Inhibition of eIF2α Dephosphorylation Protects Hepatocytes from Apoptosis by Alleviating ER Stress in Acute Liver Injury
Objectives. Protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α) is an important factor along the main pathways for endoplasmic reticulum (ER) stress-mediated apoptosis. In this study, we investigated the effects of eIF2α phosphorylation on hepatocyte apoptosis and the...
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description | Objectives. Protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α) is an important factor along the main pathways for endoplasmic reticulum (ER) stress-mediated apoptosis. In this study, we investigated the effects of eIF2α phosphorylation on hepatocyte apoptosis and the ER stress mechanisms in acute liver injury. Methods. eIF2α phosphorylation and apoptosis under ER stress were monitored and measured in male BALB/c mice with acute liver injury and human hepatocyte line LO2 cells. Results. Carbon tetrachloride (CCl4) administration triggered ER stress and hepatocyte apoptosis, as well as eIF2α phosphorylation in mice. Inhibition of eIF2α dephosphorylation, as the pretreatment with 4-phenylbutyric acid (chemical chaperone, ER stress inhibitor), mitigated CCl4-induced intrahepatic ER stress, apoptosis, and liver injury. In an ER stress model of LO2 cells induced by thapsigargin (disrupting ER calcium balance), inhibition of eIF2α dephosphorylation reduced ER stress and apoptosis, while PERK knockdown reduced eIF2α phosphorylation and exacerbated ER stress and apoptosis. Conclusions. eIF2α phosphorylation is one of the mechanisms employed by ER stress for restoring cellular homeostasis. Inhibition of eIF2α dephosphorylation mitigates hepatocyte apoptosis by alleviating ER stress in acute liver injuries. |
doi_str_mv | 10.1155/2020/2626090 |
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Protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α) is an important factor along the main pathways for endoplasmic reticulum (ER) stress-mediated apoptosis. In this study, we investigated the effects of eIF2α phosphorylation on hepatocyte apoptosis and the ER stress mechanisms in acute liver injury. Methods. eIF2α phosphorylation and apoptosis under ER stress were monitored and measured in male BALB/c mice with acute liver injury and human hepatocyte line LO2 cells. Results. Carbon tetrachloride (CCl4) administration triggered ER stress and hepatocyte apoptosis, as well as eIF2α phosphorylation in mice. Inhibition of eIF2α dephosphorylation, as the pretreatment with 4-phenylbutyric acid (chemical chaperone, ER stress inhibitor), mitigated CCl4-induced intrahepatic ER stress, apoptosis, and liver injury. In an ER stress model of LO2 cells induced by thapsigargin (disrupting ER calcium balance), inhibition of eIF2α dephosphorylation reduced ER stress and apoptosis, while PERK knockdown reduced eIF2α phosphorylation and exacerbated ER stress and apoptosis. Conclusions. eIF2α phosphorylation is one of the mechanisms employed by ER stress for restoring cellular homeostasis. Inhibition of eIF2α dephosphorylation mitigates hepatocyte apoptosis by alleviating ER stress in acute liver injuries.</description><identifier>ISSN: 2314-6133</identifier><identifier>EISSN: 2314-6141</identifier><identifier>DOI: 10.1155/2020/2626090</identifier><identifier>PMID: 32566674</identifier><language>eng</language><publisher>Cairo, Egypt: Hindawi Publishing Corporation</publisher><subject>Animals ; Antibodies ; Apoptosis ; Apoptosis - drug effects ; Apoptosis - physiology ; Calcium ; Carbon tetrachloride ; Carbon Tetrachloride - adverse effects ; Cell Line ; Chemical and Drug Induced Liver Injury - metabolism ; Dephosphorylation ; eIF-2 Kinase - metabolism ; Endoplasmic reticulum ; Endoplasmic Reticulum Stress - drug effects ; Endoplasmic Reticulum Stress - physiology ; Eukaryotic Initiation Factor-2 - antagonists & inhibitors ; Eukaryotic Initiation Factor-2 - metabolism ; Hepatocytes ; Hepatocytes - metabolism ; Homeostasis ; Humans ; Initiation factor eIF-2α ; Injuries ; Kinases ; Liver ; Liver - drug effects ; Liver - metabolism ; Liver - pathology ; Liver diseases ; Male ; Membranes ; Mice ; Mice, Inbred BALB C ; Olive oil ; Phenylbutyric acid ; Phosphorylation ; Protein kinase R ; Protein synthesis ; Proteins ; Stress ; Thapsigargin ; Transcription factors</subject><ispartof>BioMed research international, 2020, Vol.2020 (2020), p.1-16</ispartof><rights>Copyright © 2020 Yong-Jing Tang et al.</rights><rights>Copyright © 2020 Yong-Jing Tang et al. This is an open access article distributed under the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. http://creativecommons.org/licenses/by/4.0</rights><rights>Copyright © 2020 Yong-Jing Tang et al. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c471t-657f5f5fb711684513037eebc3cff24f0db9fd6f1b393e81ffc7ad0f4e7ea7d93</citedby><cites>FETCH-LOGICAL-c471t-657f5f5fb711684513037eebc3cff24f0db9fd6f1b393e81ffc7ad0f4e7ea7d93</cites><orcidid>0000-0002-8639-3436</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293739/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293739/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,4010,27900,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32566674$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Tiziana, Anelli</contributor><contributor>Anelli Tiziana</contributor><creatorcontrib>He, Yi-Huai</creatorcontrib><creatorcontrib>Cheng, Qi-Jiao</creatorcontrib><creatorcontrib>Tian, Ren-Dong</creatorcontrib><creatorcontrib>Li, Ying</creatorcontrib><creatorcontrib>Yang, Fang-Wan</creatorcontrib><creatorcontrib>Chen, Gui-Mei</creatorcontrib><creatorcontrib>Yi, Yu</creatorcontrib><creatorcontrib>Chen, Huan</creatorcontrib><creatorcontrib>Tang, Yong-Jing</creatorcontrib><creatorcontrib>Huang, Wen-Ge</creatorcontrib><title>Inhibition of eIF2α Dephosphorylation Protects Hepatocytes from Apoptosis by Alleviating ER Stress in Acute Liver Injury</title><title>BioMed research international</title><addtitle>Biomed Res Int</addtitle><description>Objectives. Protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α) is an important factor along the main pathways for endoplasmic reticulum (ER) stress-mediated apoptosis. In this study, we investigated the effects of eIF2α phosphorylation on hepatocyte apoptosis and the ER stress mechanisms in acute liver injury. Methods. eIF2α phosphorylation and apoptosis under ER stress were monitored and measured in male BALB/c mice with acute liver injury and human hepatocyte line LO2 cells. Results. Carbon tetrachloride (CCl4) administration triggered ER stress and hepatocyte apoptosis, as well as eIF2α phosphorylation in mice. Inhibition of eIF2α dephosphorylation, as the pretreatment with 4-phenylbutyric acid (chemical chaperone, ER stress inhibitor), mitigated CCl4-induced intrahepatic ER stress, apoptosis, and liver injury. In an ER stress model of LO2 cells induced by thapsigargin (disrupting ER calcium balance), inhibition of eIF2α dephosphorylation reduced ER stress and apoptosis, while PERK knockdown reduced eIF2α phosphorylation and exacerbated ER stress and apoptosis. Conclusions. eIF2α phosphorylation is one of the mechanisms employed by ER stress for restoring cellular homeostasis. Inhibition of eIF2α dephosphorylation mitigates hepatocyte apoptosis by alleviating ER stress in acute liver injuries.</description><subject>Animals</subject><subject>Antibodies</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - physiology</subject><subject>Calcium</subject><subject>Carbon tetrachloride</subject><subject>Carbon Tetrachloride - adverse effects</subject><subject>Cell Line</subject><subject>Chemical and Drug Induced Liver Injury - metabolism</subject><subject>Dephosphorylation</subject><subject>eIF-2 Kinase - metabolism</subject><subject>Endoplasmic reticulum</subject><subject>Endoplasmic Reticulum Stress - drug effects</subject><subject>Endoplasmic Reticulum Stress - physiology</subject><subject>Eukaryotic Initiation Factor-2 - antagonists & inhibitors</subject><subject>Eukaryotic Initiation Factor-2 - metabolism</subject><subject>Hepatocytes</subject><subject>Hepatocytes - metabolism</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Initiation factor eIF-2α</subject><subject>Injuries</subject><subject>Kinases</subject><subject>Liver</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Liver diseases</subject><subject>Male</subject><subject>Membranes</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Olive oil</subject><subject>Phenylbutyric acid</subject><subject>Phosphorylation</subject><subject>Protein kinase R</subject><subject>Protein synthesis</subject><subject>Proteins</subject><subject>Stress</subject><subject>Thapsigargin</subject><subject>Transcription factors</subject><issn>2314-6133</issn><issn>2314-6141</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>RHX</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkV2LEzEUhgdR3GXdO68l4KXWzdcknRuh7IdbKCh-XIdM5mSbMk3GJFOZn-Uf8TeZ2lr1zhxCDpznvHnhrarnBL8hpK6vKKb4igoqcIMfVeeUET4ThJPHp56xs-oypQ0uZ04KJ55WZ4zWQgjJz6tp6deuddkFj4JFsLyjP76jGxjWIZUbp17_mn2IIYPJCd3DoHMwU4aEbAxbtBjCkENyCbUTWvQ97FxZ8Q_o9iP6lCOkhJxHCzNmQCu3g4iWfjPG6Vn1xOo-weXxvai-3N1-vr6frd6_W14vVjPDJckzUUtbl2olIWLOa8IwkwCtYcZayi3u2sZ2wpKWNQzmxFojdYctBwladg27qN4edIex3UJnwOeoezVEt9VxUkE79e_Eu7V6CDslacMk2wu8PArE8HWElNUmjNEXz4pyQueUcE4L9fpAmRhSimBPPxCs9lmpfVbqmFXBX_zt6gT_TqYArw7A2vlOf3P_KQeFAav_0IRRwQn7CeDSqPA</recordid><startdate>2020</startdate><enddate>2020</enddate><creator>He, Yi-Huai</creator><creator>Cheng, Qi-Jiao</creator><creator>Tian, Ren-Dong</creator><creator>Li, Ying</creator><creator>Yang, Fang-Wan</creator><creator>Chen, Gui-Mei</creator><creator>Yi, Yu</creator><creator>Chen, Huan</creator><creator>Tang, Yong-Jing</creator><creator>Huang, Wen-Ge</creator><general>Hindawi Publishing Corporation</general><general>Hindawi</general><general>Hindawi Limited</general><scope>ADJCN</scope><scope>AHFXO</scope><scope>RHU</scope><scope>RHW</scope><scope>RHX</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>3V.</scope><scope>7QL</scope><scope>7QO</scope><scope>7T7</scope><scope>7TK</scope><scope>7U7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>CWDGH</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>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8639-3436</orcidid></search><sort><creationdate>2020</creationdate><title>Inhibition of eIF2α Dephosphorylation Protects Hepatocytes from Apoptosis by Alleviating ER Stress in Acute Liver Injury</title><author>He, Yi-Huai ; Cheng, Qi-Jiao ; Tian, Ren-Dong ; Li, Ying ; Yang, Fang-Wan ; Chen, Gui-Mei ; Yi, Yu ; Chen, Huan ; Tang, Yong-Jing ; Huang, Wen-Ge</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c471t-657f5f5fb711684513037eebc3cff24f0db9fd6f1b393e81ffc7ad0f4e7ea7d93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Antibodies</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - physiology</topic><topic>Calcium</topic><topic>Carbon tetrachloride</topic><topic>Carbon Tetrachloride - adverse effects</topic><topic>Cell Line</topic><topic>Chemical and Drug Induced Liver Injury - metabolism</topic><topic>Dephosphorylation</topic><topic>eIF-2 Kinase - metabolism</topic><topic>Endoplasmic reticulum</topic><topic>Endoplasmic Reticulum Stress - drug effects</topic><topic>Endoplasmic Reticulum Stress - physiology</topic><topic>Eukaryotic Initiation Factor-2 - antagonists & inhibitors</topic><topic>Eukaryotic Initiation Factor-2 - metabolism</topic><topic>Hepatocytes</topic><topic>Hepatocytes - metabolism</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Initiation factor eIF-2α</topic><topic>Injuries</topic><topic>Kinases</topic><topic>Liver</topic><topic>Liver - drug effects</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>Liver diseases</topic><topic>Male</topic><topic>Membranes</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Olive oil</topic><topic>Phenylbutyric acid</topic><topic>Phosphorylation</topic><topic>Protein kinase R</topic><topic>Protein synthesis</topic><topic>Proteins</topic><topic>Stress</topic><topic>Thapsigargin</topic><topic>Transcription factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>He, Yi-Huai</creatorcontrib><creatorcontrib>Cheng, Qi-Jiao</creatorcontrib><creatorcontrib>Tian, Ren-Dong</creatorcontrib><creatorcontrib>Li, Ying</creatorcontrib><creatorcontrib>Yang, Fang-Wan</creatorcontrib><creatorcontrib>Chen, Gui-Mei</creatorcontrib><creatorcontrib>Yi, Yu</creatorcontrib><creatorcontrib>Chen, Huan</creatorcontrib><creatorcontrib>Tang, Yong-Jing</creatorcontrib><creatorcontrib>Huang, Wen-Ge</creatorcontrib><collection>الدوريات العلمية والإحصائية - 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Protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α) is an important factor along the main pathways for endoplasmic reticulum (ER) stress-mediated apoptosis. In this study, we investigated the effects of eIF2α phosphorylation on hepatocyte apoptosis and the ER stress mechanisms in acute liver injury. Methods. eIF2α phosphorylation and apoptosis under ER stress were monitored and measured in male BALB/c mice with acute liver injury and human hepatocyte line LO2 cells. Results. Carbon tetrachloride (CCl4) administration triggered ER stress and hepatocyte apoptosis, as well as eIF2α phosphorylation in mice. Inhibition of eIF2α dephosphorylation, as the pretreatment with 4-phenylbutyric acid (chemical chaperone, ER stress inhibitor), mitigated CCl4-induced intrahepatic ER stress, apoptosis, and liver injury. In an ER stress model of LO2 cells induced by thapsigargin (disrupting ER calcium balance), inhibition of eIF2α dephosphorylation reduced ER stress and apoptosis, while PERK knockdown reduced eIF2α phosphorylation and exacerbated ER stress and apoptosis. Conclusions. eIF2α phosphorylation is one of the mechanisms employed by ER stress for restoring cellular homeostasis. Inhibition of eIF2α dephosphorylation mitigates hepatocyte apoptosis by alleviating ER stress in acute liver injuries.</abstract><cop>Cairo, Egypt</cop><pub>Hindawi Publishing Corporation</pub><pmid>32566674</pmid><doi>10.1155/2020/2626090</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-8639-3436</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Antibodies Apoptosis Apoptosis - drug effects Apoptosis - physiology Calcium Carbon tetrachloride Carbon Tetrachloride - adverse effects Cell Line Chemical and Drug Induced Liver Injury - metabolism Dephosphorylation eIF-2 Kinase - metabolism Endoplasmic reticulum Endoplasmic Reticulum Stress - drug effects Endoplasmic Reticulum Stress - physiology Eukaryotic Initiation Factor-2 - antagonists & inhibitors Eukaryotic Initiation Factor-2 - metabolism Hepatocytes Hepatocytes - metabolism Homeostasis Humans Initiation factor eIF-2α Injuries Kinases Liver Liver - drug effects Liver - metabolism Liver - pathology Liver diseases Male Membranes Mice Mice, Inbred BALB C Olive oil Phenylbutyric acid Phosphorylation Protein kinase R Protein synthesis Proteins Stress Thapsigargin Transcription factors |
title | Inhibition of eIF2α Dephosphorylation Protects Hepatocytes from Apoptosis by Alleviating ER Stress in Acute Liver Injury |
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