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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Veröffentlicht in:The Journal of pathology 2013-08, Vol.230 (4), p.365-376
Hauptverfasser: 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
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container_issue 4
container_start_page 365
container_title The Journal of pathology
container_volume 230
creator 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
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 &amp; 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 &amp; 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 &amp; 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 &amp; inhibitors ; Receptors, Lysosphingolipid - genetics ; Receptors, Lysosphingolipid - metabolism ; RNA Interference ; RNA, Messenger - metabolism ; Signal Transduction ; Sphingosine - analogs &amp; 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 &amp; 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 &amp; 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 &amp; 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 &amp; 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 &amp; 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 &amp; 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 &amp; 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 &amp; 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 &amp; 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 &amp; 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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 &amp; Sons, Ltd.</abstract><cop>Chichester, UK</cop><pub>John Wiley &amp; 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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