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

Lookup NU author(s): Professor Helen ReevesORCiD, Dr Steven MassonORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.


Publication metadata

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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Funding

Funder referenceFunder name
C18342/A23390Cancer Research UK CRUK (open competition)
C9380/A18084Cancer Research UK CRUK (open competition)
AMMF 2018/117
CM Y2018/NMT-4949
EA 18/14
BB/L023687/1
C9380/A26813
CA17112
DFG NE 2128/2-1
DTS20/00138
FP7/2010-2013
EXOHEP-CM S2017/BMD-3727
HEALTH-F2-2009-241762Commission of the European Communities
PID2020-117941RB-IOO
PIII013
RYC-2014-15242
SAF2017-87301-R
SFB/TRR57/P04
UCM-25-2019
PID2019-107036RB-I00
PID2020-11782RB-IOO
RTC2019-007125-1
RYC-2015-17438
SAF2016-78711
SAF2017-87919-R
SFB 1382-403224013/A02

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