Loading…
Hydrophobic bile acid apoptosis is regulated by sphingosine-1-phosphate receptor 2 in rat hepatocytes and human hepatocellular carcinoma cells
The hepatotoxic bile acid glycochenodeoxycholate (GCDC) modulates hepatocyte cell death through activation of JNK, Akt, and Erk. The nonhepatotoxic bile acid taurocholate activates Akt and Erk through the sphingosine-1-phosphate receptor 2 (S1PR2). The role of the S1PR2 in GCDC-mediated apoptosis an...
Saved in:
Published in: | American journal of physiology: Gastrointestinal and liver physiology 2016-05, Vol.310 (10), p.G865-G873 |
---|---|
Main Authors: | , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
cited_by | cdi_FETCH-LOGICAL-c490t-b21d5b54028a535640b1b094d2d02d24bb4dac5683698ee966df7e5ba71ca5d73 |
---|---|
cites | cdi_FETCH-LOGICAL-c490t-b21d5b54028a535640b1b094d2d02d24bb4dac5683698ee966df7e5ba71ca5d73 |
container_end_page | G873 |
container_issue | 10 |
container_start_page | G865 |
container_title | American journal of physiology: Gastrointestinal and liver physiology |
container_volume | 310 |
creator | Webster, Cynthia R L Anwer, M Sawkat |
description | The hepatotoxic bile acid glycochenodeoxycholate (GCDC) modulates hepatocyte cell death through activation of JNK, Akt, and Erk. The nonhepatotoxic bile acid taurocholate activates Akt and Erk through the sphingosine-1-phosphate receptor 2 (S1PR2). The role of the S1PR2 in GCDC-mediated apoptosis and kinase activation is unknown. Studies were done in rat hepatocytes, HUH7 cells, and HUH7 cells stably transfected with rat Ntcp (HUH7-Ntcp). Cells were treated with GCDC and apoptosis was monitored morphologically by Hoechst staining and biochemically by immunoblotting for the active cleaved fragment of caspase 3. Kinase activation was determined by immunoblotting with phospho-specific antibodies. JTE-013, an inhibitor of S1PR2, significantly attenuated morphological evidence of GCDC-induced apoptosis and prevented caspase 3 cleavage in rat hepatocytes and HUH7-Ntcp cells. In hepatocytes, JTE-013 mildly suppressed, augmented, and had no effect on GCDC-induced JNK, Akt, and Erk phosphorylation, respectively. Similar results were seen in HUH7-Ntcp cells except for mild suppression of JNK and Erk phosphorylation. Knockdown of S1PR2 in HUH7-Ntcp augmented Akt, inhibited JNK, and had no effect on Erk phosphorylation. GCDC failed to induce apoptosis or kinase activation in HUH7 cells. In conclusion, SIPR2 inhibition attenuates GCDC-induced apoptosis and inhibits and augments GCDC-induced JNK and Akt phosphorylation, respectively. In addition, GCDC must enter hepatocytes to mediate cell death or activate kinases. These results suggest that SIPR2 activation is proapoptotic in GCDC-induced cell death but that this effect is not due to direct ligation of the S1PR2 by the bile acid. |
doi_str_mv | 10.1152/ajpgi.00253.2015 |
format | article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4895872</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>4067930711</sourcerecordid><originalsourceid>FETCH-LOGICAL-c490t-b21d5b54028a535640b1b094d2d02d24bb4dac5683698ee966df7e5ba71ca5d73</originalsourceid><addsrcrecordid>eNpVUctq3DAUFSWlmabddxUEWXt6JVu2tSmUkDaFQDftWlw9ZqzBIzmSHZifyDdHkxcJCATndQ8cQr4xWDMm-HfcTVu_BuCiXnNg4gNZFZhXTDTdCVkBk3XFetGdks857wBAcMY-kVPeSil76Fbk_vpgU5yGqL2h2o-OovGW4hSnOWafaXnJbZcRZ2epPtA8DT5sCxVcxapiLEDhisi4YkmUUx9owpkObsI5msPsMsVg6bDsMbygbhxLZqIGk_Eh7pEeofyFfNzgmN3X5_-M_P919e_yurr5-_vP5c-byjQS5kpzZoUWDfAeRS3aBjTTIBvLLXDLG60bi0a0fd3K3jnZtnbTOaGxYwaF7eoz8uMpd1r03lnjwpxwVFPye0wHFdGr90zwg9rGO9X0UvQdLwEXzwEp3i4uz2oXlxRKZ8U6yUonDlBU8KQyKeac3Ob1AgN1XFA9LqgeF1THBYvl_G2zV8PLZPUDORicFA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1791356200</pqid></control><display><type>article</type><title>Hydrophobic bile acid apoptosis is regulated by sphingosine-1-phosphate receptor 2 in rat hepatocytes and human hepatocellular carcinoma cells</title><source>American Physiological Society Free</source><creator>Webster, Cynthia R L ; Anwer, M Sawkat</creator><creatorcontrib>Webster, Cynthia R L ; Anwer, M Sawkat</creatorcontrib><description>The hepatotoxic bile acid glycochenodeoxycholate (GCDC) modulates hepatocyte cell death through activation of JNK, Akt, and Erk. The nonhepatotoxic bile acid taurocholate activates Akt and Erk through the sphingosine-1-phosphate receptor 2 (S1PR2). The role of the S1PR2 in GCDC-mediated apoptosis and kinase activation is unknown. Studies were done in rat hepatocytes, HUH7 cells, and HUH7 cells stably transfected with rat Ntcp (HUH7-Ntcp). Cells were treated with GCDC and apoptosis was monitored morphologically by Hoechst staining and biochemically by immunoblotting for the active cleaved fragment of caspase 3. Kinase activation was determined by immunoblotting with phospho-specific antibodies. JTE-013, an inhibitor of S1PR2, significantly attenuated morphological evidence of GCDC-induced apoptosis and prevented caspase 3 cleavage in rat hepatocytes and HUH7-Ntcp cells. In hepatocytes, JTE-013 mildly suppressed, augmented, and had no effect on GCDC-induced JNK, Akt, and Erk phosphorylation, respectively. Similar results were seen in HUH7-Ntcp cells except for mild suppression of JNK and Erk phosphorylation. Knockdown of S1PR2 in HUH7-Ntcp augmented Akt, inhibited JNK, and had no effect on Erk phosphorylation. GCDC failed to induce apoptosis or kinase activation in HUH7 cells. In conclusion, SIPR2 inhibition attenuates GCDC-induced apoptosis and inhibits and augments GCDC-induced JNK and Akt phosphorylation, respectively. In addition, GCDC must enter hepatocytes to mediate cell death or activate kinases. These results suggest that SIPR2 activation is proapoptotic in GCDC-induced cell death but that this effect is not due to direct ligation of the S1PR2 by the bile acid.</description><identifier>ISSN: 0193-1857</identifier><identifier>EISSN: 1522-1547</identifier><identifier>DOI: 10.1152/ajpgi.00253.2015</identifier><identifier>PMID: 26999807</identifier><identifier>CODEN: APGPDF</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Animals ; Apoptosis ; Carcinoma, Hepatocellular - metabolism ; Cell Line, Tumor ; Cells, Cultured ; Glycochenodeoxycholic Acid - metabolism ; Glycochenodeoxycholic Acid - toxicity ; Hepatocytes - metabolism ; Humans ; Kinases ; Liver and Biliary Tract Physiology/Pathophysiology ; Liver Neoplasms - metabolism ; Male ; MAP Kinase Kinase 4 - metabolism ; MAP Kinase Signaling System ; Morphology ; Phosphorylation ; Proto-Oncogene Proteins c-akt - metabolism ; Pyrazoles - pharmacology ; Pyridines - pharmacology ; Rats ; Rats, Wistar ; Receptors, Lysosphingolipid - antagonists & inhibitors ; Receptors, Lysosphingolipid - metabolism ; Rodents ; Sphingosine-1-Phosphate Receptors</subject><ispartof>American journal of physiology: Gastrointestinal and liver physiology, 2016-05, Vol.310 (10), p.G865-G873</ispartof><rights>Copyright © 2016 the American Physiological Society.</rights><rights>Copyright American Physiological Society May 15, 2016</rights><rights>Copyright © 2016 the American Physiological Society 2016 American Physiological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c490t-b21d5b54028a535640b1b094d2d02d24bb4dac5683698ee966df7e5ba71ca5d73</citedby><cites>FETCH-LOGICAL-c490t-b21d5b54028a535640b1b094d2d02d24bb4dac5683698ee966df7e5ba71ca5d73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26999807$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Webster, Cynthia R L</creatorcontrib><creatorcontrib>Anwer, M Sawkat</creatorcontrib><title>Hydrophobic bile acid apoptosis is regulated by sphingosine-1-phosphate receptor 2 in rat hepatocytes and human hepatocellular carcinoma cells</title><title>American journal of physiology: Gastrointestinal and liver physiology</title><addtitle>Am J Physiol Gastrointest Liver Physiol</addtitle><description>The hepatotoxic bile acid glycochenodeoxycholate (GCDC) modulates hepatocyte cell death through activation of JNK, Akt, and Erk. The nonhepatotoxic bile acid taurocholate activates Akt and Erk through the sphingosine-1-phosphate receptor 2 (S1PR2). The role of the S1PR2 in GCDC-mediated apoptosis and kinase activation is unknown. Studies were done in rat hepatocytes, HUH7 cells, and HUH7 cells stably transfected with rat Ntcp (HUH7-Ntcp). Cells were treated with GCDC and apoptosis was monitored morphologically by Hoechst staining and biochemically by immunoblotting for the active cleaved fragment of caspase 3. Kinase activation was determined by immunoblotting with phospho-specific antibodies. JTE-013, an inhibitor of S1PR2, significantly attenuated morphological evidence of GCDC-induced apoptosis and prevented caspase 3 cleavage in rat hepatocytes and HUH7-Ntcp cells. In hepatocytes, JTE-013 mildly suppressed, augmented, and had no effect on GCDC-induced JNK, Akt, and Erk phosphorylation, respectively. Similar results were seen in HUH7-Ntcp cells except for mild suppression of JNK and Erk phosphorylation. Knockdown of S1PR2 in HUH7-Ntcp augmented Akt, inhibited JNK, and had no effect on Erk phosphorylation. GCDC failed to induce apoptosis or kinase activation in HUH7 cells. In conclusion, SIPR2 inhibition attenuates GCDC-induced apoptosis and inhibits and augments GCDC-induced JNK and Akt phosphorylation, respectively. In addition, GCDC must enter hepatocytes to mediate cell death or activate kinases. These results suggest that SIPR2 activation is proapoptotic in GCDC-induced cell death but that this effect is not due to direct ligation of the S1PR2 by the bile acid.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cells, Cultured</subject><subject>Glycochenodeoxycholic Acid - metabolism</subject><subject>Glycochenodeoxycholic Acid - toxicity</subject><subject>Hepatocytes - metabolism</subject><subject>Humans</subject><subject>Kinases</subject><subject>Liver and Biliary Tract Physiology/Pathophysiology</subject><subject>Liver Neoplasms - metabolism</subject><subject>Male</subject><subject>MAP Kinase Kinase 4 - metabolism</subject><subject>MAP Kinase Signaling System</subject><subject>Morphology</subject><subject>Phosphorylation</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyridines - pharmacology</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Receptors, Lysosphingolipid - antagonists & inhibitors</subject><subject>Receptors, Lysosphingolipid - metabolism</subject><subject>Rodents</subject><subject>Sphingosine-1-Phosphate Receptors</subject><issn>0193-1857</issn><issn>1522-1547</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNpVUctq3DAUFSWlmabddxUEWXt6JVu2tSmUkDaFQDftWlw9ZqzBIzmSHZifyDdHkxcJCATndQ8cQr4xWDMm-HfcTVu_BuCiXnNg4gNZFZhXTDTdCVkBk3XFetGdks857wBAcMY-kVPeSil76Fbk_vpgU5yGqL2h2o-OovGW4hSnOWafaXnJbZcRZ2epPtA8DT5sCxVcxapiLEDhisi4YkmUUx9owpkObsI5msPsMsVg6bDsMbygbhxLZqIGk_Eh7pEeofyFfNzgmN3X5_-M_P919e_yurr5-_vP5c-byjQS5kpzZoUWDfAeRS3aBjTTIBvLLXDLG60bi0a0fd3K3jnZtnbTOaGxYwaF7eoz8uMpd1r03lnjwpxwVFPye0wHFdGr90zwg9rGO9X0UvQdLwEXzwEp3i4uz2oXlxRKZ8U6yUonDlBU8KQyKeac3Ob1AgN1XFA9LqgeF1THBYvl_G2zV8PLZPUDORicFA</recordid><startdate>20160515</startdate><enddate>20160515</enddate><creator>Webster, Cynthia R L</creator><creator>Anwer, M Sawkat</creator><general>American Physiological Society</general><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>5PM</scope></search><sort><creationdate>20160515</creationdate><title>Hydrophobic bile acid apoptosis is regulated by sphingosine-1-phosphate receptor 2 in rat hepatocytes and human hepatocellular carcinoma cells</title><author>Webster, Cynthia R L ; Anwer, M Sawkat</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c490t-b21d5b54028a535640b1b094d2d02d24bb4dac5683698ee966df7e5ba71ca5d73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cells, Cultured</topic><topic>Glycochenodeoxycholic Acid - metabolism</topic><topic>Glycochenodeoxycholic Acid - toxicity</topic><topic>Hepatocytes - metabolism</topic><topic>Humans</topic><topic>Kinases</topic><topic>Liver and Biliary Tract Physiology/Pathophysiology</topic><topic>Liver Neoplasms - metabolism</topic><topic>Male</topic><topic>MAP Kinase Kinase 4 - metabolism</topic><topic>MAP Kinase Signaling System</topic><topic>Morphology</topic><topic>Phosphorylation</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyridines - pharmacology</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Receptors, Lysosphingolipid - antagonists & inhibitors</topic><topic>Receptors, Lysosphingolipid - metabolism</topic><topic>Rodents</topic><topic>Sphingosine-1-Phosphate Receptors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Webster, Cynthia R L</creatorcontrib><creatorcontrib>Anwer, M Sawkat</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of physiology: Gastrointestinal and liver physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Webster, Cynthia R L</au><au>Anwer, M Sawkat</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hydrophobic bile acid apoptosis is regulated by sphingosine-1-phosphate receptor 2 in rat hepatocytes and human hepatocellular carcinoma cells</atitle><jtitle>American journal of physiology: Gastrointestinal and liver physiology</jtitle><addtitle>Am J Physiol Gastrointest Liver Physiol</addtitle><date>2016-05-15</date><risdate>2016</risdate><volume>310</volume><issue>10</issue><spage>G865</spage><epage>G873</epage><pages>G865-G873</pages><issn>0193-1857</issn><eissn>1522-1547</eissn><coden>APGPDF</coden><abstract>The hepatotoxic bile acid glycochenodeoxycholate (GCDC) modulates hepatocyte cell death through activation of JNK, Akt, and Erk. The nonhepatotoxic bile acid taurocholate activates Akt and Erk through the sphingosine-1-phosphate receptor 2 (S1PR2). The role of the S1PR2 in GCDC-mediated apoptosis and kinase activation is unknown. Studies were done in rat hepatocytes, HUH7 cells, and HUH7 cells stably transfected with rat Ntcp (HUH7-Ntcp). Cells were treated with GCDC and apoptosis was monitored morphologically by Hoechst staining and biochemically by immunoblotting for the active cleaved fragment of caspase 3. Kinase activation was determined by immunoblotting with phospho-specific antibodies. JTE-013, an inhibitor of S1PR2, significantly attenuated morphological evidence of GCDC-induced apoptosis and prevented caspase 3 cleavage in rat hepatocytes and HUH7-Ntcp cells. In hepatocytes, JTE-013 mildly suppressed, augmented, and had no effect on GCDC-induced JNK, Akt, and Erk phosphorylation, respectively. Similar results were seen in HUH7-Ntcp cells except for mild suppression of JNK and Erk phosphorylation. Knockdown of S1PR2 in HUH7-Ntcp augmented Akt, inhibited JNK, and had no effect on Erk phosphorylation. GCDC failed to induce apoptosis or kinase activation in HUH7 cells. In conclusion, SIPR2 inhibition attenuates GCDC-induced apoptosis and inhibits and augments GCDC-induced JNK and Akt phosphorylation, respectively. In addition, GCDC must enter hepatocytes to mediate cell death or activate kinases. These results suggest that SIPR2 activation is proapoptotic in GCDC-induced cell death but that this effect is not due to direct ligation of the S1PR2 by the bile acid.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>26999807</pmid><doi>10.1152/ajpgi.00253.2015</doi><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0193-1857 |
ispartof | American journal of physiology: Gastrointestinal and liver physiology, 2016-05, Vol.310 (10), p.G865-G873 |
issn | 0193-1857 1522-1547 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4895872 |
source | American Physiological Society Free |
subjects | Animals Apoptosis Carcinoma, Hepatocellular - metabolism Cell Line, Tumor Cells, Cultured Glycochenodeoxycholic Acid - metabolism Glycochenodeoxycholic Acid - toxicity Hepatocytes - metabolism Humans Kinases Liver and Biliary Tract Physiology/Pathophysiology Liver Neoplasms - metabolism Male MAP Kinase Kinase 4 - metabolism MAP Kinase Signaling System Morphology Phosphorylation Proto-Oncogene Proteins c-akt - metabolism Pyrazoles - pharmacology Pyridines - pharmacology Rats Rats, Wistar Receptors, Lysosphingolipid - antagonists & inhibitors Receptors, Lysosphingolipid - metabolism Rodents Sphingosine-1-Phosphate Receptors |
title | Hydrophobic bile acid apoptosis is regulated by sphingosine-1-phosphate receptor 2 in rat hepatocytes and human hepatocellular carcinoma cells |
url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-22T23%3A24%3A23IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Hydrophobic%20bile%20acid%20apoptosis%20is%20regulated%20by%20sphingosine-1-phosphate%20receptor%202%20in%20rat%20hepatocytes%20and%20human%20hepatocellular%20carcinoma%20cells&rft.jtitle=American%20journal%20of%20physiology:%20Gastrointestinal%20and%20liver%20physiology&rft.au=Webster,%20Cynthia%20R%20L&rft.date=2016-05-15&rft.volume=310&rft.issue=10&rft.spage=G865&rft.epage=G873&rft.pages=G865-G873&rft.issn=0193-1857&rft.eissn=1522-1547&rft.coden=APGPDF&rft_id=info:doi/10.1152/ajpgi.00253.2015&rft_dat=%3Cproquest_pubme%3E4067930711%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c490t-b21d5b54028a535640b1b094d2d02d24bb4dac5683698ee966df7e5ba71ca5d73%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1791356200&rft_id=info:pmid/26999807&rfr_iscdi=true |