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Activation of necroptosis in human and experimental cholestasis

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dc.contributor.authorAfonso, Marta
dc.contributor.authorRodrigues, Pedro
dc.contributor.authorSimão, André
dc.contributor.authorOfengeim, Dimitry
dc.contributor.authorCarvalho, Tânia
dc.contributor.authorAmaral, Joana D.
dc.contributor.authorGaspar, Maria Manuela
dc.contributor.authorCortez-Pinto, Helena
dc.contributor.authorCastro, Rui E.
dc.contributor.authorYuan, Junying
dc.contributor.authorRodrigues, Cecília M. P.
dc.date.accessioned2021-02-03T13:48:55Z
dc.date.available2021-02-03T13:48:55Z
dc.date.issued2016
dc.description© The Author(s) 2016. Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/pt_PT
dc.description.abstractCholestasis encompasses liver injury and inflammation. Necroptosis, a necrotic cell death pathway regulated by receptor-interacting protein (RIP) 3, may mediate cell death and inflammation in the liver. We aimed to investigate the role of necroptosis in mediating deleterious processes associated with cholestatic liver disease. Hallmarks of necroptosis were evaluated in liver biopsies of primary biliary cholangitis (PBC) patients and in wild-type and RIP3-deficient (RIP3-/-) mice subjected to common bile duct ligation (BDL). The functional link between RIP3, heme oxygenase-1 (HO-1) and antioxidant response was investigated in vivo after BDL and in vitro. We demonstrate increased RIP3 expression and mixed lineage kinase domain-like protein (MLKL) phosphorylation in liver samples of human PBC patients, coincident with thioflavin T labeling, suggesting activation of necroptosis. BDL resulted in evident hallmarks of necroptosis, concomitant with progressive bile duct hyperplasia, multifocal necrosis, fibrosis and inflammation. MLKL phosphorylation was increased and insoluble aggregates of RIP3, MLKL and RIP1 formed in BLD liver tissue samples. Furthermore, RIP3 deficiency blocked BDL-induced necroinflammation at 3 and 14 days post-BDL. Serum hepatic enzymes, fibrogenic liver gene expression and oxidative stress decreased in RIP3-/- mice at 3 days after BDL. However, at 14 days, cholestasis aggravated and fibrosis was not halted. RIP3 deficiency further associated with increased hepatic expression of HO-1 and accumulation of iron in BDL mice. The functional link between HO-1 activity and bile acid toxicity was established in RIP3-deficient primary hepatocytes. Necroptosis is triggered in PBC patients and mediates hepatic necroinflammation in BDL-induced acute cholestasis. Targeting necroptosis may represent a therapeutic strategy for acute cholestasis, although complementary approaches may be required to control progression of chronic cholestatic liver disease.pt_PT
dc.description.sponsorshipThe study was supported in part by Fundação para a Ciência e a Tecnologia through grant HMSP-ICT/0018/2011 and fellowships SFRH/BD/91119/2012 (MBA), SFRH/BD/ 88212/2012 (PMR), and SFRH/BD/104160/201 (ALS) as well as through UID/DTP/ 04138/2013.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCell Death Dis. 2016 Sep 29;7(9):e2390pt_PT
dc.identifier.doi10.1038/cddis.2016.280pt_PT
dc.identifier.eissn2041-4889
dc.identifier.urihttp://hdl.handle.net/10451/46134
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relationSFRH/BD/104160/201pt_PT
dc.relationTREAT LIVER DISEASES BY TARGETING HEPATOCYTE NECROPTOSIS
dc.relation.publisherversionhttps://www.nature.com/cddis/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleActivation of necroptosis in human and experimental cholestasispt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleTREAT LIVER DISEASES BY TARGETING HEPATOCYTE NECROPTOSIS
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/HMSP-ICT%2F0018%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F91119%2F2012/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F88212%2F2012/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FDTP%2F04138%2F2013/PT
oaire.citation.endPagee2390pt_PT
oaire.citation.issue9pt_PT
oaire.citation.startPagee2390pt_PT
oaire.citation.titleCell Death & Diseasept_PT
oaire.citation.volume7pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStreamSFRH
oaire.fundingStreamSFRH
oaire.fundingStream5876
person.familyNameBento Afonso
person.familyNameRodrigues
person.familyNameSimão
person.familyNameCarvalho
person.familyNameSão José Dias Amaral
person.familyNamede Jesus Guilherme Gaspar
person.familyNameCortez-Pinto
person.familyNameCastro
person.familyNameRodrigues
person.givenNameMarta
person.givenNamePedro
person.givenNameAndré
person.givenNameTânia
person.givenNameJoana
person.givenNameMaria Manuela
person.givenNameHelena
person.givenNameRui
person.givenNameCecilia
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project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
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