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http://hdl.handle.net/2445/206278
Title: | Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy |
Author: | Ye, Hui Chen, Chaobo Wu, Hhanghang 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. Lucena, M. Isabel Martínez Chantar, María Luz Reeves, Helen L. Masson, Steven Blumberg, Richard S. Gracia Sancho, Jordi Nevzorova, Yulia A. Martínez Naves, Eduardo Cubero, Francisco Javier |
Keywords: | Ratolins (Animals de laboratori) Citocrom P-450 Mice (Laboratory animals) Cytochrome P-450 |
Issue Date: | 10-Feb-2022 |
Publisher: | Springer Nature |
Abstract: | 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.© 2022. The Author(s). |
Note: | Reproducció del document publicat a: https://doi.org/10.1038/s41419-022-04580-8 |
It is part of: | Cell Death & Disease, 2022, vol. 13, num. 143 |
URI: | http://hdl.handle.net/2445/206278 |
Related resource: | https://doi.org/10.1038/s41419-022-04580-8 |
ISSN: | 2041-4889 |
Appears in Collections: | Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) |
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Genetic and pharmacological inhibition of XBP1 protects against APAP_NatureCDDpress.pdf | 6.28 MB | Adobe PDF | View/Open |
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