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

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dc.contributor.authorHui, Ye
dc.contributor.authorChaobo, Chen
dc.contributor.authorHanghang, Wu
dc.contributor.authorKang, Zheng
dc.contributor.authorMartín Adrados, Beatriz
dc.contributor.authorCaparros, Esther
dc.contributor.authorFrancés, Rubén
dc.contributor.authorNelson, Leonard J.
dc.contributor.authorGómez Del Moral Martín-Consuegra, Manuel María
dc.contributor.authorAsensio, Iris
dc.contributor.authorJavier Vaquero
dc.contributor.authorBañares Cañizares, Rafael
dc.contributor.authorÁvila, Matías A.
dc.contributor.authorAndrade, Raúl J.
dc.contributor.authorLucena, María Isabel
dc.contributor.authorMartínez Chantar, Maria Luz
dc.contributor.authorReeves, Helen L.
dc.contributor.authorMasson, Steven
dc.contributor.authorBlumberg, Richard S.
dc.contributor.authorGracia Sancho, Jordi
dc.contributor.authorNevzorova, Yulia
dc.contributor.authorMartínez Naves, Eduardo
dc.contributor.authorCubero Palero, Francisco Javier
dc.date.accessioned2024-01-10T13:05:28Z
dc.date.available2024-01-10T13:05:28Z
dc.date.issued2022-02-10
dc.description.abstractAcetaminophen (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.
dc.description.departmentDepto. de Inmunología, Oftalmología y ORL
dc.description.facultyFac. de Medicina
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Economía, Comercio y Empresa
dc.description.sponsorshipGerman Research Foundation
dc.description.statuspub
dc.identifier.citatione, H., Chen, C., Wu, H. et al. Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy. Cell Death Dis 13, 143 (2022). https://doi.org/10.1038/s41419-022-04580-8
dc.identifier.doi10.1038/s41419-022-04580-8
dc.identifier.issn2041-4889
dc.identifier.officialurlhttps://www.nature.com/articles/s41419-022-04580-8
dc.identifier.urihttps://hdl.handle.net/20.500.14352/92253
dc.issue.numberArticle number 143
dc.journal.titleCell Death and Disease
dc.language.isoeng
dc.publisherSpringer Nature
dc.relation.projectIDF2016-78711
dc.relation.projectIDSAF2017-87919-R
dc.relation.projectIDPID2020-11782RB-IOO
dc.relation.projectIDPID2020-117941RB-IOO
dc.relation.projectIDEXOHEP-CM
dc.relation.projectIDS2017/BMD-3727
dc.relation.projectIDNanoLiver-CM Y2018/NMT-4949
dc.relation.projectIDERAB Ref. EA 18/14
dc.relation.projectIDAMMF 2018/117
dc.relation.projectIDUCM-25-2019
dc.relation.projectIDCOST Action CA17112
dc.relation.projectIDFB/TRR57/P04
dc.relation.projectIDSFB 1382-403224013/A02
dc.relation.projectIDDFG NE 2128/2-1
dc.rightsAttribution 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subject.cdu612.017
dc.subject.ucmCiencias Biomédicas
dc.subject.unesco2412 Inmunología
dc.titleGenetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number13
dspace.entity.typePublication
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