Activation of necroptosis in human and experimental cholestasis
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2016 |
| Outros Autores: | , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| Texto Completo: | http://hdl.handle.net/10451/46134 |
Resumo: | © 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/ |
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Activation of necroptosis in human and experimental cholestasis© 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/Cholestasis 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.The 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.Springer NatureRepositório da Universidade de LisboaAfonso, MartaRodrigues, PedroSimão, AndréOfengeim, DimitryCarvalho, TâniaAmaral, Joana D.Gaspar, Maria ManuelaCortez-Pinto, HelenaCastro, Rui E.Yuan, JunyingRodrigues, Cecília M. P.2021-02-03T13:48:55Z20162016-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/46134engCell Death Dis. 2016 Sep 29;7(9):e239010.1038/cddis.2016.2802041-4889info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:48:19Zoai:repositorio.ul.pt:10451/46134Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:58:24.368326Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
| dc.title.none.fl_str_mv |
Activation of necroptosis in human and experimental cholestasis |
| title |
Activation of necroptosis in human and experimental cholestasis |
| spellingShingle |
Activation of necroptosis in human and experimental cholestasis Afonso, Marta |
| title_short |
Activation of necroptosis in human and experimental cholestasis |
| title_full |
Activation of necroptosis in human and experimental cholestasis |
| title_fullStr |
Activation of necroptosis in human and experimental cholestasis |
| title_full_unstemmed |
Activation of necroptosis in human and experimental cholestasis |
| title_sort |
Activation of necroptosis in human and experimental cholestasis |
| author |
Afonso, Marta |
| author_facet |
Afonso, Marta Rodrigues, Pedro Simão, André Ofengeim, Dimitry Carvalho, Tânia Amaral, Joana D. Gaspar, Maria Manuela Cortez-Pinto, Helena Castro, Rui E. Yuan, Junying Rodrigues, Cecília M. P. |
| author_role |
author |
| author2 |
Rodrigues, Pedro Simão, André Ofengeim, Dimitry Carvalho, Tânia Amaral, Joana D. Gaspar, Maria Manuela Cortez-Pinto, Helena Castro, Rui E. Yuan, Junying Rodrigues, Cecília M. P. |
| author2_role |
author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
| dc.contributor.author.fl_str_mv |
Afonso, Marta Rodrigues, Pedro Simão, André Ofengeim, Dimitry Carvalho, Tânia Amaral, Joana D. Gaspar, Maria Manuela Cortez-Pinto, Helena Castro, Rui E. Yuan, Junying Rodrigues, Cecília M. P. |
| 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/ |
| publishDate |
2016 |
| dc.date.none.fl_str_mv |
2016 2016-01-01T00:00:00Z 2021-02-03T13:48:55Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
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http://hdl.handle.net/10451/46134 |
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http://hdl.handle.net/10451/46134 |
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eng |
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eng |
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Cell Death Dis. 2016 Sep 29;7(9):e2390 10.1038/cddis.2016.280 2041-4889 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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Springer Nature |
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Springer Nature |
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RCAAP |
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