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Metformin protects rat hepatocytes against bile acid-induced apoptosis
Metformin is used in the treatment of Diabetes Mellitus type II and improves liver function in patients with non-alcoholic fatty liver disease (NAFLD). Metformin activates AMP-activated protein kinase (AMPK), the cellular energy sensor that is sensitive to changes in the AMP/ATP-ratio. AMPK is an in...
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Published in: | PloS one 2013-08, Vol.8 (8), p.e71773 |
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description | Metformin is used in the treatment of Diabetes Mellitus type II and improves liver function in patients with non-alcoholic fatty liver disease (NAFLD). Metformin activates AMP-activated protein kinase (AMPK), the cellular energy sensor that is sensitive to changes in the AMP/ATP-ratio. AMPK is an inhibitor of mammalian target of rapamycin (mTOR). Both AMPK and mTOR are able to modulate cell death.
To evaluate the effects of metformin on hepatocyte cell death.
Apoptotic cell death was induced in primary rat hepatocytes using either the bile acid glycochenodeoxycholic acid (GCDCA) or TNFα in combination with actinomycin D (actD). AMPK, mTOR and phosphoinositide-3 kinase (PI3K)/Akt were inhibited using pharmacological inhibitors. Apoptosis and necrosis were quantified by caspase activation, acridine orange staining and Sytox green staining respectively.
Metformin dose-dependently reduces GCDCA-induced apoptosis, even when added 2 hours after GCDCA, without increasing necrotic cell death. Metformin does not protect against TNFα/ActD-induced apoptosis. The protective effect of metformin is dependent on an intact PI3-kinase/Akt pathway, but does not require AMPK/mTOR-signaling. Metformin does not inhibit NF-κB activation.
Metformin protects against bile acid-induced apoptosis and could be considered in the treatment of chronic liver diseases accompanied by inflammation. |
doi_str_mv | 10.1371/journal.pone.0071773 |
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To evaluate the effects of metformin on hepatocyte cell death.
Apoptotic cell death was induced in primary rat hepatocytes using either the bile acid glycochenodeoxycholic acid (GCDCA) or TNFα in combination with actinomycin D (actD). AMPK, mTOR and phosphoinositide-3 kinase (PI3K)/Akt were inhibited using pharmacological inhibitors. Apoptosis and necrosis were quantified by caspase activation, acridine orange staining and Sytox green staining respectively.
Metformin dose-dependently reduces GCDCA-induced apoptosis, even when added 2 hours after GCDCA, without increasing necrotic cell death. Metformin does not protect against TNFα/ActD-induced apoptosis. The protective effect of metformin is dependent on an intact PI3-kinase/Akt pathway, but does not require AMPK/mTOR-signaling. Metformin does not inhibit NF-κB activation.
Metformin protects against bile acid-induced apoptosis and could be considered in the treatment of chronic liver diseases accompanied by inflammation.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0071773</identifier><identifier>PMID: 23951244</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>1-Phosphatidylinositol 3-kinase ; Acids ; Acridine orange ; Actinomycin ; Activation ; AKT protein ; AMP ; AMP-activated protein kinase ; AMP-Activated Protein Kinases - metabolism ; Animals ; Antidiabetics ; Apoptosis ; Apoptosis - drug effects ; Bile ; Bile Acids and Salts - metabolism ; Bile Acids and Salts - pharmacology ; Biology ; Caspase ; Caspase 3 - metabolism ; Cell death ; Cell Membrane - metabolism ; Deoxycholic acid ; Diabetes mellitus ; Diabetes therapy ; Dose-Response Relationship, Drug ; Fatty liver ; Glycochenodeoxycholic Acid - metabolism ; Hepatocytes ; Hepatocytes - drug effects ; Hepatocytes - metabolism ; Hepatocytes - pathology ; Hypoglycemic Agents - pharmacology ; Kinases ; Laboratories ; Liver ; Liver diseases ; Male ; Medical treatment ; Medicine ; Metformin ; Metformin - pharmacology ; Mortality ; Necrosis - drug therapy ; NF-kappa B - metabolism ; NF-κB protein ; Pharmacology ; Phosphatidylinositol 3-Kinases - metabolism ; Protein kinases ; Proto-Oncogene Proteins c-akt - metabolism ; Rapamycin ; Rats ; Rodents ; Signal Transduction ; Signaling ; Staining ; TOR protein ; TOR Serine-Threonine Kinases - metabolism ; Tumor necrosis factor ; Tumor necrosis factor-α</subject><ispartof>PloS one, 2013-08, Vol.8 (8), p.e71773</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Woudenberg-Vrenken et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Woudenberg-Vrenken et al 2013 Woudenberg-Vrenken et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-6bcd075f48979a175f512205df5a4daef2b4fd148221ff8a7e2ad13775d2e33f3</citedby><cites>FETCH-LOGICAL-c692t-6bcd075f48979a175f512205df5a4daef2b4fd148221ff8a7e2ad13775d2e33f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1430421024/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1430421024?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23951244$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Mott, Justin L.</contributor><creatorcontrib>Woudenberg-Vrenken, Titia E</creatorcontrib><creatorcontrib>Conde de la Rosa, Laura</creatorcontrib><creatorcontrib>Buist-Homan, Manon</creatorcontrib><creatorcontrib>Faber, Klaas Nico</creatorcontrib><creatorcontrib>Moshage, Han</creatorcontrib><title>Metformin protects rat hepatocytes against bile acid-induced apoptosis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Metformin is used in the treatment of Diabetes Mellitus type II and improves liver function in patients with non-alcoholic fatty liver disease (NAFLD). Metformin activates AMP-activated protein kinase (AMPK), the cellular energy sensor that is sensitive to changes in the AMP/ATP-ratio. AMPK is an inhibitor of mammalian target of rapamycin (mTOR). Both AMPK and mTOR are able to modulate cell death.
To evaluate the effects of metformin on hepatocyte cell death.
Apoptotic cell death was induced in primary rat hepatocytes using either the bile acid glycochenodeoxycholic acid (GCDCA) or TNFα in combination with actinomycin D (actD). AMPK, mTOR and phosphoinositide-3 kinase (PI3K)/Akt were inhibited using pharmacological inhibitors. Apoptosis and necrosis were quantified by caspase activation, acridine orange staining and Sytox green staining respectively.
Metformin dose-dependently reduces GCDCA-induced apoptosis, even when added 2 hours after GCDCA, without increasing necrotic cell death. Metformin does not protect against TNFα/ActD-induced apoptosis. The protective effect of metformin is dependent on an intact PI3-kinase/Akt pathway, but does not require AMPK/mTOR-signaling. Metformin does not inhibit NF-κB activation.
Metformin protects against bile acid-induced apoptosis and could be considered in the treatment of chronic liver diseases accompanied by inflammation.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>Acids</subject><subject>Acridine orange</subject><subject>Actinomycin</subject><subject>Activation</subject><subject>AKT protein</subject><subject>AMP</subject><subject>AMP-activated protein kinase</subject><subject>AMP-Activated Protein Kinases - metabolism</subject><subject>Animals</subject><subject>Antidiabetics</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Bile</subject><subject>Bile Acids and Salts - metabolism</subject><subject>Bile Acids and Salts - pharmacology</subject><subject>Biology</subject><subject>Caspase</subject><subject>Caspase 3 - metabolism</subject><subject>Cell death</subject><subject>Cell Membrane - metabolism</subject><subject>Deoxycholic acid</subject><subject>Diabetes mellitus</subject><subject>Diabetes therapy</subject><subject>Dose-Response Relationship, Drug</subject><subject>Fatty liver</subject><subject>Glycochenodeoxycholic Acid - metabolism</subject><subject>Hepatocytes</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - metabolism</subject><subject>Hepatocytes - pathology</subject><subject>Hypoglycemic Agents - pharmacology</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Liver</subject><subject>Liver diseases</subject><subject>Male</subject><subject>Medical treatment</subject><subject>Medicine</subject><subject>Metformin</subject><subject>Metformin - pharmacology</subject><subject>Mortality</subject><subject>Necrosis - drug therapy</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Pharmacology</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Protein kinases</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Rapamycin</subject><subject>Rats</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Staining</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Tumor necrosis factor</subject><subject>Tumor necrosis factor-α</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl2L1TAQhoso7rr6D0QLguBFj_lq094Iy-LqgZUFv27DNB89ObRNTVJx_71ZT3c5BQXJRULmmXcmkzfLnmO0wZTjt3s3-xH6zeRGvUGIY87pg-wUN5QUFUH04dH5JHsSwh6hktZV9Tg7IbQpMWHsNLv8pKNxfrBjPnkXtYwh9xDznZ4gOnkTdcihAzuGmLe21zlIqwo7qllqlcPkpuiCDU-zRwb6oJ8t-1n27fL914uPxdX1h-3F-VUhq4bEomqlQrw0rG54AzidUhsElcqUwBRoQ1pmFGY1IdiYGrgmoNJreamIptTQs-zlQXfqXRDLCILAjCJGMCIsEdsDoRzsxeTtAP5GOLDiz4XznQAfrey1QFVN2rZKpWrDmtJA21TUVBJrrHiKJa13S7W5HbSSeowe-pXoOjLanejcT0E5wxjVSeDVIuDdj1mH-I-WF6qD1JUdjUticrBBinPGa5qUyiZRm79QaSk9WJlMYNL3rBPerBISE_Wv2MEcgth--fz_7PX3Nfv6iN1p6OMuuH6O1o1hDbIDKL0LwWtzPzmMxK2H76Yhbj0sFg-ntBfHU79PujMt_Q1tw-wT</recordid><startdate>20130812</startdate><enddate>20130812</enddate><creator>Woudenberg-Vrenken, Titia E</creator><creator>Conde de la Rosa, Laura</creator><creator>Buist-Homan, Manon</creator><creator>Faber, Klaas Nico</creator><creator>Moshage, Han</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130812</creationdate><title>Metformin protects rat hepatocytes against bile acid-induced apoptosis</title><author>Woudenberg-Vrenken, Titia E ; Conde de la Rosa, Laura ; Buist-Homan, Manon ; Faber, Klaas Nico ; Moshage, Han</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-6bcd075f48979a175f512205df5a4daef2b4fd148221ff8a7e2ad13775d2e33f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>Acids</topic><topic>Acridine orange</topic><topic>Actinomycin</topic><topic>Activation</topic><topic>AKT protein</topic><topic>AMP</topic><topic>AMP-activated protein kinase</topic><topic>AMP-Activated Protein Kinases - metabolism</topic><topic>Animals</topic><topic>Antidiabetics</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Bile</topic><topic>Bile Acids and Salts - metabolism</topic><topic>Bile Acids and Salts - pharmacology</topic><topic>Biology</topic><topic>Caspase</topic><topic>Caspase 3 - metabolism</topic><topic>Cell death</topic><topic>Cell Membrane - metabolism</topic><topic>Deoxycholic acid</topic><topic>Diabetes mellitus</topic><topic>Diabetes therapy</topic><topic>Dose-Response Relationship, Drug</topic><topic>Fatty liver</topic><topic>Glycochenodeoxycholic Acid - metabolism</topic><topic>Hepatocytes</topic><topic>Hepatocytes - drug effects</topic><topic>Hepatocytes - metabolism</topic><topic>Hepatocytes - pathology</topic><topic>Hypoglycemic Agents - pharmacology</topic><topic>Kinases</topic><topic>Laboratories</topic><topic>Liver</topic><topic>Liver diseases</topic><topic>Male</topic><topic>Medical treatment</topic><topic>Medicine</topic><topic>Metformin</topic><topic>Metformin - pharmacology</topic><topic>Mortality</topic><topic>Necrosis - drug therapy</topic><topic>NF-kappa B - metabolism</topic><topic>NF-κB protein</topic><topic>Pharmacology</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Protein kinases</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Rapamycin</topic><topic>Rats</topic><topic>Rodents</topic><topic>Signal Transduction</topic><topic>Signaling</topic><topic>Staining</topic><topic>TOR protein</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><topic>Tumor necrosis factor</topic><topic>Tumor necrosis factor-α</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Woudenberg-Vrenken, Titia E</creatorcontrib><creatorcontrib>Conde de la Rosa, Laura</creatorcontrib><creatorcontrib>Buist-Homan, Manon</creatorcontrib><creatorcontrib>Faber, Klaas Nico</creatorcontrib><creatorcontrib>Moshage, Han</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Opposing Viewpoints Resource Center</collection><collection>Science (Gale in Context)</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Databases</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Metformin activates AMP-activated protein kinase (AMPK), the cellular energy sensor that is sensitive to changes in the AMP/ATP-ratio. AMPK is an inhibitor of mammalian target of rapamycin (mTOR). Both AMPK and mTOR are able to modulate cell death.
To evaluate the effects of metformin on hepatocyte cell death.
Apoptotic cell death was induced in primary rat hepatocytes using either the bile acid glycochenodeoxycholic acid (GCDCA) or TNFα in combination with actinomycin D (actD). AMPK, mTOR and phosphoinositide-3 kinase (PI3K)/Akt were inhibited using pharmacological inhibitors. Apoptosis and necrosis were quantified by caspase activation, acridine orange staining and Sytox green staining respectively.
Metformin dose-dependently reduces GCDCA-induced apoptosis, even when added 2 hours after GCDCA, without increasing necrotic cell death. Metformin does not protect against TNFα/ActD-induced apoptosis. The protective effect of metformin is dependent on an intact PI3-kinase/Akt pathway, but does not require AMPK/mTOR-signaling. Metformin does not inhibit NF-κB activation.
Metformin protects against bile acid-induced apoptosis and could be considered in the treatment of chronic liver diseases accompanied by inflammation.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23951244</pmid><doi>10.1371/journal.pone.0071773</doi><tpages>e71773</tpages><oa>free_for_read</oa></addata></record> |
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subjects | 1-Phosphatidylinositol 3-kinase Acids Acridine orange Actinomycin Activation AKT protein AMP AMP-activated protein kinase AMP-Activated Protein Kinases - metabolism Animals Antidiabetics Apoptosis Apoptosis - drug effects Bile Bile Acids and Salts - metabolism Bile Acids and Salts - pharmacology Biology Caspase Caspase 3 - metabolism Cell death Cell Membrane - metabolism Deoxycholic acid Diabetes mellitus Diabetes therapy Dose-Response Relationship, Drug Fatty liver Glycochenodeoxycholic Acid - metabolism Hepatocytes Hepatocytes - drug effects Hepatocytes - metabolism Hepatocytes - pathology Hypoglycemic Agents - pharmacology Kinases Laboratories Liver Liver diseases Male Medical treatment Medicine Metformin Metformin - pharmacology Mortality Necrosis - drug therapy NF-kappa B - metabolism NF-κB protein Pharmacology Phosphatidylinositol 3-Kinases - metabolism Protein kinases Proto-Oncogene Proteins c-akt - metabolism Rapamycin Rats Rodents Signal Transduction Signaling Staining TOR protein TOR Serine-Threonine Kinases - metabolism Tumor necrosis factor Tumor necrosis factor-α |
title | Metformin protects rat hepatocytes against bile acid-induced apoptosis |
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