title: Sphingosine kinase 1 inhibition improves lipopolysaccharide/D-galactosamine-induced acute liver failure by inhibiting mitogen-activated protein kinases pathway.
abstract: BACKGROUND
  Sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P)/sphingosine-1-phosphate receptors (S1PRs) signaling plays a key role in inflammatory responses. Lei et al. showed that SphK1 inhibition presented a hepatoprotective effect on acute liver damage via decreasing hepatic high-mobility group box 1 (HMGB1) cytoplasmic translocation.
  
  
  OBJECTIVE
  We aim to determine whether SphK1 or S1PRs inhibition improves lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced acute liver failure by inhibiting the mitogen-activated protein kinases (MAPKs) pathway.
  
  
  METHODS
  A mouse model of acute liver failure was induced by LPS/GalN. Male C57BL/6J mice (6-8 weeks) were randomly distributed into five groups: control group, LPS/GalN group, SphK1 inhibition group (LPS/GalN+SKI-5c), S1PR1 inhibition group (LPS/GalN+W146), and S1PR3 inhibition group (LPS/GalN+CAY10444).
  
  
  RESULTS
  We confirmed the findings of Lei et al. that hepatic SphK1 expression was upregulated; serum transaminase activity (AST, ALT), as well as serum TNF-α and IL-6, were decreased by SphK1 inhibition. We further showed that the expression of S1PR1 and S1PR3 was augmented in response to LPS/GalN. SphK1 inhibition improves hepatic hemorrhage, and the activities of hepatic caspase-3 and myeloperoxidase (MPO). Furthermore, the activation of the MAPKs family (JNK, ERK and p38) was suppressed by SphK1 inhibition. However, S1PR1 or S1PR3 inhibition did not protect the mouse against liver damage, though S1PR1 or S1PR3 inhibition reduced serum TNF-α and IL-6, and partially attenuated the phosphorylation of the MAPKs signaling.
  
  
  CONCLUSIONS
  SphK1 inhibition improves LPS/GalN-induced liver injury by inhibiting activation of MAPKs signaling.
authors.affiliation: Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Tian
authors.affiliation: Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Tian
authors.affiliation: Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: Risheng
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: Yunzhao
authors.initials: Y
authors.lastname: Zhao
keywords: Acute liver failure; D-galactosamine; lipopolysaccharide; mitogen-activated protein kinases; sphingosine kinase 1