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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Veröffentlicht in:BioMed research international 2020, Vol.2020 (2020), p.1-16
Hauptverfasser: 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
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container_issue 2020
container_start_page 1
container_title BioMed research international
container_volume 2020
creator 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
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 &amp; 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. 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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. 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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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