Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy.

Acetaminophen (APAP) hepatotoxicity induces endoplasmic reticulum (ER) stress which triggers the unfolded protein response (UPR) in hepatocytes. However, the mechanisms underlying ER stress remain poorly understood, thus reducing the options for exploring new pharmacological therapies for patients w...

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Autores: Ye, Hui, Chen, Chaobo, Wu, Hanghang, Zheng, Kang, Martín-Adrados, Beatriz, Caparrós, Esther, Francés, Rubén, Nelson, Leonard J, Gómez Del Moral, Manuel, Asensio, Iris, Vaquero, Javier, Bañares, Rafael, Ávila, Matías A, Andrade, Raúl J, Isabel Lucena, M, Martínez-Chantar, Maria Luz, Reeves, Helen L, Masson, Steven, Blumberg, Richard S, Gracia-Sancho, Jordi, Nevzorova, Yulia A, Martínez-Naves, Eduardo, Cubero, Francisco Javier
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/18603
Acceso en línea:http://hdl.handle.net/20.500.12105/18603
Access Level:acceso abierto
Palabra clave:Acetaminophen
Animals
Autophagy
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spelling Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy.Ye, HuiChen, ChaoboWu, HanghangZheng, KangMartín-Adrados, BeatrizCaparrós, EstherFrancés, RubénNelson, Leonard JGómez Del Moral, ManuelAsensio, IrisVaquero, JavierBañares, RafaelÁvila, Matías AAndrade, Raúl JIsabel Lucena, MMartínez-Chantar, Maria LuzReeves, Helen LMasson, StevenBlumberg, Richard SGracia-Sancho, JordiNevzorova, Yulia AMartínez-Naves, EduardoCubero, Francisco JavierAcetaminophenAnimalsAutophagyAcetaminophen (APAP) hepatotoxicity induces endoplasmic reticulum (ER) stress which triggers the unfolded protein response (UPR) in hepatocytes. However, the mechanisms underlying ER stress remain poorly understood, thus reducing the options for exploring new pharmacological therapies for patients with hyperacute liver injury. Eight-to-twelve-week-old C57BL/6J Xbp1-floxed (Xbp1f/f) and hepatocyte-specific knockout Xbp1 mice (Xbp1∆hepa) were challenged with either high dose APAP [500 mg/kg] and sacrificed at early (1-2 h) and late (24 h) stages of hepatotoxicity. Histopathological examination of livers, immunofluorescence and immunohistochemistry, Western blot, real time (RT)-qPCR studies and transmission electron microscopy (TEM) were performed. Pharmacological inhibition of XBP1 using pre-treatment with STF-083010 [STF, 75 mg/kg] and autophagy induction with Rapamycin [RAPA, 8 mg/kg] or blockade with Chloroquine [CQ, 60 mg/kg] was also undertaken in vivo. Cytoplasmic expression of XBP1 coincided with severity of human and murine hyperacute liver injury. Transcriptional and translational activation of the UPR and sustained activation of JNK1/2 were major events in APAP hepatotoxicity, both in a human hepatocytic cell line and in a preclinical model. Xbp1∆hepa livers showed decreased UPR and JNK1/2 activation but enhanced autophagy in response to high dose APAP. Additionally, blockade of XBP1 splicing by STF, mitigated APAP-induced liver injury and without non-specific off-target effects (e.g., CYP2E1 activity). Furthermore, enhanced autophagy might be responsible for modulating CYP2E1 activity in Xbp1∆hepa animals. Genetic and pharmacological inhibition of Xbp1 specifically in hepatocytes ameliorated APAP-induced liver injury by enhancing autophagy and decreasing CYP2E1 expression. These findings provide the basis for the therapeutic restoration of ER stress and/or induction of autophagy in patients with hyperacute liver injury.20242024-02-2720222022-02-1020222022-02-10research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articlehttp://hdl.handle.net/20.500.12105/18603reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/186032026-06-12T12:43:37Z
dc.title.none.fl_str_mv Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy.
title Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy.
spellingShingle Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy.
Ye, Hui
Acetaminophen
Animals
Autophagy
title_short Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy.
title_full Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy.
title_fullStr Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy.
title_full_unstemmed Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy.
title_sort Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy.
dc.creator.none.fl_str_mv Ye, Hui
Chen, Chaobo
Wu, Hanghang
Zheng, Kang
Martín-Adrados, Beatriz
Caparrós, Esther
Francés, Rubén
Nelson, Leonard J
Gómez Del Moral, Manuel
Asensio, Iris
Vaquero, Javier
Bañares, Rafael
Ávila, Matías A
Andrade, Raúl J
Isabel Lucena, M
Martínez-Chantar, Maria Luz
Reeves, Helen L
Masson, Steven
Blumberg, Richard S
Gracia-Sancho, Jordi
Nevzorova, Yulia A
Martínez-Naves, Eduardo
Cubero, Francisco Javier
author Ye, Hui
author_facet Ye, Hui
Chen, Chaobo
Wu, Hanghang
Zheng, Kang
Martín-Adrados, Beatriz
Caparrós, Esther
Francés, Rubén
Nelson, Leonard J
Gómez Del Moral, Manuel
Asensio, Iris
Vaquero, Javier
Bañares, Rafael
Ávila, Matías A
Andrade, Raúl J
Isabel Lucena, M
Martínez-Chantar, Maria Luz
Reeves, Helen L
Masson, Steven
Blumberg, Richard S
Gracia-Sancho, Jordi
Nevzorova, Yulia A
Martínez-Naves, Eduardo
Cubero, Francisco Javier
author_role author
author2 Chen, Chaobo
Wu, Hanghang
Zheng, Kang
Martín-Adrados, Beatriz
Caparrós, Esther
Francés, Rubén
Nelson, Leonard J
Gómez Del Moral, Manuel
Asensio, Iris
Vaquero, Javier
Bañares, Rafael
Ávila, Matías A
Andrade, Raúl J
Isabel Lucena, M
Martínez-Chantar, Maria Luz
Reeves, Helen L
Masson, Steven
Blumberg, Richard S
Gracia-Sancho, Jordi
Nevzorova, Yulia A
Martínez-Naves, Eduardo
Cubero, Francisco Javier
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv
dc.subject.none.fl_str_mv Acetaminophen
Animals
Autophagy
topic Acetaminophen
Animals
Autophagy
description Acetaminophen (APAP) hepatotoxicity induces endoplasmic reticulum (ER) stress which triggers the unfolded protein response (UPR) in hepatocytes. However, the mechanisms underlying ER stress remain poorly understood, thus reducing the options for exploring new pharmacological therapies for patients with hyperacute liver injury. Eight-to-twelve-week-old C57BL/6J Xbp1-floxed (Xbp1f/f) and hepatocyte-specific knockout Xbp1 mice (Xbp1∆hepa) were challenged with either high dose APAP [500 mg/kg] and sacrificed at early (1-2 h) and late (24 h) stages of hepatotoxicity. Histopathological examination of livers, immunofluorescence and immunohistochemistry, Western blot, real time (RT)-qPCR studies and transmission electron microscopy (TEM) were performed. Pharmacological inhibition of XBP1 using pre-treatment with STF-083010 [STF, 75 mg/kg] and autophagy induction with Rapamycin [RAPA, 8 mg/kg] or blockade with Chloroquine [CQ, 60 mg/kg] was also undertaken in vivo. Cytoplasmic expression of XBP1 coincided with severity of human and murine hyperacute liver injury. Transcriptional and translational activation of the UPR and sustained activation of JNK1/2 were major events in APAP hepatotoxicity, both in a human hepatocytic cell line and in a preclinical model. Xbp1∆hepa livers showed decreased UPR and JNK1/2 activation but enhanced autophagy in response to high dose APAP. Additionally, blockade of XBP1 splicing by STF, mitigated APAP-induced liver injury and without non-specific off-target effects (e.g., CYP2E1 activity). Furthermore, enhanced autophagy might be responsible for modulating CYP2E1 activity in Xbp1∆hepa animals. Genetic and pharmacological inhibition of Xbp1 specifically in hepatocytes ameliorated APAP-induced liver injury by enhancing autophagy and decreasing CYP2E1 expression. These findings provide the basis for the therapeutic restoration of ER stress and/or induction of autophagy in patients with hyperacute liver injury.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022-02-10
2022
2022-02-10
2024
2024-02-27
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/18603
url http://hdl.handle.net/20.500.12105/18603
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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