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Hepatopoietin Cn reduces ethanol‐induced hepatoxicity via sphingosine kinase 1 and sphingosine 1‐phosphate receptors
Author(s) -
Liu Yang,
Saiyan Saiyan,
Men TongYi,
Gao HuiYing,
Wen Chuan,
Liu Yong,
Zhou Xu,
Wu ChuTse,
Wang LiSheng,
Cui ChunPing
Publication year - 2013
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4194
Subject(s) - sphingosine kinase , sphingosine 1 phosphate , sphingosine , s1pr1 , liver injury , hepatic stellate cell , sphingosine kinase 1 , hepatocyte , sphingolipid , chemistry , sphingosine 1 phosphate receptor , cancer research , microbiology and biotechnology , biology , pharmacology , receptor , biochemistry , endocrinology , vascular endothelial growth factor a , vascular endothelial growth factor , vegf receptors , in vitro
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 ( CCl 4 ). 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. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.