Lysophosphatidylmethanol is a pan lysophosphatidic acid receptor agonist and is produced by autotaxin in blood
Lysophosphatidylmethanol is a pan lysophosphatidic acid receptor agonist and is produced by autotaxin in blood
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DOI：
10.1093/jb/mvp068
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发表时间：
2009-08-01
影响因子：
2.7
通讯作者：
Aoki, Junken
中科院分区：
文献类型：
--
作者：
Endo, Tomoko;Kano, Kuniyuki;Aoki, Junken
溶血磷脂酸（LPA）是一种简单的磷脂，但通过一系列针对LPA的g蛋白偶联受体具有多种生物学作用。一般来说，LPA在体内应用时是短暂的，这阻碍了大多数药理实验。在我们继续研究能够在体内应用的稳定的LPA类似物时，我们在这里确定溶血磷脂酰甲醇（LPM）是一种稳定的泛LPA受体激动剂。合成的LPM激活了所有五种LPA受体（LPA(1-5)），并刺激细胞增殖和LPA受体依赖的细胞运动。此外，LPM在体内对啮齿动物也有降压作用。我们发现，当胎牛血清在甲醇的存在下孵育时，LPM的形成迅速发生，而它被autotaxin （ATX）的耗尽完全阻断，ATX是一种将溶血磷脂酰胆碱（LPC）转化为LPA的血浆酶。重组ATX与LPC在甲醇存在下孵育，生成LPM和LPA的比例为1:10，表明ATX除具有溶血磷脂酶D活性外，还具有转磷脂酰化活性。小鼠经甲醇处理后，血浆中形成了数微摩尔的LPM，其含量远高于LPA。本研究发现LPM是一种新型且稳定的溶血磷脂介质，具有lpa样活性，ATX是LPM潜在的合成酶。
Lysophosphatidic acid (LPA) is a simple phospholipid but has numerous biological effects through a series of G-protein-coupled receptors specific to LPA. In general, LPA is short-lived when applied in vivo, which hinders most pharmacological experiments. In our continuing study to identify stable LPA analogues capable of in vivo applications, we identified here lysophosphatidylmethanol (LPM) as a stable and pan-LPA receptor agonist. A synthetic LPM activated all five LPA receptors (LPA(1-5)), and stimulates both cell proliferation and LPA-receptor-dependent cell motility. In addition, LPM showed a hypertensive effect in rodent when applied in vivo. We found that, when fetal calf serum was incubated in the presence of methanol, formation of LPM occurred rapidly, whereas it was completely blocked by depletion of autotaxin (ATX), a plasma enzyme that converts lysophosphatidylcholine (LPC) to LPA. When recombinant ATX was incubated with LPC in the presence of methanol, both LPM and LPA were produced with a ratio of 1:10, showing that ATX has transphosphatidylation activity in addition to its lysophospholipase D activity. Administration of methanol in mice resulted in the formation of several micromoles of LPM in plasma, which is much higher than that of LPA. The present study identified LPM as a novel and stable lysophospholipid mediator with LPA-like activities and ATX as a potential synthetic enzyme for LPM.