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

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.

Sirtuin 1 activator alleviated lethal inflammatory injury via promotion of autophagic degradation of pyruvate kinase M2

“…To investigate the roles of autophagy in the regulation of PKM2 in inflamed-lung tissue, rapamycin, a widely used mTOR inhibitor and autophagy inducer ( Ye et al, 2022 ), was administered. As expected, administration of rapamycin increased the level of LC3B-II but decreased the level of p62 in LPS-insulted mice ( Figures 1G, H ).…”

Nuciferine Effectively Protects Mice against Acetaminophen-Induced Liver Injury

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Nanomedicine Strategies for Heating “Cold” Ovarian Cancer (OC): Next Evolution in Immunotherapy of OC

“…[ 107 , 108 ] 4‐HNE induces endoplasmic reticulum (ER) stress to lead to hyperactivation of inositol‐requiring kinase 1 α (IRE1 α )‐X‐box binding protein 1 (XBP1). [ 109 , 110 ] XBP1 promotes aberrant lipid accumulation to manipulate metabolic signaling for DCs deactivation by enhancing fatty acid oxidation, which is closely related to the immature resting phenotype of DCs with the little secretion of cytokines and weak ability to activate T cells. [ 111 ] Collectively, lipid accumulation and ER stress inhibit TIDC activation in OC.…”