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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 principales: Ye, Hui, Chen, Chaobo, Wu, Hanghang, Zheng, Kang, Martín-Adrados, Beatriz, Caparros, 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8831621/
https://www.ncbi.nlm.nih.gov/pubmed/35145060
http://dx.doi.org/10.1038/s41419-022-04580-8
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author Ye, Hui
Chen, Chaobo
Wu, Hanghang
Zheng, Kang
Martín-Adrados, Beatriz
Caparros, 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_facet Ye, Hui
Chen, Chaobo
Wu, Hanghang
Zheng, Kang
Martín-Adrados, Beatriz
Caparros, 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_sort Ye, Hui
collection PubMed
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 (Xbp1(f/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.
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spelling pubmed-88316212022-02-24 Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy Ye, Hui Chen, Chaobo Wu, Hanghang Zheng, Kang Martín-Adrados, Beatriz Caparros, 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 Cell Death Dis Article 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 (Xbp1(f/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. Nature Publishing Group UK 2022-02-10 /pmc/articles/PMC8831621/ /pubmed/35145060 http://dx.doi.org/10.1038/s41419-022-04580-8 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Ye, Hui
Chen, Chaobo
Wu, Hanghang
Zheng, Kang
Martín-Adrados, Beatriz
Caparros, 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
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
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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8831621/
https://www.ncbi.nlm.nih.gov/pubmed/35145060
http://dx.doi.org/10.1038/s41419-022-04580-8
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