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Lookup NU author(s): Professor Helen ReevesORCiD, Dr Steven MassonORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022. The Author(s). 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.
Author(s): Ye H, Chen C, Wu H, Zheng K, Martin-Adrados B, Caparros E, Frances R, Nelson LJ, Gomez Del Moral M, Asensio I, Vaquero J, Banares R, Avila MA, Andrade RJ, Isabel Lucena M, Martinez-Chantar ML, Reeves HL, Masson S, Blumberg RS, Gracia-Sancho J, Nevzorova YA, Martinez-Naves E, Cubero FJ
Publication type: Article
Publication status: Published
Journal: Cell death & disease
Year: 2022
Volume: 13
Online publication date: 10/02/2022
Acceptance date: 26/01/2022
Date deposited: 07/03/2022
ISSN (electronic): 2041-4889
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/s41419-022-04580-8
DOI: 10.1038/s41419-022-04580-8
PubMed id: 35145060
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