Elsevier

Biochimie

Volume 95, Issue 4, April 2013, Pages 667-679
Biochimie

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

https://doi.org/10.1016/j.biochi.2012.10.009Get rights and content

Abstract

Based on the results of research conducted over last two decades, lysophospholipids (LPLs) were observed to be not only structural components of cellular membranes but also biologically active molecules 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 of extracellular lysophospholipids in both normal physiology and pathology, it has become evident that those small molecules may have therapeutic potential. While lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) have been studied in detail, other LPLs such as lysophosphatidylglycerol (LPG), lysophosphatidylserine (LPS), lysophosphatidylinositol (LPI), lysophosphatidylethanolamine (LPE) or even lysophosphatidylcholine (LPC) have not been elucidated to such a high degree. Although information concerning the latter LPLs is sparse as compared to LPA and S1P, within the last couple of years much progress has been made. Recently published data suggest that these compounds may regulate fundamental cellular activities by modulating multiple molecular targets, e.g. by binding to specific receptors and/or altering the structure and fluidity of lipid rafts. Therefore, the present review is devoted to novel bioactive glycerol-based lysophospholipids and recent findings concerning their functions and possible signaling pathways regulating physiological and pathological processes.

Graphical abstract

Multiple activities of bioactive lysophospholipids. LPLs act mainly through direct interaction with a specific GPCR or/and ion channel or through modulation of lipid rafts organization. Incorporation of LPLs into the cell membrane also leads to dimerisation/oligomerisation of receptors and triggering downstream signaling pathways. Besides, micelles composed of LPLs are able to disrupt cell membrane integrity and lysis of whole cells.

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Highlights

► The review is devoted to novel bioactive lysophospholipids: LPI, LPE, LPS, LPG, LPC. ► We summarize their in vivo distribution and biosynthesis pathways. ► Those LPLs regulate fundamental cellular functions by modulating multiple targets. ► They alter the structure and fluidity of lipid rafts. ► We comprehend the progress in deorphanizing GPCRs for LPC, LPS, LPI, LPG and LPE.

Introduction

For many years lysophospholipids (LPLs) have shied away from the limelight. However, the rapidly expanding field of bioactive LPLs has recently shown that they are not only intermediates in the pathways for the synthesis of various phospholipids – the main constituents of biological membranes, but are also important signaling mediators in their own right, with wide-ranging biological effects. In particular, LPLs with glycerol (lysophosphatidic acid, LPA) or sphingoid (sphingosine-1-phosphate, S1P) backbones are attracting attention in this area. While LPA and S1P have been studied in detail, the actions of other LPLs such as lysophosphatidylglycerol (LPG), lysophosphatidylserine (LPS), lysophosphatidylinositol (LPI), lysophosphatidylethanolamine (LPE) or even lysophosphatidylcholine (LPC) have not been elucidated to such a high degree. Although very little is known about their endogenous receptors, recent in vitro studies suggest that they can induce various and unique cellular responses.

In spite of their simple structure, LPLs were found to be very important biologically active compounds. Glycerol derivatives of lysophospholipids share a few structural features: they possess a glycerol backbone, a phosphate head group at the sn-3 position, a hydroxyl group at the sn-2 (or sn-1) position and a single fatty acid chain at the sn-1 (or sn-2) position (Fig. 1). There are no more properties that characterize the whole family, as the linkage between the phosphate head group and fatty acid tail, the level of unsaturation and substituents vary within different molecules. It is also well known that the acyl chain at the sn-2 position of the 2-acyl-lysophospholipid has a tendency to migrate to the sn-1 position, thus resulting in the creation of the 1-acyl-lysophospholipid [1].

The relative simplicity and diversity of lysophospholipid structures lead to interactions of those compounds with various biomolecular targets. The hydrophobic tail of fatty acid residue and the hydrophilic head group determine the specific chemical construction of LPL molecules and consequently affect their unique biological activities: detergent-like action, an ability to alter mechanical properties of lipid membranes, and interaction with G-protein coupled receptors and ion channels. A broad range of LPL's biological properties has prompted many synthetic efforts to construct new lysophospholipid analogs. Special attention has been paid to a class of ether-linked LPL analogs (Fig. 1) due to their antitumor activities [2]. Another example comes from studies by Iwashita et al. who synthesized 2-deoxy derivatives of LPS and replaced its serine with threonine residue (Fig. 1) [3]. These modifications led to changes in activities of the new compounds both in vitro and in vivo.

Since biological activities of LPA and S1P have been amply reviewed elsewhere [4], [5], this paper will focus on other aforementioned LPLs, and in particular glycerol-based lysophospholipids. Those molecules have been shown to be involved in such diseases as cancer, diabetes, obesity, atherosclerosis, and inflammation. Within the last couple of years much progress has been made in deorphanizing novel GPCRs for LPC, LPS, LPI, LPG and LPE as well as in identifying other targets responsible for their biological activity. Therefore, the present review is devoted to novel glycerol-based lysophospholipids and recent findings concerning their functions and possible signaling pathways regulating physiological and pathological processes.

Section snippets

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

LPLs have been observed to be produced by various pathways: by enzymes mediated de novo synthesis from glycerol-3-phosphate and fatty acyl-CoA, and through hydrolysis of one acyl group of phospholipids (PLs). In enzymatic biosynthesis of LPLs from PLs mainly phospholipases and acyltransferases are involved [1], [6], [7] (Table 1).

Lysophospholipids interfere with lipid membrane structure and ion channel activities

Based on the results of several studies, lysophospholipids were observed to be inducing a wide array of effects in a cell-specific manner. Besides, the diverse activities induced by LPLs appeared to be attributed, mainly, to an interaction with specific receptors. However, a number of receptor-independent effects were also noticed, e.g., partitioning into the lipid bilayer and altering the properties of cell membranes, or directly binding to the non-receptor protein partners, such as ion

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

Evolutionary conservatism indicates that LPLs as molecules involved in intercellular communication have ancient nature [104]. The signal transduction mechanism of bioactive lipids is rather complex and cannot be always defined by one pathway. LPLs may exert regulatory activities in cells for example by changing properties of lipid rafts into which they are incorporated or/and directly via G-protein coupled receptors. Accumulated data have now demonstrated that most of the biological effects of

Conclusions

The last two decades have shown that lysophospholipids regulate fundamental cellular mechanisms and might reveal therapeutic targets for drug development. The development of analytical methods such as mass spectrometry has demonstrated the existence in vivo not only LPA and S1P, but also other bioactive LPLs. However, the more we know about their biology the more questions arise. Present discoveries show that this area of cellular biology is more surprising than one could expect, especially

Acknowledgments

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

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