Lysophosphatidic acid (LPA)

Lipidomics Gateway (28 October 2009) [doi:10.1038/lipidmaps.2009.31]

One of the most active of the bioactive phospholipids, LPA is soluble in both cell membranes and in aqueous fluid, and acts in many cell signaling pathways.

Structure of LPA with a saturated acyl chain in the sn1 position (top) or an unsaturated acyl chain in the sn2 position (bottom). Image created using the LIPID MAPS glycerophospholipid structure drawing tool. For nomenclature information, visit Author Tools.

The bulk of LPA production occurs in bodily fluids, outside the cell. From there, it can bind to, and activate, upwards of six different cell surface receptors, initiating a diverse range of signaling cascades. LPA also has unclearly defined intracellular roles, and activates at least one nuclear receptor. Besides these direct interactions, the regulated presence of LPA in the membrane can induce curvature, and is involved in membrane transport processes.

LPA: Composition, production and destruction

As the name suggests, LPA is identical in structure to phosphatidic acid (PA), except that LPA has a single acyl chain. LPA can be directly generated from PA, through the action of phospholipase A-type enzymes, but in the main pathway of production the choline headgroup from lysophosphatidylcholine (LPC) is removed by the secreted enzyme autotaxin ¹ . Circulating LPA is rapidly turned over by lipid phosphate phosphatases (LPPs), which terminate its signal by dephosphorylation ² . The LPP superfamily includes three LPP enzymes and a number of related proteins that are thought to possess LPP activity. However, recent data suggests that a brain-specific family member modulates LPA signaling at excitatory synapses by simply binding, not hydrolyzing, the phospholipid, thus preventing its interaction with a receptor ³ .

Signaling: Tailored reception

The functions of LPA are extensive and include roles in development, but individual cellular responses vary widely. Specific effects are determined by the local concentration of LPA, and on the receptors expressed by a cell. Five G-protein-coupled receptors (GPCRs) have been identified as specific for LPA (designated LPA_1–5), and a further three candidates await full validation ⁴ . One of these, P2Y5, was identified as essential for the maintenance of human hair growth ⁵ , and was recently reported to reduce intestinal cell adhesion ⁶ . In common with other LPA receptors, P2Y5 can transactivate the epidermal growth factor receptor ⁶ , introducing a further layer of complexity to LPA-mediated signaling.

Most reported cellular responses to LPA have been attributed to cell surface GPCR activation, but it can also bind the nuclear peroxisome proliferator-activated receptor gamma (PPARγ), and initiate early stages of atherosclerosis ⁷ . A few other intracellular targets have been reported, including LPA₁, which appears to be trafficked to the nucleus in response to extracellular LPA ⁸ . Furthermore, our article this month “Lipid signaling: LPA's ways of actin” highlights another potential intracellular activity of LPA as it binds to and inhibits the actin-modifying protein villin ⁹ .

Membrane transport: Curves required

A further way in which LPA can modulate cell behavior is by altering membrane dynamics. LPA acyltransferase (LPAAT) enzymes condense LPA and fatty acyl-coenzyme A to produce PA. The LPA used can be taken from either the membrane or cytosolic pool, with profound consequences for membrane architecture as both LPA and PA promote curvature, but in opposite directions ¹⁰ . Recently, we highlighted the role of a novel LPAAT in Golgi transport function (See “Lipids and Golgi function: An acyltransferase stops traffic”) ¹¹ .

Detection: Diseases, species and identity crises

With so many physiological responses to LPA, there is great potential for things to go wrong. Aberrant LPA signaling is implicated in numerous pathologies, including cancer and heart disease ^{12 b13} , and the pathways involved are potential therapeutic targets. To counteract specific functions of LPA, there is a need to define the roles of distinct molecular species in different tissues and developmental stages. It is also unclear how the intra and extracellular functions of LPA are related. Modern lipidomics techniques, as for phosphatidylcholine, are increasingly capable of answering these questions. For example, the work highlighted this month in “Brain lipids: Male mice show their age” found that levels of LPA increase with age in the brains of male, but not female, mice ¹⁴ .

These techniques, however, are still being refined; a recent study by Zhao & Xu suggests that for quantification of LPA using a favored lipidomics approach (electrospray ionization coupled with tandem mass spectrometry, ESI–MS/MS), it is first necessary to separate LPA from any LPC in the sample, because a proportion of LPC loses its choline headgroup at the ionization source and can generate a false LPA signal ¹⁵ .

Emma Leah