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.
Highlights
Lysophosphatidic acid (LPA) is a bioactive lipid mediator
To attempt to measure akylglycerol phosphate (AGP) in mouse plasma and to investigate their potential sensitivity to ATX inhibition, we developed a method using HPLC to separate LPA species with ether and ester chains, which were identified by high-resolution MS using a quadrupole time-of-flight mass spectrometry
Metabolic stability of LPA species in human plasma There is a general consensus that LPAs with ester-linked 18:2, 18:1, 18:0, 16:0, and 20:4 fatty acids account for LPA is rapidly eliminated from the circulation of live mice without significant enzymatic degradation in situ
Summary
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. PF8380 induced a statistically significant decrease in most of the major LPA species 10 min after administration, indicating that plasma levels of these lipids decline at comparable rates when their synthesis by ATX is blocked (Fig. 1D, E).
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