Metabolic pathways and physiological and pathological significances of lysolipid phosphate mediators

Abstract

Lysophosphatidic acid and sphingosine 1-phosphate are structurally simple and physiologically very important lysophospholipids. Because they possess distinct structural backbones (glycerol and sphingosine, respectively), there are different metabolic pathways for their intracellular production. Recently, several key enzymes that produce or degrade these lysolipid phosphate mediators extracellularly have been characterized. This review focuses on the physiological and pathophysiological significances of the extracellular metabolic pathways involving recently characterized exo-type lysophospholipase D, ecto-type phospholipase A, and ecto-type lipid phosphate phosphatase.

Proteolytic maturation and activation of autotaxin (NPP2), a secreted metastasis-enhancing lysophospholipase D

“…However, after a pretreatment of the cellular and secreted pool of NPP2 with N-glycosidase F they migrated identically, showing that the composition of their N-linked oligosaccharides is different. Tokumura et al previously speculated that NPP2 is a heterodimer of full-length NPP2 and a C-terminal 30-kDa fragment, roughly corresponding to the nuclease-like domain (Tokumura, 2004;Tokumura et al, 2002). However, we did not detect lower-molecular-mass bands in crude or purified preparations of NPP2 with antibodies against the C-terminal Myc-tag.…”

“…Indeed, NPP2 not only stimulates the growth of cancer cells (Umezu-Goto et al, 2002), but also acts as a tumour cell motility factor (Kohn et al, 1993;Lee et al, 1996), augments the tumorigenicity of rastransformed cells (Nam et al, 2000) and induces a strong angiogenic response (Nam et al, 2001). All known biological effects of NPP2 can be explained by its ability to act as an extracellular lysophospholipase D (reviewed by Moolenaar, 2002;Moolenaar et al, 2004;Tokumura, 2004;Xie and Meier, 2004). A major substrate of NPP2 is lysophosphatidylcholine (Umezu-Goto et al, 2002;Tokumura et al, 2002;Hama et al, 2004), which is hydrolyzed into lysophosphatidic acid (LPA) and choline.…”

Alterations of Plasma Levels of Lysophosphatidic Acid in Response to Fasting of Rats

“…1) Both circulating and local levels of LPA are regulated tightly by LPA-producing enzymes, LPA-degrading enzymes and LPA-binding proteins. 2,3) Both abnormal production and degradation of LPA are assumed to be relevant to pathophysiological conditions of human such as cancer metastasis, 4) atherosclerosis, 5) organ fibrosis 6) and pain. 7) Although LPA-producing enzymatic activity in human plasma and bovine fetal serum was demonstrated to be largely due to autotaxin (ATX), 8,9) physiological regulation of the circulating LPA level is not yet well understood.…”

“…7) Although LPA-producing enzymatic activity in human plasma and bovine fetal serum was demonstrated to be largely due to autotaxin (ATX), 8,9) physiological regulation of the circulating LPA level is not yet well understood. 3,10) In this study, we focused our inquiry on whether the stress of nutritional restriction affected the in vivo plasma level and molecular species composition of LPA using quantifying lysophosphatidylcholine (LPC) and LPA by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and its mechanism by comparing LPA-producing and -degrading enzymatic activities during 12 and 24 h fasting.…”

Physiological Significance of Lysophospholipids that Act on the Lumen Side of Mammalian Lower Digestive Tracts

“…The extracellular enzymatic conversion of LPC to LPA was first investigated in secretory lysoPLD activity in rat plasma, 73) and later in plasma or serum from different animals and several biological fluids including human peritoneal fluid including malignant ascites, human urine, human follicular fluids, human and dog cerebrospinal fluids, human blister fluid and hen egg white were studied. [74][75][76] Autotaxin (ATX), the second member of the ecto-nucleotide pyrophosphatase/phosphodiesterase family, was originally isolated from human A 2058 melanoma cells as a tumor cell mobility-stimulating protein. 77) Later, lysoPLD activities that convert LPC to LPA in human plasma 78) and fetal calf serum 79) were both found to be due to ATX, supporting the pathophysiological significance of LPA as a tumor-aggression factor.…”