Mechanisms of lysophosphatidic acid production

Lysophosphaticlic acid is one of the most attractive phospholipid mediator with multiple biological functions and is implicated in various human diseases. In the past ten years much has been learned about the physiological roles of LPA through series of studies on LPA actions and its receptors. However, the molecular mechanisms of LPA have been poorly understood. LPA is produced in various conditions both in cells and in biological fluids, where multiple synthetic reactions occur. At least two pathways are postulated. In serum and plasma, LPA is mainly converted from lysophospholipids. By contrast, in platelets and some cancer cells, LPA is converted from phosphatidic acid. In each pathway, at least two phospholipase activities are required: phospholipase A(1) (PLA(1))/PLA(2) plus lysophospholipase D (lysoPLD) activities are involved in the first pathway and phospholipase D (PLD) plus PLA(1)/PLA(2) activities are involved in the second pathway. Now multiple phospholipases are identified that account for PLA(1), PLA(2), PLD, and lysoPLD activities. In the absence of specific inhibitors and genetically modified animals and individuals, the contribution of each phospholipase to LPA production can not be easily determined. However, apparently certain extracellular phospholipases such as secretory PLA(2) (sPLA(2)-IIA), membrane-associated PA-selective PLA(1) (mPA-PLA(1)), lecithin-cholesterol acyltransferase (LCAT), and lysoPLD are involved in LPA production. (C) 2004 Elsevier Ltd. All rights reserved.