Mechanism of rapid elimination of lysophosphatidic acid and related lipids from the circulation of mice.
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.
Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky Lexington, Lexington, KY 40536; and.
Abdel K
AK
Salous
Manikandan
M
Panchatcharam
Manjula
M
Sunkara
Paul
P
Mueller
Anping
A
Dong
Yuhuan
Y
Wang
Gregory A
GA
Graf
Susan S
SS
Smyth
Andrew J
AJ
Morris
D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D002478:Cells, Cultured; D006207:Half-Life; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008246:Lysophospholipids / Q000097:blood* / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D000099189:Lysophospholipase D
D001583:Benzoxazoles; D008246:Lysophospholipids; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D010879:Piperazines; D000099189:Lysophospholipase D; C550725:6-(3-(piperazin-1-yl)propanoyl)benzo(d)oxazol-2(3H)-one; C032881:lysophosphatidic acid
autotaxin; lipid phosphate phosphatase; mass spectrometry; transcellular uptake