Abstract 9730: Hepatic Apolipoprotein M Overexpression Increased Total Sphingosine 1-phosphate Mass and Ameliorate Insulin Resistance in Diet Induced Obesity Mice

Abstract

Backgrounds: Sphingosine 1-phosphate (S1P) is a vasoprotective lipid mediator that is mainly carried on HDL and albumin in the circulation. 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. Moreover, while both apoM and S1P have been proposed to be involved in glucose metabolism, we also investigated the modulation of glucose metabolism by the overexpression of apoM in mice liver.

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 and ApoM increased mainly in HDL fractions. The incubation of S1P in the conditional medium of apoM-overexpressing HepG2 cells interfered with S1P degradation. Failure of HeLa cells to release S1P extracellularly (despite efficient ApoM production and intracellular S1P production) suggests that liver possesses special machinery for S1P export. 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 C₁₇-sphingosine resulted in the increase in the C₁₇-S1P level both in livers and in plasma, but again not in blood cells. Regarding glucose metabolism, we found that hepatic apoM overexpression improved fasting blood glucose (Control 156.2 mg/dL vs ApoM 104.8 mg/dL) and ameliorated insulin resistance in diet induced obesity mice, which were partially inhibited by administering VPC23019, an S1P receptor 1 antagonist, but not JTE013, an S1P receptor 2 antagonist, rather with JTE013 insulin resistance tended to be improved more than treated with vehicle.

Conclusions: These results suggest liver involvement in S1P dynamism through production of apoM, which increases circulating plasma S1P by augmenting the S1P output from livers and modifies extracellular S1P metabolism. Regarding the function of ApoM-S1P, ApoM-S1P might ameliorate insulin resistance depending on S1P receptor 1.