Inhibition of sphingosine kinase 1 ameliorates acute liver failure by reducing high-mobility group box 1 cytoplasmic translocation in liver cells

Figure 2 Inhibition of Sphk1 activity with DMS decreases serum S1P concentrations, improves survival, and attenuates liver enzyme release in a mouse model of acute liver failure. Animals were treated with vehicle or DMS (50 μmol/L) 30 min before the induction of acute liver failure. A: Inhibition of Sphk1 activity with DMS reduced S1P, a downstream substrate of SphK1 (735.77 nmol/L ± 87.39 nmol/L vs 1789.23 nmol/L ± 201.79 nmol/L, t = 20.39, ^bP < 0.01); B: Kaplan-Meier analysis of the effect of DMS on survival rate of the animals. ^bP = 0.004, F = 8.276, log rank test; C and D: ALT and AST levels in peripheral blood samples collected at 6, 12, 24, 48, 72, 120, 144, and 168 h after treatment. DMS treatment significantly decreased serum levels of ALT at 6, 12, and 24 h (332.8 U/L ± 124.2 U/L, 2788.2 U/L ± 839.2 U/L, 1265.1 U/L ± 371.7 U/L vs 836.6 U/L ± 221.5 U/L, 7612.8 U/L ± 1579.1 U/L, 3741.4 U/L ± 771.7 U/L, t = 6.87, 10.44, and 10.01, respectively, ^bP < 0.01) and AST at 6, 12, and 24 h (257.1 U/L ± 134.9 U/L, 2196.3 U/L ± 676.3 U/L, 982.3 U/L ± 255.9 U/L vs 853.7 U/L ± 202.3 U/L, 6993.6 U/L ± 1209.5 U/L, 2991.1 U/L ± 678.5 U/L, t = 8.50, 12.00, and 9.60, respectively, ^bP < 0.01) compared with those of the control group. The mean ± SE of three independent experiments is shown (error bar indicates standard error). DMS: N,N-dimethylsphingosine; S1P: Sphingosine-1-phosphate; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase.