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

Simple item page
dc.contributor.authorZhao, Yuan Y.
dc.contributor.authorMcMullen,Todd P. W.
dc.contributor.authorBrindley, David N.
dc.contributor.authorCurtis, Jonathan M.
dc.contributor.authorBenesch, Matthew G. K.
dc.date.accessioned2025-05-01T11:54:59Z
dc.date.available2025-05-01T11:54:59Z
dc.date.issued2015
dc.descriptionAutotaxin (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.
dc.identifier.doihttps://doi.org/10.7939/R3T43JG73
dc.language.isoen
dc.relationhttp://dx.doi.org/10.1194/jlr.M057661
dc.relation.isversionofBenesch, M. G. K., Zhao, Y. -Y., Curtis, J. M., McMullen, T. P. W., & Brindley, D. N. (2015). Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate. Journal of Lipid Research, 56(6), 1134-1144. http://dx.doi.org/10.1194/jlr.M057661
dc.rights© 2015 by the American Society for Biochemistry and Molecular Biology, Inc.
dc.subjectAutotaxin Inhibition
dc.subjectLysophosphatidylcholine
dc.subjectCytokines
dc.subjectFluorescent Substrate-3 Assay
dc.subjectInflammation
dc.titleRegulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate
dc.typehttp://purl.org/coar/resource_type/c_6501 http://purl.org/coar/version/c_970fb48d4fbd8a85
ual.jupiterAccesshttp://terms.library.ualberta.ca/public

Files

Original bundle

Now showing 1 - 1 of 1
Thumbnail Image
Name:
JLR_56_6_1134.pdf
Size:
1.39 MB
Format:
Adobe Portable Document Format
Download

Collections

Journal Articles (Agricultural, Food and Nutritional Science)