JNKs protect from cholestatic liver disease progression by modulating Apelin signalling

Background & aims: Cholestatic liver injury is associated with c-Jun N-terminal kinases (JNK) activation in distinct cell types. Its hepatocyte-specific function during cholestasis, however, has not yet been established. Therefore, in our present study, we investigated the role of JNK1/2 during...

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Detalles Bibliográficos
Autores: Ramadan Mohamed, Mohamed, Wu, Hanghang, Cubero Palero, Francisco Javier, Trautwein, Christian
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/102058
Acceso en línea:https://hdl.handle.net/20.500.14352/102058
Access Level:acceso abierto
Palabra clave:611.36
c-Jun N-terminal kinases (JNK)
Cholestasis
Fibrosis
Hepatocytes
Apelin
Ciencias Biomédicas
Gastroenterología y hepatología
Inmunología
24 Ciencias de la Vida
2412 Inmunología
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oai_identifier_str oai:docta.ucm.es:20.500.14352/102058
network_acronym_str ES
network_name_str España
repository_id_str
spelling JNKs protect from cholestatic liver disease progression by modulating Apelin signallingRamadan Mohamed, MohamedWu, HanghangCubero Palero, Francisco JavierTrautwein, Christian611.36c-Jun N-terminal kinases (JNK)CholestasisFibrosisHepatocytesApelinCiencias BiomédicasGastroenterología y hepatologíaInmunología24 Ciencias de la Vida2412 InmunologíaBackground & aims: Cholestatic liver injury is associated with c-Jun N-terminal kinases (JNK) activation in distinct cell types. Its hepatocyte-specific function during cholestasis, however, has not yet been established. Therefore, in our present study, we investigated the role of JNK1/2 during cholestasis and dissected its hepatocyte-specific function. Methods: A cohort of patients with primary biliary cholangitis (n = 29) and primary sclerosing cholangitis (n = 37) was examined. Wild-type, hepatocyte-specific knockout mice for Jnk2 (Jnk2Δhepa) or Jnk1 and Jnk2 (Jnk1Δhepa/2Δhepa) were generated. Mice were subjected to bile duct ligation (BDL) or carbon tetrachloride (CCl4) treatment. Finally, Apelin signalling was blocked using a specific inhibitor. As an interventional approach, Jnk1/2 were silenced in wild-type mice using lipid nanoparticles for small interfering RNA delivery. Results: JNK activation was increased in liver specimens from patients with chronic cholestasis (primary biliary cholangitis and primary sclerosing cholangitis) and in livers of Mdr2-/- and BDL-treated animals. In Jnk1Δhepa/2Δhepa animals, serum transaminases increased after BDL, and liver histology demonstrated enhanced cell death, compensatory proliferation, hepatic fibrogenesis, and inflammation. Furthermore, microarray analysis revealed that hepatocytic Jnk1/2 ablation induces JNK-target genes involved in oxidative stress and Apelin signalling after BDL. Consequently, blocking Apelin signalling attenuated BDL-induced liver injury and fibrosis in Jnk1Δhepa/2Δhepa mice. Finally, we established an interventional small interfering RNA approach of selective Jnk1/2 targeting in hepatocytes in vivo, further demonstrating the essential protective role of Jnk1/2 during cholestasis. Conclusions: Jnk1 and Jnk2 work together to protect hepatocytes from cholestatic liver disease by controlling Apelin signalling. Dual modification of JNK signalling in hepatocytes is feasible, and enhancing its expression might be an attractive therapeutic approach for cholestatic liver disease. Impact and implications: The cell-specific function of Jnk genes during cholestasis has not been explicitly explored. In this study, we showed that combined Jnk1/2, but not Jnk2 deficiency, in hepatocytes exacerbates liver damage and fibrosis by enhancing Apelin signalling, which contributes to cholestasis progression. Combined cell-specific Jnk targeting may be a new molecular strategy for treating cholestatic liver disease.Universidad Complutense de Madrid20232023-01-0120232023-01-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/102058reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1020582026-06-02T12:44:21Z
dc.title.none.fl_str_mv JNKs protect from cholestatic liver disease progression by modulating Apelin signalling
title JNKs protect from cholestatic liver disease progression by modulating Apelin signalling
spellingShingle JNKs protect from cholestatic liver disease progression by modulating Apelin signalling
Ramadan Mohamed, Mohamed
611.36
c-Jun N-terminal kinases (JNK)
Cholestasis
Fibrosis
Hepatocytes
Apelin
Ciencias Biomédicas
Gastroenterología y hepatología
Inmunología
24 Ciencias de la Vida
2412 Inmunología
title_short JNKs protect from cholestatic liver disease progression by modulating Apelin signalling
title_full JNKs protect from cholestatic liver disease progression by modulating Apelin signalling
title_fullStr JNKs protect from cholestatic liver disease progression by modulating Apelin signalling
title_full_unstemmed JNKs protect from cholestatic liver disease progression by modulating Apelin signalling
title_sort JNKs protect from cholestatic liver disease progression by modulating Apelin signalling
dc.creator.none.fl_str_mv Ramadan Mohamed, Mohamed
Wu, Hanghang
Cubero Palero, Francisco Javier
Trautwein, Christian
author Ramadan Mohamed, Mohamed
author_facet Ramadan Mohamed, Mohamed
Wu, Hanghang
Cubero Palero, Francisco Javier
Trautwein, Christian
author_role author
author2 Wu, Hanghang
Cubero Palero, Francisco Javier
Trautwein, Christian
author2_role author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 611.36
c-Jun N-terminal kinases (JNK)
Cholestasis
Fibrosis
Hepatocytes
Apelin
Ciencias Biomédicas
Gastroenterología y hepatología
Inmunología
24 Ciencias de la Vida
2412 Inmunología
topic 611.36
c-Jun N-terminal kinases (JNK)
Cholestasis
Fibrosis
Hepatocytes
Apelin
Ciencias Biomédicas
Gastroenterología y hepatología
Inmunología
24 Ciencias de la Vida
2412 Inmunología
description Background & aims: Cholestatic liver injury is associated with c-Jun N-terminal kinases (JNK) activation in distinct cell types. Its hepatocyte-specific function during cholestasis, however, has not yet been established. Therefore, in our present study, we investigated the role of JNK1/2 during cholestasis and dissected its hepatocyte-specific function. Methods: A cohort of patients with primary biliary cholangitis (n = 29) and primary sclerosing cholangitis (n = 37) was examined. Wild-type, hepatocyte-specific knockout mice for Jnk2 (Jnk2Δhepa) or Jnk1 and Jnk2 (Jnk1Δhepa/2Δhepa) were generated. Mice were subjected to bile duct ligation (BDL) or carbon tetrachloride (CCl4) treatment. Finally, Apelin signalling was blocked using a specific inhibitor. As an interventional approach, Jnk1/2 were silenced in wild-type mice using lipid nanoparticles for small interfering RNA delivery. Results: JNK activation was increased in liver specimens from patients with chronic cholestasis (primary biliary cholangitis and primary sclerosing cholangitis) and in livers of Mdr2-/- and BDL-treated animals. In Jnk1Δhepa/2Δhepa animals, serum transaminases increased after BDL, and liver histology demonstrated enhanced cell death, compensatory proliferation, hepatic fibrogenesis, and inflammation. Furthermore, microarray analysis revealed that hepatocytic Jnk1/2 ablation induces JNK-target genes involved in oxidative stress and Apelin signalling after BDL. Consequently, blocking Apelin signalling attenuated BDL-induced liver injury and fibrosis in Jnk1Δhepa/2Δhepa mice. Finally, we established an interventional small interfering RNA approach of selective Jnk1/2 targeting in hepatocytes in vivo, further demonstrating the essential protective role of Jnk1/2 during cholestasis. Conclusions: Jnk1 and Jnk2 work together to protect hepatocytes from cholestatic liver disease by controlling Apelin signalling. Dual modification of JNK signalling in hepatocytes is feasible, and enhancing its expression might be an attractive therapeutic approach for cholestatic liver disease. Impact and implications: The cell-specific function of Jnk genes during cholestasis has not been explicitly explored. In this study, we showed that combined Jnk1/2, but not Jnk2 deficiency, in hepatocytes exacerbates liver damage and fibrosis by enhancing Apelin signalling, which contributes to cholestasis progression. Combined cell-specific Jnk targeting may be a new molecular strategy for treating cholestatic liver disease.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-01-01
2023
2023-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/102058
url https://hdl.handle.net/20.500.14352/102058
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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