Hepatopoietin Cn reduces ethanol-induced hepatoxicity via sphingosine kinase 1 and sphingosine 1-phosphate receptors
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. Th...
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description | 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 (HPPCnliver+/+) 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. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
doi_str_mv | 10.1002/path.4194 |
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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 (HPPCnliver+/+) 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. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</description><identifier>ISSN: 0022-3417</identifier><identifier>EISSN: 1096-9896</identifier><identifier>DOI: 10.1002/path.4194</identifier><identifier>PMID: 23839903</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Ltd</publisher><subject>Animals ; Apoptosis ; Cells, Cultured ; Disease Models, Animal ; Ethanol ; fibrosis development ; Gene Expression Regulation ; hepatic stellate cell ; Hepatic Stellate Cells - enzymology ; Hepatic Stellate Cells - pathology ; hepatocyte ; Hepatocyte Growth Factor - genetics ; Hepatocyte Growth Factor - metabolism ; hepatopoietin Cn ; Humans ; Liver - drug effects ; Liver - enzymology ; Liver - pathology ; Liver Cirrhosis, Alcoholic - enzymology ; Liver Cirrhosis, Alcoholic - etiology ; Liver Cirrhosis, Alcoholic - genetics ; Liver Cirrhosis, Alcoholic - pathology ; Liver Cirrhosis, Alcoholic - prevention & control ; liver injury ; Lysophospholipids - metabolism ; Mice ; Mice, Transgenic ; Mitogen-Activated Protein Kinase 1 - metabolism ; Mitogen-Activated Protein Kinase 3 - metabolism ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Oxidative Stress ; Phosphorylation ; Phosphotransferases (Alcohol Group Acceptor) - genetics ; Phosphotransferases (Alcohol Group Acceptor) - metabolism ; Receptors, Lysosphingolipid - antagonists & inhibitors ; Receptors, Lysosphingolipid - genetics ; Receptors, Lysosphingolipid - metabolism ; RNA Interference ; RNA, Messenger - metabolism ; Signal Transduction ; Sphingosine - analogs & derivatives ; Sphingosine - metabolism ; sphingosine kinase 1/sphingosine 1-phosphate/S1P receptors pathway ; Time Factors ; Transfection ; Tumor Necrosis Factor-alpha - metabolism</subject><ispartof>The Journal of pathology, 2013-08, Vol.230 (4), p.365-376</ispartof><rights>Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</rights><rights>Copyright © 2013 Pathological Society of Great Britain and Ireland</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4574-f339fc3a0b1c3d3927bd724698350cc60961d2551f4be7bb5b01c6fb0c2c46e93</citedby><cites>FETCH-LOGICAL-c4574-f339fc3a0b1c3d3927bd724698350cc60961d2551f4be7bb5b01c6fb0c2c46e93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fpath.4194$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fpath.4194$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,778,782,1414,27907,27908,45557,45558</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23839903$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Yang</creatorcontrib><creatorcontrib>Saiyan, Saiyan</creatorcontrib><creatorcontrib>Men, Tong-Yi</creatorcontrib><creatorcontrib>Gao, Hui-Ying</creatorcontrib><creatorcontrib>Wen, Chuan</creatorcontrib><creatorcontrib>Liu, Yong</creatorcontrib><creatorcontrib>Zhou, Xu</creatorcontrib><creatorcontrib>Wu, Chu-Tse</creatorcontrib><creatorcontrib>Wang, Li-Sheng</creatorcontrib><creatorcontrib>Cui, Chun-Ping</creatorcontrib><title>Hepatopoietin Cn reduces ethanol-induced hepatoxicity via sphingosine kinase 1 and sphingosine 1-phosphate receptors</title><title>The Journal of pathology</title><addtitle>J. Pathol</addtitle><description>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 (HPPCnliver+/+) 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. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Cells, Cultured</subject><subject>Disease Models, Animal</subject><subject>Ethanol</subject><subject>fibrosis development</subject><subject>Gene Expression Regulation</subject><subject>hepatic stellate cell</subject><subject>Hepatic Stellate Cells - enzymology</subject><subject>Hepatic Stellate Cells - pathology</subject><subject>hepatocyte</subject><subject>Hepatocyte Growth Factor - genetics</subject><subject>Hepatocyte Growth Factor - metabolism</subject><subject>hepatopoietin Cn</subject><subject>Humans</subject><subject>Liver - drug effects</subject><subject>Liver - enzymology</subject><subject>Liver - pathology</subject><subject>Liver Cirrhosis, Alcoholic - enzymology</subject><subject>Liver Cirrhosis, Alcoholic - etiology</subject><subject>Liver Cirrhosis, Alcoholic - genetics</subject><subject>Liver Cirrhosis, Alcoholic - pathology</subject><subject>Liver Cirrhosis, Alcoholic - prevention & control</subject><subject>liver injury</subject><subject>Lysophospholipids - metabolism</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Mitogen-Activated Protein Kinase 1 - metabolism</subject><subject>Mitogen-Activated Protein Kinase 3 - metabolism</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Oxidative Stress</subject><subject>Phosphorylation</subject><subject>Phosphotransferases (Alcohol Group Acceptor) - genetics</subject><subject>Phosphotransferases (Alcohol Group Acceptor) - metabolism</subject><subject>Receptors, Lysosphingolipid - antagonists & inhibitors</subject><subject>Receptors, Lysosphingolipid - genetics</subject><subject>Receptors, Lysosphingolipid - metabolism</subject><subject>RNA Interference</subject><subject>RNA, Messenger - metabolism</subject><subject>Signal Transduction</subject><subject>Sphingosine - analogs & derivatives</subject><subject>Sphingosine - metabolism</subject><subject>sphingosine kinase 1/sphingosine 1-phosphate/S1P receptors pathway</subject><subject>Time Factors</subject><subject>Transfection</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><issn>0022-3417</issn><issn>1096-9896</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kUFv1DAQhS0EokvhwB9AlrjQQ1o7jp34WK2gi6iAQ1G5WY4zIW6zdmo7tPvvcdilEkicRp753tN4HkKvKTmlhJRnk07DaUVl9QStKJGikI0UT9Eqz8qCVbQ-Qi9ivCGESMn5c3RUsoZJSdgKpQ1ktZ-8hWQdXjscoJsNRAxp0M6PhXXLu8PDb_DBGpt2-KfVOE6DdT98tA7wrXU6AqZYu-6vAS2mweeGTpCdDUzJh_gSPev1GOHVoR6jbx_eX603xeWXi4_r88vCVLyuip4x2RumSUsN65gs67ary0rIhnFijMg_pV3JOe2rFuq25S2hRvQtMaWpBEh2jN7tfafg72aISW1tNDCO2oGfo6L5CJzUsikz-vYf9MbPweXtFqoRlSCEZepkT5ngYwzQqynYrQ47RYlaolBLFGqJIrNvDo5zu4Xukfxz-wyc7YF7O8Lu_07q6_nV5mBZ7BU2Jnh4VOhwq0TNaq6uP18odi3Fd7b5pGr2C8IGo4A</recordid><startdate>201308</startdate><enddate>201308</enddate><creator>Liu, Yang</creator><creator>Saiyan, Saiyan</creator><creator>Men, Tong-Yi</creator><creator>Gao, Hui-Ying</creator><creator>Wen, Chuan</creator><creator>Liu, Yong</creator><creator>Zhou, Xu</creator><creator>Wu, Chu-Tse</creator><creator>Wang, Li-Sheng</creator><creator>Cui, Chun-Ping</creator><general>John Wiley & Sons, Ltd</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201308</creationdate><title>Hepatopoietin Cn reduces ethanol-induced hepatoxicity via sphingosine kinase 1 and sphingosine 1-phosphate receptors</title><author>Liu, Yang ; Saiyan, Saiyan ; Men, Tong-Yi ; Gao, Hui-Ying ; Wen, Chuan ; Liu, Yong ; Zhou, Xu ; Wu, Chu-Tse ; Wang, Li-Sheng ; Cui, Chun-Ping</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4574-f339fc3a0b1c3d3927bd724698350cc60961d2551f4be7bb5b01c6fb0c2c46e93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Cells, Cultured</topic><topic>Disease Models, Animal</topic><topic>Ethanol</topic><topic>fibrosis development</topic><topic>Gene Expression Regulation</topic><topic>hepatic stellate cell</topic><topic>Hepatic Stellate Cells - enzymology</topic><topic>Hepatic Stellate Cells - pathology</topic><topic>hepatocyte</topic><topic>Hepatocyte Growth Factor - genetics</topic><topic>Hepatocyte Growth Factor - metabolism</topic><topic>hepatopoietin Cn</topic><topic>Humans</topic><topic>Liver - drug effects</topic><topic>Liver - enzymology</topic><topic>Liver - pathology</topic><topic>Liver Cirrhosis, Alcoholic - enzymology</topic><topic>Liver Cirrhosis, Alcoholic - etiology</topic><topic>Liver Cirrhosis, Alcoholic - genetics</topic><topic>Liver Cirrhosis, Alcoholic - pathology</topic><topic>Liver Cirrhosis, Alcoholic - prevention & control</topic><topic>liver injury</topic><topic>Lysophospholipids - metabolism</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Mitogen-Activated Protein Kinase 1 - metabolism</topic><topic>Mitogen-Activated Protein Kinase 3 - metabolism</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - metabolism</topic><topic>Oxidative Stress</topic><topic>Phosphorylation</topic><topic>Phosphotransferases (Alcohol Group Acceptor) - genetics</topic><topic>Phosphotransferases (Alcohol Group Acceptor) - metabolism</topic><topic>Receptors, Lysosphingolipid - antagonists & inhibitors</topic><topic>Receptors, Lysosphingolipid - genetics</topic><topic>Receptors, Lysosphingolipid - metabolism</topic><topic>RNA Interference</topic><topic>RNA, Messenger - metabolism</topic><topic>Signal Transduction</topic><topic>Sphingosine - analogs & derivatives</topic><topic>Sphingosine - metabolism</topic><topic>sphingosine kinase 1/sphingosine 1-phosphate/S1P receptors pathway</topic><topic>Time Factors</topic><topic>Transfection</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Yang</creatorcontrib><creatorcontrib>Saiyan, Saiyan</creatorcontrib><creatorcontrib>Men, Tong-Yi</creatorcontrib><creatorcontrib>Gao, Hui-Ying</creatorcontrib><creatorcontrib>Wen, Chuan</creatorcontrib><creatorcontrib>Liu, Yong</creatorcontrib><creatorcontrib>Zhou, Xu</creatorcontrib><creatorcontrib>Wu, Chu-Tse</creatorcontrib><creatorcontrib>Wang, Li-Sheng</creatorcontrib><creatorcontrib>Cui, Chun-Ping</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Yang</au><au>Saiyan, Saiyan</au><au>Men, Tong-Yi</au><au>Gao, Hui-Ying</au><au>Wen, Chuan</au><au>Liu, Yong</au><au>Zhou, Xu</au><au>Wu, Chu-Tse</au><au>Wang, Li-Sheng</au><au>Cui, Chun-Ping</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hepatopoietin Cn reduces ethanol-induced hepatoxicity via sphingosine kinase 1 and sphingosine 1-phosphate receptors</atitle><jtitle>The Journal of pathology</jtitle><addtitle>J. Pathol</addtitle><date>2013-08</date><risdate>2013</risdate><volume>230</volume><issue>4</issue><spage>365</spage><epage>376</epage><pages>365-376</pages><issn>0022-3417</issn><eissn>1096-9896</eissn><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 (HPPCnliver+/+) 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. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>23839903</pmid><doi>10.1002/path.4194</doi><tpages>12</tpages></addata></record> |
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subjects | Animals Apoptosis Cells, Cultured Disease Models, Animal Ethanol fibrosis development Gene Expression Regulation hepatic stellate cell Hepatic Stellate Cells - enzymology Hepatic Stellate Cells - pathology hepatocyte Hepatocyte Growth Factor - genetics Hepatocyte Growth Factor - metabolism hepatopoietin Cn Humans Liver - drug effects Liver - enzymology Liver - pathology Liver Cirrhosis, Alcoholic - enzymology Liver Cirrhosis, Alcoholic - etiology Liver Cirrhosis, Alcoholic - genetics Liver Cirrhosis, Alcoholic - pathology Liver Cirrhosis, Alcoholic - prevention & control liver injury Lysophospholipids - metabolism Mice Mice, Transgenic Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - metabolism Nuclear Proteins - genetics Nuclear Proteins - metabolism Oxidative Stress Phosphorylation Phosphotransferases (Alcohol Group Acceptor) - genetics Phosphotransferases (Alcohol Group Acceptor) - metabolism Receptors, Lysosphingolipid - antagonists & inhibitors Receptors, Lysosphingolipid - genetics Receptors, Lysosphingolipid - metabolism RNA Interference RNA, Messenger - metabolism Signal Transduction Sphingosine - analogs & derivatives Sphingosine - metabolism sphingosine kinase 1/sphingosine 1-phosphate/S1P receptors pathway Time Factors Transfection Tumor Necrosis Factor-alpha - metabolism |
title | Hepatopoietin Cn reduces ethanol-induced hepatoxicity via sphingosine kinase 1 and sphingosine 1-phosphate receptors |
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