Liver involvement in sphingosine 1-phosphate dynamism revealed by adenoviral hepatic overexpression of apolipoprotein M

Objectives: Sphingosine 1-phosphate (S1P) is a vasoprotective lipid mediator that is mainly carried on HDL in the circulation and several anti-atherosclerotic properties of HDL is considered to be ascribed to S1P. Since S1P riding on HDL was recently shown to bind to apolipoprotein M (apoM), which is derived from liver, we analyzed the possible involvement of liver in S1P metabolism. Methods and results: Using adenoviruses, we overexpressed apoM in HepG2 cells and mice livers and found that both the medium/plasma and cell/liver S1P contents increased. Among lipoprotein subclasses, S1P contents increased mainly in HDL fractions. On the other hand, hepatectomy resulted in the reduction of plasma S1P levels in mice. The incubation of S1P in the conditional medium of apoM-overexpressing HepG2 cells interfered with S1P degradation. Furthermore, adenoviral hepatic overexpression of apoM resulted in increase in the S1P level of plasma but not of blood cells, while combination of hepatic apoM overexpression and intraperitoneal administration of C-17-sphingosine resulted in the increase in the C-17-S1P level both in livers and in plasma, but again not in blood cells. Conclusions: Livers are involved in S1P dynamism, and it was suggested that apoM, produced from livers, increases circulating plasma S1P by augmenting the S1P output from livers and modifies extracellular S1P metabolism. (C) 2013 Elsevier Ireland Ltd. All rights reserved.