Hepatopoietin Cn reduces ethanol‐induced hepatoxicity via sphingosine kinase 1 and sphingosine 1‐phosphate receptors

Abstract

The hepatic growth factor hepatopoietin Cn (HPPCn) prevents liver injury induced by carbon tetrachloride in rats. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid produced by sphingosine kinase (SphK). S1P and S1P receptors (S1PRs) are involved in liver fibrogenesis and oxidative injury. This work sought to understand the mechanism by which SphK/S1P/S1PRs are involved in the protective effects of HPPCn on ethanol-induced liver injury and fibrosis. Transgenic mice with liver-specific overexpression of HPPCn (HPPCn(liver) (+/+)) were generated. Two ethanol feeding protocols were used to assess the protective effect of HPPCn on acute and chronic liver injury in mice. Specific inhibitors of S1PR1, S1PR2 and S1PR3 and siRNA were used to examine the roles of S1PRs in hepatic stellate cell (HSC) activation and hepatocyte apoptosis. Increased HPPCn expression in transgenic mice attenuated fibrosis induced by ethanol and carbon tetrachloride (CCl4). Treatment with recombinant human HPPCn prevented human hepatocyte apoptosis and HSC activation. JTE-013 or S1PR2-siRNA attenuated the effect of HPPCn on HSC activation induced by tumour necrosis factor-α (TNF-α). Consistent with the effect of N,N-dimethylsphingosine (DMS), suramin or S1PR3-siRNA treatment blocked HPPCn-induced Erk1/2 phosphorylation in human hepatocytes. This study demonstrated that HPPCn attenuated oxidative injury and fibrosis induced by ethanol feeding and that the SphK1/S1P/S1PRs signalling pathway contributes to the protective effect of HPPCn on hepatocyte apoptosis and HSC activation.

Role of sphingosine-1-phosphate receptor 1 and sphingosine-1-phosphate receptor 2 in hyperglycemia-induced endothelial cell dysfunction

“…Multiple lines of evidence have indicated that S1PRs are involved in both the generation of oxidative stress and oxidative stress-mediated injuries (32)(33)(34). S1PR1 affects EC function through its anti-inflammatory effects in diabetic ECs (35,36).…”

Sphingosine kinase and sphingosine-1-phosphate in liver pathobiology

“…Curiously, although in most studies S1P seems to contribute to liver damage, in others, it seems to have a protective role. For example, S1P is important for recruitment and activation of liver-damaging immune cells, and yet several in vitro studies indicate that S1P protects hepatocytes from apoptotic insults (Osawa et al 2005, Liu et al 2013, Nowatari et al 2015). …”

Hepatitis B virus X protein promotes human hepatoma cell growth via upregulation of transcription factor AP2α and sphingosine kinase 1

“…The sequences of si-SPHK1 and the construction of psi-HBx were reported in previous studies [9,24] . The control cells were treated with 100 nmol/L si-Control (NControl_05815) synthesized by Ribobio Co Lit or 2 μg pSilence vector.…”