Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate

J Lipid Res. 2015 Jun;56(6):1134-44. doi: 10.1194/jlr.M057661. Epub 2015 Apr 20.

Abstract

Autotaxin (ATX) is a secreted enzyme, which produces extracellular lysophosphatidate (LPA) from lysophosphatidylcholine (LPC). LPA activates six G protein-coupled receptors and this is essential for vasculogenesis during embryonic development. ATX is also involved in wound healing and inflammation, and in tumor growth, metastasis, and chemo-resistance. It is, therefore, important to understand how ATX is regulated. It was proposed that ATX activity is inhibited by its product LPA, or a related lipid called sphingosine 1-phosphate (S1P). We now show that this apparent inhibition is ineffective at the high concentrations of LPC that occur in vivo. Instead, feedback regulation by LPA and S1P is mediated by inhibition of ATX expression resulting from phosphatidylinositol-3-kinase activation. Inhibiting ATX activity in mice with ONO-8430506 severely decreased plasma LPA concentrations and increased ATX mRNA in adipose tissue, which is a major site of ATX production. Consequently, the amount of inhibitor-bound ATX protein in the plasma increased. We, therefore, demonstrate the concept that accumulation of LPA in the circulation decreases ATX production. However, this feedback regulation can be overcome by the inflammatory cytokines, TNF-α or interleukin 1β. This enables high LPA and ATX levels to coexist in inflammatory conditions. The results are discussed in terms of ATX regulation in wound healing and cancer.

Keywords: autotaxin inhibition; cytokines; fluorescent substrate-3 assay; inflammation; lysophosphatidylcholine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Carbolines / administration & dosage
  • Gene Expression Regulation / drug effects
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Lysophospholipids / blood*
  • Lysophospholipids / genetics
  • Lysophospholipids / metabolism*
  • Mice
  • Phosphoric Diester Hydrolases / biosynthesis*
  • Phosphoric Diester Hydrolases / blood
  • Phosphoric Diester Hydrolases / genetics
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • Wound Healing / genetics

Substances

  • Carbolines
  • Lysophospholipids
  • ONO-8430506
  • Receptors, G-Protein-Coupled
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • sphingosine 1-phosphate
  • Phosphoric Diester Hydrolases
  • alkylglycerophosphoethanolamine phosphodiesterase
  • Sphingosine
  • lysophosphatidic acid