title: 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.
authors.affiliation: Department of Experimental Hematology, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Saiyan
authors.initials: S
authors.lastname: Saiyan
authors.forename: Tong-Yi
authors.initials: TY
authors.lastname: Men
authors.forename: Hui-Ying
authors.initials: HY
authors.lastname: Gao
authors.forename: Chuan
authors.initials: C
authors.lastname: Wen
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Xu
authors.initials: X
authors.lastname: Zhou
authors.forename: Chu-Tse
authors.initials: CT
authors.lastname: Wu
authors.forename: Li-Sheng
authors.initials: LS
authors.lastname: Wang
authors.forename: Chun-Ping
authors.initials: CP
authors.lastname: Cui
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000431:Ethanol; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000201:enzymology / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008104:Liver Cirrhosis, Alcoholic / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000431:Ethanol; D017228:Hepatocyte Growth Factor; D008246:Lysophospholipids; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009687:Nuclear Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase; C553972:hepatopoietin Cn, human; C060506:sphingosine 1-phosphate; C535150:MAPK1 protein, human
keywords: fibrosis development; hepatic stellate cell; hepatocyte; hepatopoietin Cn; liver injury; sphingosine kinase 1/sphingosine 1-phosphate/S1P receptors pathway