RT Journal Article
T1 Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy.
A1 Ye, Hui
A1 Chen, Chaobo
A1 Wu, Hanghang
A1 Zheng, Kang
A1 Martín-Adrados, Beatriz
A1 Caparros, Esther
A1 Francés, Rubén
A1 Nelson, Leonard J
A1 Gómez Del Moral, Manuel
A1 Asensio, Iris
A1 Vaquero, Javier
A1 Bañares, Rafael
A1 Ávila, Matías A
A1 Andrade, Raúl J
A1 Isabel Lucena, M
A1 Martínez-Chantar, Maria Luz
A1 Reeves, Helen L
A1 Masson, Steven
A1 Blumberg, Richard S
A1 Gracia-Sancho, Jordi
A1 Nevzorova, Yulia A
A1 Martínez-Naves, Eduardo
A1 Cubero, 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.
YR 2022
FD 2022-02-10
LK http://hdl.handle.net/10668/19527
UL http://hdl.handle.net/10668/19527
LA en
DS RISalud
RD Apr 18, 2025