Mechanism of rapid elimination of lysophosphatidic acid and related lipids from the circulation of mice

Abdel K. Salous, Manikandan Panchatcharam, Manjula Sunkara, Paul Mueller, Anping Dong, Yuhuan Wang, Gregory A. Graf, Susan S. Smyth, Andrew J. Morris

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

Lysophosphatidic acid (LPA) is a bioactive lipid mediator. Concentrations of the major LPA species in mouse plasma decreased uniformly following administration of a potent selective inhibitor of the LPA-generating lysophospholipase D autotaxin, identifying an active mechanism for removal of LPA from the circulation. LPA, akylglycerol phosphate (AGP), sphingosine 1-phosphate (S1P), and a variety of structural mimetics of these lipids, including phosphatase- resistant phosphonate analogs of LPA, were rapidly eliminated (t1/2 < 30 s) from the circulation of mice following intravenous administration of a single bolus dose without significant metabolism in situ in the blood. These lipids accumulated in the liver. Elimination of intravenously administered LPA was blunted by ligation of the hepatic circulation, and ~90% of LPA administered through the portal vein was accumulated by the isolated perfused mouse liver at first pass. At early times following intravenous administration, more LPA was associated with a nonparenchymal liver cell fraction than with hepatocytes. Primary cultures of nonparenchymal liver cells rapidly assimilated exogenously provided LPA. Our results identify hepatic uptake as an important determinant of the bioavailability of LPA and bioactive lysophospholipid mimetics and suggest a mechanism to explain changes in circulating LPA levels that have been associated with liver dysfunction in humans.

Original languageEnglish
Pages (from-to)2775-2784
Number of pages10
JournalJournal of Lipid Research
Volume54
Issue number10
DOIs
StatePublished - Oct 2013

Keywords

  • Autotaxin
  • Lipid phosphate phosphatase
  • Mass spectrometry
  • Transcellular uptake

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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