Lysophosphatidic acid (LPA) is one of the simplest glycerophospholipids with one fatty acid chain and a phosphate group as a polar head. Although LPA had been viewed just as a metabolic intermediate in de novo lipid synthetic pathways, it has recently been paid much attention as a lipid mediator. LPA exerts many kinds of cellular processes, such as cell proliferation and smooth muscle contraction, through cognate G protein-coupled receptors. Because lipids are not coded by the genome directly, it is difficult to know their patho- and physiological roles. However, recent studies have identified several key factors mediating the biological roles of LPA, such as receptors and producing enzymes. In addition, studies of transgenic and gene knockout animals for these LPA-related genes, have revealed the biological significance of LPA. In this review we will summarize recent advances in the studies of LPA production and its roles in both physiological and pathological conditions.

This article is available online at http://www.jlr.org by specific receptors belonging to the class A G proteincoupled receptor (GPCR) family ( 1 ). To date, 16 such GPCRs have been identified, including 6 lysophosphatidic acid (LPA) receptors, 5 sphingosine 1-phosphate receptors, 4 lysophosphatidylserine (LysoPS) receptors, and 1 lysophosphatidylinositol (LPI) receptor ( 1-4 ). Recent studies of gene-targeting mice have clearly shown that these receptors function individually in various pathological and physiological conditions ( 5 ).Glycero-LysoGPs have one acyl chain that is linked to either the sn -1 or sn -2 position of glycerol. Phospholipase A (PLA) 1 and PLA 2 cleave diacyl-phospholipids (GPs) and produce 2-acyl-1-lysophospholipids (2-acyl-1-LysoGPs) and 1-acyl-2-LysoGPs, respectively. Recent studies have suggested that some LysoGP receptors discriminate 1-acyl-2-LysoGPs from 2-acyl-1-LysoGPs. For example, LPA 3 / Edg7 ( 6, 7 ) and LPA 6 /P2Y5 ( 8 ) prefer 2-acyl-1-LPA to 1-acyl-2-LPA. In addition, they prefer LPA with unsaturated fatty acids, which are usually attached at the sn -2 position of GPs. LPS 1 /GPR34 also shows preference for 2-acyl-1-LysoPS ( 9 ). These fi ndings indicate that 2-acyl-1-LysoGPs exert their activities through specific receptors. Because of their different activities, 2-acyl-1-LysoGPs and 1-acyl-2-LysoGPs should be quantifi ed separately.However, it has been diffi cult to detect and quantify 2-acyl-1-LysoGPs in biological samples because 2-acyl-1-LysoGPs

Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator generated by hydrolysis of membrane phospholipid phosphatidylserine. Recent ligand screening of orphan G-protein-coupled receptors (GPCRs) identified two LysoPS-specific human GPCRs, namely, P2Y10 (LPS2) and GPR174 (LPS3), which, together with previously reported GPR34 (LPS1), comprise a LysoPS receptor family. Herein, we examined the structure-activity relationships of a series of synthetic LysoPS analogues toward these recently deorphanized LysoPS receptors, based on the idea that LysoPS can be regarded as consisting of distinct modules (fatty acid, glycerol, and l-serine) connected by phosphodiester and ester linkages. Starting from the endogenous ligand (1-oleoyl-LysoPS, 1), we optimized the structure of each module and the ester linkage. Accordingly, we identified some structural requirements of each module for potency and for receptor subtype selectivity. Further assembly of individually structure-optimized modules yielded a series of potent and LysoPS receptor subtype-selective agonists, particularly for P2Y10 and GPR174.

Objective-Lysophosphatidic acids (LPA) have important roles in the field of vascular biology and are derived mainly from lysophosphatidylcholine via autotaxin. However, in our previous study, only the plasma LPA levels, and not the serum autotaxin levels, increased in patients with acute coronary syndrome (ACS). The aim of this study was to elucidate the pathway by which LPA is increased in patients with ACS. Approach and Results-We measured the plasma lysophospholipids species in 141 consecutive patients undergoing coronary angiography (ACS, n=38; stable angina pectoris, n=71; angiographically normal coronary arteries, n=32) using a liquid chromatography-tandem mass spectrometry analysis. Among the ACS subjects, notable increases in the 22:6 LPA, 18:2 LPA, and 20:4 LPA levels were observed. The in vitro experiments revealed that serum incubation mainly increased the 18:2 LPA level, whereas platelet activation increased the 20:4 LPA level. Minor lysophospholipids other than LPA were also elevated in ACS subjects and were well correlated with the corresponding LPA species, including 22:6 LPA. A multiple regression analysis also revealed that lysophosphatidylinositol, lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidylglycerol were independent explanatory variables for several LPA species. Conclusions-Specific LPA species, especially long-chain unsaturated LPA, were elevated in ACS patients, along with the corresponding minor lysophospholipids. The elevation of these LPA species might be mainly caused by presently unidentified LPA-producing pathway(s). Minor lysophospholipids might be involved in the generation of LPA, especially 22:6 LPA, and in the pathogenesis of ACS. LPA levels were elevated in patients with ACS but not in those with stable angina pectoris (SAP). 16 This result suggested that LPA might be involved in plaque instability and platelet activation in human subjects. In addition, we also found that serum autotaxin levels were not elevated in patients with ACS; LPA is hydrolyzed from lysophosphatidylcholine (LPC) by autotaxin/lysophospholipase D. 17 This discrepancy between LPA and autotaxin interested us greatly because autotaxin is a key enzyme in the production of LPA. Actually, we previously reported a strong positive correlation between LPA and autotaxin in healthy subjects, 18 patients with chronic hepatitis, 19 and patients with follicular lymphoma.20 Therefore, the discordance between ACS subjects and other subjects prompted us to investigate the origins of the elevation in LPA in patients with ACS.LPA is structurally composed of a fatty acid linked to snglycerol-3 phosphate, and the molecular species of the fatty acid chain are varied and determine the molecular species of LPA. In a previous report, 16 we measured the total LPA and LPC levels using previously described enzymatic methods. 21 Using these methods, we could not obtain any information concerning which molecular species of LPA were elevated in patients with ACS. To overcome this limitation, we determined th...