [44].

2.5. Lysophosphatidylethanolamine

LPE accumulates in human serum (16:0, 18:0, 18:1,18:2, 20:1,20:3, 20:4, 22:6) [6] reaching concentration of several hundreds ng/mL [66], and in ischemic heart [67]. Under in vivo conditions, it isgenerated by phospholipases A2 [68] and other lipases. The endo-thelial lipase shows the polar head group specificity in the order ofPE > PC > PS [69].

Information concerning LPE as a bioactive lipid is rather sparseas compared to other phospholipids. Very recently, 16:0 LPEtogether with taurocholic acid, and 22:5 LPC have been defined as“marker metabolites” which can be used to distinguish thedifferent stages of hepatocarcinogenesis [70]. Regarding carcino-genesis, LPE was found to induce intracellular calciummobilizationin OVCAR-3 and SK-OV3 human ovarian cancer cells as well aschemotactic migration and cellular invasion in SK-OV3 cells [71].Furthermore, LPE frommushroom Grifola frondosa extract inhibitedserum deprivation-induced apoptosis and induced neuronaldifferentiation in cultured PC12 cells with involvement of theMAPK signal cascade [72].

The anti-inflammatory action of orally administered LPE, inzymosan A-induced peritonitis was demonstrated in mice. 2-Polyunsaturated acyl LPE was found to lower the formation ofLTC4, a lipid mediator responsible for vascular permeability as wellas the formation of LTB4 and 12-HETE, potent chemotactic factors.The decrease of the level of pro-inflammatory mediators (IL-1 b, IL-6, TNF-a or nitric oxide) in contrast to the augmentation of anti-inflammatory IL-10 was also observed [73]. In addition, LPE andLPC were shown to be important regulators of rat growth platechondrocytes by direct and indirect activation of extracellularmatrix stored TGF-b1 [74].

3. Lysophospholipids interfere with lipid membranestructure and ion channel activities

Based on the results of several studies, lysophospholipids wereobserved to be inducing a wide array of effects in a cell-specificmanner. Besides, the diverse activities induced by LPLs appearedto be attributed, mainly, to an interaction with specific receptors.However, a number of receptor-independent effects were alsonoticed, 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 channels. At low concentra-tions, LPC exists in a solution as a single molecule, and can readilyget into the outer layer of cell membrane as well membrane [75].However, above the critical micelle concentration (CMC), LPC canform small micelles composed of approximately 180 molecules[76]. Moreover, the micelles composed of LPLs are capable of dis-rupting the integrity and selective permeability of cell membrane,thus affecting the activities of numerous membrane proteins [77]along with the lysis of whole [78]. The critical micelle concentra-tion is highly determined by structures of LPLs (Table 3), namelylength and saturation status of fatty acid chains [77,79,80].

Themechanisms, which were proposed to explain the activity ofLPLs, are: (i) mechanical membrane deformation, and (ii) alteringmembrane curvature. In contrast to the phospholipids, whichpossess an approximately cylindrical molecular shape concerningits bulk hydrophilic head group similar in size to fatty acid chain,LPLs consist of a large polar head and a thin hydrophobic tail(Fig. 2). However, when such cone-shaped LPLs migrate into anouter leaflet of the bilayer, they enhance the intrinsic curvature, aswell as the surface area of the outer leaflet of the cell membrane.Lundbaek and Andersen, by using the artificial system, have shownthat LPLs insertion into the cell membrane leads to a modificationof the mechanical properties of the bilayer (decrease of bothenergetic cost of membrane deformation, and overall energetic costof channel formation), thus causing changes in the gramicidinchannel stability [81]. Moreover, because of direct contact of ionchannels with surrounding lipid bilayer, an insertion of LPLs intomembrane can affect their conformation and thereby influence thegating pattern of calcium channels [82].

Modulation of the membrane environment by LPLs explainstheir ability to regulate some membrane proteins properties.Studies have shown that in neutrophils LPC, LPS and LPE, despitedifferences in structures of their head groups, induce Ca2þ mobi-lization via G2A-dependent pathway. This effect was not due to thedirect interaction of LPLs with the receptor, but resulted from theirinfluence on the structure of the cell membrane. The bilayerperturbation caused by LPLs might lead to G2A dimerization/olig-omerization and subsequent activation of signaling pathwaythrough Gai and phosholipase C [83]. Notably, recent data suggestthat LPC causes direct activation and internalization of the G2Areceptor resulting in the rapid release of two Ga subunits (Gaie1 andGaq/11) without membrane perturbation effect [84].

LPLs may also modify the activities of ion channels via physicaldistortion of the lipid bilayer. LPC and LPI have been found to beactivators of the transient receptor potential canonical 5 (TRPC5)protein, thus having almost direct influence on the channel struc-ture. TRPC5 activation occurs either by ligand binding to thechannel or by sensitivity of the channel to perturbation of the cellmembrane [85]. A similar mechanism of action of conically shapedLPC and LPI was proposed with regard to another member of TRPfamily, namely TRPM8 [86,87]. Moreover, LPI has been shown to act

Fig. 2. Structures of cylindrical (phosphatidylcholine 18:0) phospholipid and cone-shaped (lysophosphatidylcholine 18:0) lysophospholipid.


as a direct receptor-independent dual modulator of endotheliallarge-conductance Ca2þ-activated Kþ channels (BKCa) [88] anda stimulator of intermediate-conductance Ca2þ-activated Kþ (IKCa)channels [77]. The two-pore (2P) domain Kþ channels (TREK-1 andTRAAK) are also activated by LPC and LPI, while only weaklyresponding to small-headed LPLs (LPE and LPS) [89]. The results ofMaingret et al. have suggested that extracellular LPC produced bysecretory PLA2 activates those channels, while intracellular LPCproduced by cytosolic PLA2 has the opposite effect. Besides, in thecase of LPC also the length of the fatty acid chain influenced theability of the compound to the ion channel opening. LPC speciesbearing longer fatty acids (14:0, 18:0, 18:1) were stronger activatorsof TREK-1 and TRAAK than LPC 6:0 and LPC 10:0. The modulation ofbTREK-1 channel leak by LPC and LPI has been also demonstrated inbovine adrenal zona fasciculata cells [90]. Similarly, LPC and LPI, incontrast to LPS and LPE, exerted a greater effect on the activity of L-type calcium channel currents (IL) in pituitary cells, thus suggestinga common cone shape lipid-dependent mechanism of their action[82]. Nevertheless, the precise mechanisms by which LPLs directlyactivate ion channels should be still addressed in future studies.

The abovementioned studies provide examples showing, thatLPLs may regulate cell signaling through altering the structure andfluidity of a lipid bilayer and/or certain membrane microdomainsknown as “lipid rafts”. Biological membranes are nowconsidered asheterogeneous or clustered bilayers that undergo remodeling byfission and fusion, what is critical to their function. Detergent-insoluble, cholesterol-rich microdomains, termed “lipid rafts,”have received much attention in the last few years due to theirdiverse cellular functions. Lipid rafts are specialized, cholesterol-and sphingolipid-enriched microdomains of the plasmamembrane, highly enriched in glycosylphosphatidylinositol-anchored proteins. They act as platforms, where membraneproteins transmit information concerning extracellular conditionsacross the cell surface in order to initiate intracellular responses. An

easy insertion of cone-shaped LPLs into the plasma membranedisturbs the structure and properties of a variety of microdomains.Since the physiological concentrations of LPC in human body fluidsare the highest among LPLs, ranging from 5 to 180 mM [91], themembrane effects of LPC have been studied most extensively. Firstcytotoxic effect caused by LPC was observed in erythrocytes. LPC atconcentrations above its CMC disrupted plasma membrane integ-rity leading to hemolysis [78]. In rat vascular smooth muscle cellsLPC has been also demonstrated to induce apoptosis at lowconcentrations and necrosis at concentrations higher than 25 mM.The necrosis induced by the LPC was apparently caused by itsdetergent-like property [92]. LPC-induced membrane rupture,nuclear expansion, and cell lysis were also observed in mouse aortaendothelial cells [93]. The explanation of such effect comes fromthe amphipathic nature of LPC and its detergent-like properties.The detergent-like action has been also demonstrated for otherLPLs. In Jurkat T cells the cytotoxic effect was observed for LPA, LPS,LPE, and LPG although among structurally related LPLs (LPC, LPA,LPS, and LPG) themost prominent effect was seen for LPC. PalmitoylLPC was the most toxic among tested LPC species (6:0, 8:0, 10:0,12:0, 14:0, 16:0, 18:0, 18:1, 19:0, 20:0, and 24:0) [91].

It should be noticed that the effect of LPLs on the cellular activitymay depend not only on the LPL concentration and cell type butalso on incubation conditions. Several studies have suggested thatplasma proteins attenuate the activity of LPLs. For example, serumproteins neutralize the toxic effects of LPC [94] and albumin is themajor serum constituent ameliorating LPC-induced cytotoxicity[91]. The fact that under in vivo conditions some of the LPC mole-cules in plasma may be bound to serum albumin or certain lipo-proteins may protect cells from LPLs toxicity.

Cytotoxic properties of LPC led to the synthesis of a family ofantitumor lipids called alkyl-lysophospholipid analogs, with edel-fosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine,Et-18-OCH3) as the first one reported to induce apoptosis in cancercells [95]. Edelfosine, structurally resembles LPC, having the samepolar head group and a single long nonpolar hydrocarbon chain,which allows for an easy insertion into the plasma membrane.Whereas membrane-inserted LPC undergoes rapid turnover, edel-fosine with its stable ether bonds is not metabolized and thereforeaccumulated in cell membranes. It has been shown that thecompound inhibits cancer cell proliferation, invasion and angio-genesis [96] by accumulating in lipid rafts and co-clustering of lipidrafts and Fas/CD95 death receptor [97]. As a result, edelfosineinduces apoptosis in a broad spectrum of tumor cells while notaffecting normal cells [2]. Such an effect is probably connected withability of some cell types to its internalization by lipid raft-dependent endocytosis [98]. The compound is not incorporatedby normal cell lines such as HUVEC, peripheral blood humanneutrophils, normal bone marrow human hematopoietic progeni-tors and human fibroblasts and, therefore, the cells do not undergoapoptosis [95]. In leukemic cells, edelfosine accumulates in lipidrafts at very high concentration (21.7% of total lipid content) leadingto modification of their biophysical properties [99].

Easy penetration of lysophospholipids into the plasmamembrane also seems to mediate membrane-raft fission. LPC at0.2 mM concentration causes release of alkaline phosphatase(ALP), a membrane-raft associated glycosylphosphatidylinositol-anchored protein. In differentiated Caco-2 cells LPC and LPI effec-tively release ALP (approximately 13e14-fold and 7e8-fold ascompared to untreated control, respectively) but LPE shows weakreleasing ability [100]. Other studies have demonstrated that LPCmediates the release of intestinal ALP (IAP) from the brush-borderapical membranes of Caco-2 cells and rat jejunum as well asincreases the level of mRNA encoding IAP. Additionally, membranerafts are released from brush borders when enterocytes are


exposed to luminal LPC. This fact plays a physiological role in hostdefense mechanism because the latter dephosphorylates toxicmembrane lipopolysaccharides [101]. Aforementioned data suggestthat cells utilize inverted cone-shaped LPLs generated by iPLA2 tomodulate plasma membrane structure and promote the budding ofmembrane-raft-associated plasma membrane particles.

Changes in lipid rafts properties, induced by incorporation ofLPLs to the membrane, may also prevent the protein binding tothose regions. For example it has been demonstrated that LPI pre-vented binding of ostreolysin to cell and to artificial lipidmembranes resembling lipid rafts, by partitioning into the lipidbilayer and altering the properties of cholesterol-rich micro-domains. Ostreolysin is a cytolytic protein from the edible oystermushroom (Pleurotus ostreatus), which specifically recognizes andbinds to raft-like sterol-enriched membrane domains that exist inthe liquid-ordered phase [102]. LPI has been proven to induceexocytosis in rat pheochromocytoma-12 cells in a lipid raft-dependent manner [103].

4. GPCR-mediated effects of LPC, LPS, LPI, LPG and LPE

Evolutionary conservatism indicates that LPLs as moleculesinvolved in intercellular communication have ancient nature [104].The signal transduction mechanism of bioactive lipids is rathercomplex and cannot be always defined by one pathway. LPLs mayexert regulatory activities in cells for example by changing prop-erties of lipid rafts into which they are incorporated or/and directlyvia G-protein coupled receptors. Accumulated data have nowdemonstrated that most of the biological effects of LPLs are mainlymediated by G-protein coupled receptors. The identification andcloning of cell surface GPCRs having high affinity for LPA (LPA1e

LPA6) in the last years has dramatically improved our under-standing of the diverse roles of LPA in biological processes, sug-gesting implementation of preclinical and clinical evaluation of LPAand its analogs [105]. Recently, various orphan GPCRs have beenidentified as specific targets for LPC, LPS, LPI and LPE (Table 2).Although the understanding of LPLs molecular nature is stillincomplete, studies on explaining their role in health and diseaseare in constant progress.

The activities of LPC, such as intracellular Ca2þ mobilization andmodulation of cAMP level have been shown to be dependent ofGPCR activation. LPC was discovered to act as a ligand for widelyexpressed G-protein coupled receptors, G2A and GPR4 [84,106]. Itwas also reported that LPC triggers signaling cascade throughGPR119 [26].

The receptor target for LPI remained unknown until 2007, whenit was demonstrated to be an agonist of GPR55 [107]. It was alsofound that LPI significantly induced intracellular cAMP accumula-tion in cells expressing human GPR119 [26].

Recently, two orphan G-protein coupled receptors have beenidentified as LPS targets, namely GPR34 [108] and G2A [29]. Inaddition, accumulated data have suggested that LPS does not targetLPA or S1P receptors [39e41]. It was shown that LPS-stimulatedchemotaxis in L2071 mouse fibroblasts was not inhibited byVPC32183 (an LPA1- and LPA3-selective antagonist) [39]. In thecourse of other studies it was found that the effect of VPC32183varied from complete inhibition in mouse bone marrow-derivedmast cells and C6 glioma cells to partial inhibition in humanHCT116 colon cancer cells. Similarly, Kim et al. observed thatKi16425 (an LPA1- and LPA3-selective antagonist) completelyinhibited an LPS-induced Ca2þ response in three cell types [109].LPS-induced chemotactic migration was also completely inhibitedby Ki16425 in U87 cells. LPS seems to target two GPCR subtypes:one being the VPC32183-insensitive and the other being Ki16425-sensitive, coupled to PTX-sensitive G proteins and expressed in

U87 cells. Since U87 cells do not express LPA1, LPA4 and GPR34, theauthors rule out the possibility that LPS stimulates U87 chemotaxisvia those receptors [40].

Any specific receptors activated exclusively by LPE have notbeen so far recognized. Park et al. suggested that LPE stimulatesa membrane bound receptor different from LPA1eLPA5, resulting inchemotactic migration and cellular invasion in SK-OV3 ovariancancer cells. The putative PTX-sensitive LPE receptor most probablycouples to Gai/o [71]. A candidate for a receptor target activated byLPE seemed to be GPR119, although RH7777 cells stably expressedhuman GPR119 weremost efficiently activated by LPC [26]. Notably,since GPR119 is coupled to the Gas, it cannot be involved in theactivation of SK-OV3 cells. Regarding LPE-induced intracellularcalcium mobilization in OVCAR-3 cells [71], one should take intoconsideration the involvement of LPI-specific GPR55 expressedendogenously in those cells [110]. In addition, G2A was alsodemonstrated to be activated not only with LPC and LPS but alsowith LPE [29]. Nevertheless, further studies are needed to identifythe receptor targets for LPE.

LPG-induced downstream signaling pathways include intracel-lular Ca2þ mobilization, phosphorylation of ERK1/2 and Aktproteins, thus suggesting involvement of specific G-protein coupledreceptor [61,63,111]. LPG, in contrary to other LPLs, was demon-strated to prevent binding of LPA to a putative LPA receptor presentin mouse NIE-115 neuroblastoma cells [112]. LPG also inhibitedLPA- but not LPS-induced intracellular calcium level increase inHEY ovarian cancer cells [42]. These results are correlated with thereport demonstrating that LPG-dependent migration of humanneutral killer cells is abolished by Ki16425 e an LPA1 and LPA3antagonist, thus supporting the idea that LPG acts as an LPAreceptor antagonist [63]. On the contrary, LPG-induced chemotacticmigration in HUVECs was not inhibited by Ki16425 [61] and LPGitself failed to stimulate NF-kB-driven luciferase activity in exoge-nously LPA1, LPA2, or LPA3-transfected HepG2 cells [111]. Moreover,LPG modulates chemotactic migration independently from PTX-sensitive G-proteins in HUVECs [61], as opposite to its action innatural killer and OVCAR-3 human ovarian cancer cells [63,111].Therefore, the results suggest that LPG targets at least two GPCRsubtypes. One specific candidate may be GPR55 receptor. Althoughthe most potent agonist for GPR55 seems to be LPI, LPG was alsoreported to activate this receptor [47].

4.1. G2A and GPR4 receptors

G2A and GPR4 belong to OGR1 receptor family regulated byeither specific lipid agonists or protons. G2A (also known as G2accumulation protein, GPR132) has been originally discovered asa transcriptionally regulated GPCR in lymphocytes. It was namedfor its ability to cause accumulation of cells in G2/M phase of thecell cycle, which blocked further progression of mitosis [113]. Thereceptor expression has been detected in hematopoietic tissues,endothelial cells, dendritic cells and keratinocytes [114]. It has beenfound that G2A expressed in mammalian cells responded to someoxidized free fatty acids, such as 9-hydroxyoctadecadienoic acid (9-HODE) e one of the major lipid components of oxidized low-density lipoproteins [115]. According to the study of Obinataet al., further screening revealed oxidized free fatty acids such as 9-HODE to be agonists of G2A. G2Awas also to some extend activatedby linoleic acid (nonoxidized precursor to 9-HODE) but not by LPCor lauric acid [116].

Subsequently, G2A was demonstrated to be a proton-sensingreceptor antagonized by LPC [117]. However, in contrast to OGR1,GPR4, and TDAG8, G2A lacks the essential histidine residuesimportant for pH sensing [118]. Studies by Frasch et al. suggest thatLPLs activators of G2A are not thought to be direct ligands but most


likely alter the oligomerization of the receptor by insertion into themembrane leaflet [83]. In addition, Wang et al. observed that G2Awas spontaneously internalized and accumulated in endosomalcompartments, whereas its surface expression was enhanced andstabilized by LPC treatment [119]. However, the literatureregarding G2A receptor remains still controversial since recentlyKhan et al. have demonstrated that LPC, when bound to albumin,elicited a rapid intracellular internalization and activation of theG2A without decrease in cellular integrity or membrane pertur-bation [84].

Using transfected cells and primary lymphocytes, Lin and Yehave shown that G2A couples to multiple G proteins that includeGas, Gaq, and Ga13 [120]. Other studies have indicated the involve-ment of Gai and Gaq/11 proteins in LPC-dependent signaling cascade[84]. Downstream signaling pathways which are triggered by LPC-activated G2A receptor are not fully known, although as in the caseof other LPLs one of the major effects is intracellular Ca2þ mobili-zation. LPC also induces G2A-dependent ERK1/2 activation via Gaiin hamster ovary cells and elevation of cAMP via Gas in HeLa cells[120]. Moreover, in polymorphonuclear leukocytes LPC causes therelease of the Gbg subunit which then rapidly co-localizes withactivated haemopoietic cell kinase (Hck) [84]. Activation of G2A byLPC leads to activation of not only ERK1/2 but also other subfamiliesof MAPKs, such as p38 MAPK and JNK [20].

In murine DO11.10 T lymphoid cell line naturally expressingG2A, LPC stimulation has not altered the basal growth rate of thecells, however, DO11.10 cells have an ability to migrate toward LPC,similarly to G2A-expressing Jurkat T cells [118]. More andmore datahighlight macrophage chemotaxis as a main cellular response toLPC-dependent activation of G2A and suggest that this receptormay play important role in controlling the ability of phagocytic cellsto recognize and/or subsequently respond to immunogenic andLPC-rich moieties [121]. G2A also appears to play a functional rolein apoptosis [120]. G2A, in contrast to its relative GPR4, was alsoidentified as the crucial phagocyte receptor activated by LPC actingas the major phospholipid find-me attraction signal released byapoptotic cells [122]. Other G2A-mediated cellular responses to LPChave been recently reviewed by Kabarowski [121].

Recently, G2A has been identified as a candidate for LPSreceptor. As with 18:1 LPC, 18:1 LPS was also found to inducetransient calcium flux in human neutrophils without evidence ofpermeabilization, thus suggesting G2A-mediated event. As in caseof LPC, it was hypothesized that LPS-induced signaling can beexplained by their perturbing effects on the plasmamembrane thatmay lead to G2A dimerization/oligomerization [83]. However, G2Ahas been shown to react not only with LPC and LPS but also withLPE [83] and oxidized fatty acids [115]. Interactions of LPS with G2Aseem to play important role in inflammation and promotion ofphagocytosis of apoptotic cells (so-called efferocytosis) [29,114].

Both SCP and LPC were postulated by Sin et al. to bind to GPR4,however LPC appeared to be rather low-affinity ligand of thisreceptor [106]. Furthermore, it was reported that LPC-mediatedendothelial barrier dysfunction in endothelial cells was regulatedby GPR4 [123,124] as well as monocyte transmigration [125]. GPR4and OGR1 were described quite recently as proton-sensing recep-tors. These receptors were shown to be either inactive or onlyslightly active at pH 7.6 to 7.8, being much more active at pH 7.0 to7.2. The authors hypothesized that five histidine residues identifiedas conserved in both ORG1 and GPR4 were required for protonsensing [126]. Moreover, the same authors reported that GPR4senses acidic pH and that this process is not affected by highconcentrations of SPC or LPC [127]. Currently, two hypotheses havebeen proposed: GPR4 is thought to be a proton-sensing receptorand/or to be activated in lipid-dependent manner. According toproposed model the receptors have two regulatory sites, one for

protons and the other for lipids The lipids were suggested tointeract with both sites, as antagonist and agonist, respectively[128,129].

GPR4 is mainly expressed in vascular endothelial and smoothmuscle cells as well as in lung, kidney, heart, liver, ovary, andplacenta [127,129,130]. Despite reported controversy, variousstudies suggested a special role for LPC and GPR4 in endothelium.GPR4 was found to be expressed in diverse endothelial cells [131],whereas siRNA knockdown of GPR4 in endothelial cells inhibitedLPC-stimulated decrease in monolayer resistance [124].

4.2. GPR34 receptor

GPR34, belonging to the P2Y12-like receptor family is highlyconserved across vertebrate species and is ubiquitously expressed[132]. Fairly constant levels of GPR34 message were detectable inalmost all human and mouse tissues as examined by Schöneberget al. [133]. The extended analyses revealed that GPR34 transcriptsare expressed in human HL60 and K562 cells, WEHI-3B cells,murine macrophage cell line RAW 264.7 [132,134] and mast cells[108]. GPR34 plays important role in many physiological andpathological processes, including mast cells degranulation [108],cellular response to immunological challenges [132], tumorigenesis[135] and neuroinflammation [136].

Sugo et al. suggested that GPR34 receptor is a mediator for LPS-dependent rat and mouse peritoneal as well as LAD 2 human mastcells degranulation. In CHO cells expressing human GPR34, LPSactivated ERK via a PTX-sensitive G-protein. Moreover, the authorsshowed the activation to be dependent upon the length of fatty acidresidues with a preference for LPS 16:0 and 14:0 [108]. Iwashitaet al. confirmed that 18:0 LPS activated GPR34-expressing CHO-K1cells and exhibited degranulation of rat and mouse peritoneal mastcells. Furthermore, they found that a corresponding deoxy analog,i.e. 2-deoxy-LPS, showed similar activity to LPS itself havinga hydroxyl group opposite to sn-2-acyl lysoPS analog, i.e. sn-2-acyl-1-deoxy-lysoPS which was inactive (Fig. 1). Finally, the authorsshowed that the replacement of the serine residue of LPS with thethreonine residue (lysophosphatidylthreonine, LPT) caused 10-foldincrease of potency in inducing histamine release from rat ormouse peritoneal mast cells. Although LPT induced hypothermiaand anaphylactic shock in vivo, unexpectedly, it did not induce anyresponses in CHO-GPR34 cells [3]. Although LPT has not beendetected in vivo, its potential precursor, phosphatidylthreonine hasbeen found in tissues of various species [137]. Moreover, it wasshown that rat hippocampal neurons synthesize phosphatidyl-threonine in the absence of exogenous L-serine [138], thus sug-gesting its physiological relevance.

Further studies confirmed that GPR34 is a cellular target for LPS,especially with a fatty acid at the sn-2 position [139]. However,Liebscher et al. and Ritscher et al. did not find experimental supportthat LPS-stimulated mast cell degranulation is mediated by GPR34[132,140]. Similarly, 16:0 and 18:0 LPS failed to stimulate humanand mouse GPR34-transfected COS-7 cells [132]. The GPR34orthologues from chicken, xenopus and zebra fish also showed nosignificant response in the yeast cell expression system, howeverthe carp GPR34 displayed a robust response to 16:0 and 18:0 LPS.The authors suggested that LPS has some residual activity withrespect to GPR34, however is not the natural agonist of mammalianGPR34 orthologues. In addition, they identified aminoethylecarbamoyl ATP as an antagonist of fish GPR34 indicating ligandspecificity also to non-lipid compounds [109]. 18:1 LPS also did nottrigger any GPR34-mediated signal increase at concentrations ashigh as 100 mM [116]. The results reported recently by Liebscheret al. showed that mast cells derived from GPR34�/� mice stillrelease histamine upon LPS stimulation, however, GPR34 function


appeared to be required for an appropriate response of the immunesystem to antigen and pathogen contact [132].

Such conflicting reports suggest that while GPR34 may be ableto mediate LPS signaling in some circumstances, it does not appearto be required in other. In addition, the presence of other undefinedreceptor reactive LPS cannot be excluded.

4.3. GPR119 receptor

GPR119 identified with the use of bioinformatic approach wasoriginally suspected to be a cannabinoid receptor, as it exhibitsclose homology to receptors of this group [141]. GPR119 expressionis restricted mostly to pancreatic islets, although some messagewas also detected in human intestinal tissues and in rodent brain[26,142]. High expression level was also found in the insulinomacell lines NIT-1, MIN6, and HIT-T15 [26,143,144]. LPC and oleoyle-thanolamide (OEA) were identified as endogenous ligands forGPR119 receptor [26,142]. Although RH7777 rat hepatoma cellsstably expressing human GPR119 were activated not only by LPCbut also by LPE and LPI, both LPC 16:0 and LPC 18:1 seem to bemostpotent agonists of GPR119. Since GPR119 is coupled to the G proteina-subunit Gas, LPC was demonstrated to bind to GPR119, causingintracellular cAMP accumulation and an increase of glucose-stimulated insulin secretion in the perfused pancreas and NIT-1insulinoma cells [26]. It was also demonstrated that OEA-dependent activation of GPR119 is connected to protein kinase Astimulation [145]. However, on the contrary Lan et al. showed inGPR119 KOmice that the effects of LPC and OEA on insulin secretionwere GPR119-independent [146]. Beneficial influence on glucosehomeostasis was also revealed by demonstrating that LPC stimu-lates glucose uptake in 3T3-L1 adipocytes [38]. Despite theremaining uncertainties regarding the physiological role ofendogenous ligands, activation of GPR119 by synthetic agonistsresults in an increase of the release of insulin and glucagon-likepeptide 1, and significantly improves glucose tolerance [147].

4.4. GPR55

GPR55 has been considered for a long time as a receptor specificfor cannabinoids [148,149]. It was identified as an atypical canna-binoid receptor (CBx) because it was stimulated by atypicalcannabinoids and abnormal cannabidiol [150]. However, GPR55shares only ca 14% sequence identity with CBx and lacks cannabioidbinding pocket [107,151]. Oka et al. showed recently that amongvarious compounds recognized earlier as receptor ligands, LPIseems to be the most active endogenous GPR55 activator [107] anddemonstrated that 2-arachidonoyl LPI is the most potent ligandamong the LPI species [47]. By molecular modeling approach,Kotsikoru et al. found reasons for high affinity of GPR55 towardboth LPI, and cannabinoids. According to their results, bindingpocket of GPR55 can bind ligands having inverted L- or T-shapeswith long, thin profiles. As the authors underlined, the phosphategroup of LPI is very important for the receptorelipid interaction,since the primary interaction site for LPI involves a salt bridgebetween the exposed, charged phosphate oxygen with lysineresidue assigned as K2.60. The K2.60 residue also hydrogen bondsto the glycerol hydroxyl of LPI. In addition, glutamine residue(Q2.65) can hydrogen bond to the glycerol hydroxyl of K2.60 and tothe other exposed oxygen of LPI phosphate. Among other LPI-receptor interactions, the chargeecharge interaction of the LPIphosphate group with K2.60 is a major contributor to the energyinvolved [152].

Oka et al. found that LPI induces rapid phosphorylation of theextracellular signal-regulated kinases and an increase of intracel-lular Ca2þ level in GPR55-expressing cells. High levels of human

GPR55 mRNA have been found in regions of the central nervoussystem, including frontal cortex, hippocampus, hypothalamus aswell as in several peripheral tissues such as adrenal glands,gastrointestinal tract, breast adipose tissues, testes, spleen, andendothelium [148,153e155]. GPR55 is also expressed in manyhuman cancer cell lines such as glioblastoma, astrocytoma, pros-tate, ovarian and breast carcinoma [56,57,110,154,156].

LPI and GPR55 may regulate various cellular processes throughthe activation of diverse signaling cascades. Main transductionpathways concerning activation of GPR55 include primarily Ga13family, although a link to Gaq/11 has also been suggested. This leadsto activation of RhoA, RhoA kinase (ROCK), cdc42 and rac1 [157].Ryberg et al. showed that in recombinant system after stimulationwith cannabinoids, GPR55 is able to couple with Ga13 and mediateactivation of the small G proteins such as rhoA, cdc42 and rac1[148]. Gaq and Ga12 can also participate in signal transductionpathways of the receptor [149]. In HEK293 cells overexpressingGPR55, LPI-dependent release of Ca2þ from intracellular stores isobserved as well as activation of Ga13 protein, phospholipase C(PLC) and RhoA-dependent signaling cascade [158]. GPR55 stimu-lation induces transcriptional regulators including nuclear factor ofactivated T cells (NFAT), nuclear factor-kappaB (NF-kappaB) andcAMP response element binding protein (CREB) [159]. What isworth emphasizing, activation of GPR55 by LPI results in phos-phorylation of ERK1/2 in variousmodels [107,110,159,160] as well asp38 mitogen-activated protein kinase with its downstream target,activating transcription factor 2 (ATF-2) in GPR55-overexpressingcells and in IM-9 lymphoblastoid cells [154].

There is strong evidence that LPI and GPR55 play the regulatoryrole in carcinogenesis [55]. In highly metastatic MDA-MB-231breast cancer cells expressing GPR55 at significant level as well asin MCF-7 cells transiently overexpressing GPR55, LPI-mediatedmigration has been significantly reduced with siRNA targeting thereceptor [56]. LPI, together with GPR55, has been shown to beinvolved in an autocrine loop regulating proliferation of prostateand ovarian cancer cells. LPI added exogenously or synthesizedintracellularly by cPLA2 and later released by the ATP-bindingcassette transporter (ABCC1) induces proliferation of cancer cells,ovarian cancer cells OVCAR3 and prostate cancer cells PC-3expressing GPR55 endogenously. A knock down of both GPR55and cPLA2 blunts the LPI-dependent cellular functions conse-quently reducing PC-3 cells proliferation level [110]. An observationthat the knock down of GPR55 in subcutaneous tumors generatedin mice with glioma reduces growth of tumors supports thehypothesis that LPI and its receptor (GPR55) are key regulators ofcell proliferation in many types of cancer [156]. Interestinglyenough, LPI and GPR55 are also regulators in the nervous system[161], bone morphogenesis [160], inflammatory response [58] andadiposity [59].

5. Conclusions

The last two decades have shown that lysophospholipids regu-late fundamental cellular mechanisms and might reveal thera-peutic targets for drug development. The development of analyticalmethods such as mass spectrometry has demonstrated the exis-tence in vivo not only LPA and S1P, but also other bioactive LPLs.However, the more we know about their biology the more ques-tions arise. Present discoveries show that this area of cellularbiology is more surprising than one could expect, especially thatmany data are contradictory. In such a situation, further biologicalstudies are awaited since the present results demonstrate useful-ness of these molecules, their receptors and other targets fortherapeutic intervention in many pathophysiological processes.The novel LPLs have been shown to be involved in cancer, diabetes,


obesity, atherosclerosis, and inflammation. Furthermore, many oftheir molecular targets have been already confirmed, howevermost probably additional ones still need to be discovered. Anotherfield to go through is a discovery of novel structures of lipidmolecules. As it has been shown in the case of edelfosine, stableanalogs of LPLs are of special relevance. Specific and selective small-molecule agonists/antagonists of GPCRs activated by LPC, LPS, LPI,LPE and LPG will be also crucial.

Acknowledgments

This work was supported by a Grant (2011/01/B/ST5/06383)from the National Science Centre.

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Novel bioactive glycerol-based lysophospholipids: New data – New insight into their function

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