RT Journal Article
T1 Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy
A1 Ye, Hui
A1 Wu, Hanghang
A1 Martín Adrados, Beatriz
A1 Gómez Del Moral Martín-Consuegra, Manuel María
A1 Bañares Cañizares, Rafael
A1 Nevzorova, Yulia
A1 Martínez Naves, Eduardo
A1 Cubero Palero, Francisco Javier
AB 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.
PB Elsevier
SN 2041-4889
YR 2022
FD 2022
LK https://hdl.handle.net/20.500.14352/102059
UL https://hdl.handle.net/20.500.14352/102059
LA eng
NO Ye H, Chen C, Wu H, Zheng K, Martín-Adrados B, Caparros E, Francés R, Nelson LJ, Gómez Del Moral M, Asensio I, Vaquero J, Bañares R, Ávila MA, Andrade RJ, Isabel Lucena M, Martínez-Chantar ML, Reeves HL, Masson S, Blumberg RS, Gracia-Sancho J, Nevzorova YA, Martínez-Naves E, Cubero FJ. Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy. Cell Death Dis. 2022 Feb 10;13(2):143. doi: 10.1038/s41419-022-04580-8. PMID: 35145060; PMCID: PMC8831621.
NO Ministerio de Economía, Comercio y Empresa
NO German Research Foundation
NO Ministerio de Ciencia, Innovación y Universidades
NO Fundación Científica de la Asociación Española Contra el Cancer
DS Docta Complutense
RD 21 ago 2024