Kinase analysis in alcoholic hepatitis identifies p90RSK as a potential mediator of liver fibrogenesis

Objective Alcoholic hepatitis (AH) is often associated with advanced fibrosis, which negatively impacts survival. We aimed at identifying kinases deregulated in livers from patients with AH and advanced fibrosis in order to discover novel molecular targets. Design Extensive phosphoprotein analysis b...

Descripción completa

Detalles Bibliográficos
Autores: Morales-Ibanez, Oriol, Affò, Silvia, Rodrigo Torres, Daniel, Blaya, Delia, Millán, Cristina, Coll, Mar, Perea, Luis, Odena, Gemma, Knorpp, Thomas, Templin, Markus F, Moreno Sánchez, Montserrat, Altamirano, José, Miquel Morera, Rosa, Arroyo, Vicente, Ginès i Gibert, Pere, Caballería Rovira, Joan, Sancho Bru, Pau, Bataller Alberola, Ramón
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2016
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/160082
Acceso en línea:https://hdl.handle.net/2445/160082
Access Level:acceso abierto
Palabra clave:Hepatitis
Consum d'alcohol
Drinking of alcoholic beverages
id ES_7ca5ac560fb27d7a76b4e931ab74e211
oai_identifier_str oai:diposit.ub.edu:2445/160082
network_acronym_str ES
network_name_str España
repository_id_str
spelling Kinase analysis in alcoholic hepatitis identifies p90RSK as a potential mediator of liver fibrogenesisMorales-Ibanez, OriolAffò, SilviaRodrigo Torres, DanielBlaya, DeliaMillán, CristinaColl, MarPerea, LuisOdena, GemmaKnorpp, ThomasTemplin, Markus FMoreno Sánchez, MontserratAltamirano, JoséMiquel Morera, RosaArroyo, VicenteGinès i Gibert, PereCaballería Rovira, JoanSancho Bru, PauBataller Alberola, RamónHepatitisConsum d'alcoholHepatitisDrinking of alcoholic beveragesObjective Alcoholic hepatitis (AH) is often associated with advanced fibrosis, which negatively impacts survival. We aimed at identifying kinases deregulated in livers from patients with AH and advanced fibrosis in order to discover novel molecular targets. Design Extensive phosphoprotein analysis by reverse phase protein microarrays was performed in AH (n=12) and normal human livers (n=7). Ribosomal S6 kinase (p90RSK) hepatic expression was assessed by qPCR, Western blot and immunohistochemistry. Kaempferol was used as a selective pharmacological inhibitor of the p90RSK pathway to assess the regulation of experimentally-induced liver fibrosis and injury, using in vivo and in vitro approaches. Results Proteomic analysis identified p90RSK as one of the most deregulated kinases in AH. Hepatic p90RSK gene and protein expression was also upregulated in livers with chronic liver disease. Immunohistochemistry studies showed increased p90RSK staining in areas of active fibrogenesis in cirrhotic livers. Therapeutic administration of kaempferol to carbon tetrachloride-treated mice resulted in decreased hepatic collagen deposition, and expression of profibrogenic and proinflammatory genes, compared to vehicle administration. In addition, kaempferol reduced the extent of hepatocellular injury and degree of apoptosis. In primary hepatic stellate cells, kaempferol and small interfering RNA decreased activation of p90RSK, which in turn regulated key profibrogenic actions. In primary hepatocytes, kaempferol attenuated proapoptotic signalling. Conclusions p90RSK is upregulated in patients with chronic liver disease and mediates liver fibrogenesis in vivo and in vitro. These results suggest that the p90RSK pathway could be a new therapeutic approach for liver diseases characterised by advanced fibrosis.BMJ Publishing Group2016info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/160082Articles publicats en revistes (Medicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprint del document publicat a: https://doi.org/10.1136/gutjnl-2014-307979Gut, 2016, vol. 65, num. 5, p. 1-12https://doi.org/10.1136/gutjnl-2014-307979(c) Morales-Ibanez, Oriol et al., 2016info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1600822026-05-27T06:46:51Z
dc.title.none.fl_str_mv Kinase analysis in alcoholic hepatitis identifies p90RSK as a potential mediator of liver fibrogenesis
title Kinase analysis in alcoholic hepatitis identifies p90RSK as a potential mediator of liver fibrogenesis
spellingShingle Kinase analysis in alcoholic hepatitis identifies p90RSK as a potential mediator of liver fibrogenesis
Morales-Ibanez, Oriol
Hepatitis
Consum d'alcohol
Hepatitis
Drinking of alcoholic beverages
title_short Kinase analysis in alcoholic hepatitis identifies p90RSK as a potential mediator of liver fibrogenesis
title_full Kinase analysis in alcoholic hepatitis identifies p90RSK as a potential mediator of liver fibrogenesis
title_fullStr Kinase analysis in alcoholic hepatitis identifies p90RSK as a potential mediator of liver fibrogenesis
title_full_unstemmed Kinase analysis in alcoholic hepatitis identifies p90RSK as a potential mediator of liver fibrogenesis
title_sort Kinase analysis in alcoholic hepatitis identifies p90RSK as a potential mediator of liver fibrogenesis
dc.creator.none.fl_str_mv Morales-Ibanez, Oriol
Affò, Silvia
Rodrigo Torres, Daniel
Blaya, Delia
Millán, Cristina
Coll, Mar
Perea, Luis
Odena, Gemma
Knorpp, Thomas
Templin, Markus F
Moreno Sánchez, Montserrat
Altamirano, José
Miquel Morera, Rosa
Arroyo, Vicente
Ginès i Gibert, Pere
Caballería Rovira, Joan
Sancho Bru, Pau
Bataller Alberola, Ramón
author Morales-Ibanez, Oriol
author_facet Morales-Ibanez, Oriol
Affò, Silvia
Rodrigo Torres, Daniel
Blaya, Delia
Millán, Cristina
Coll, Mar
Perea, Luis
Odena, Gemma
Knorpp, Thomas
Templin, Markus F
Moreno Sánchez, Montserrat
Altamirano, José
Miquel Morera, Rosa
Arroyo, Vicente
Ginès i Gibert, Pere
Caballería Rovira, Joan
Sancho Bru, Pau
Bataller Alberola, Ramón
author_role author
author2 Affò, Silvia
Rodrigo Torres, Daniel
Blaya, Delia
Millán, Cristina
Coll, Mar
Perea, Luis
Odena, Gemma
Knorpp, Thomas
Templin, Markus F
Moreno Sánchez, Montserrat
Altamirano, José
Miquel Morera, Rosa
Arroyo, Vicente
Ginès i Gibert, Pere
Caballería Rovira, Joan
Sancho Bru, Pau
Bataller Alberola, Ramón
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Hepatitis
Consum d'alcohol
Hepatitis
Drinking of alcoholic beverages
topic Hepatitis
Consum d'alcohol
Hepatitis
Drinking of alcoholic beverages
description Objective Alcoholic hepatitis (AH) is often associated with advanced fibrosis, which negatively impacts survival. We aimed at identifying kinases deregulated in livers from patients with AH and advanced fibrosis in order to discover novel molecular targets. Design Extensive phosphoprotein analysis by reverse phase protein microarrays was performed in AH (n=12) and normal human livers (n=7). Ribosomal S6 kinase (p90RSK) hepatic expression was assessed by qPCR, Western blot and immunohistochemistry. Kaempferol was used as a selective pharmacological inhibitor of the p90RSK pathway to assess the regulation of experimentally-induced liver fibrosis and injury, using in vivo and in vitro approaches. Results Proteomic analysis identified p90RSK as one of the most deregulated kinases in AH. Hepatic p90RSK gene and protein expression was also upregulated in livers with chronic liver disease. Immunohistochemistry studies showed increased p90RSK staining in areas of active fibrogenesis in cirrhotic livers. Therapeutic administration of kaempferol to carbon tetrachloride-treated mice resulted in decreased hepatic collagen deposition, and expression of profibrogenic and proinflammatory genes, compared to vehicle administration. In addition, kaempferol reduced the extent of hepatocellular injury and degree of apoptosis. In primary hepatic stellate cells, kaempferol and small interfering RNA decreased activation of p90RSK, which in turn regulated key profibrogenic actions. In primary hepatocytes, kaempferol attenuated proapoptotic signalling. Conclusions p90RSK is upregulated in patients with chronic liver disease and mediates liver fibrogenesis in vivo and in vitro. These results suggest that the p90RSK pathway could be a new therapeutic approach for liver diseases characterised by advanced fibrosis.
publishDate 2016
dc.date.none.fl_str_mv 2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/160082
url https://hdl.handle.net/2445/160082
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1136/gutjnl-2014-307979
Gut, 2016, vol. 65, num. 5, p. 1-12
https://doi.org/10.1136/gutjnl-2014-307979
dc.rights.none.fl_str_mv (c) Morales-Ibanez, Oriol et al., 2016
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Morales-Ibanez, Oriol et al., 2016
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv BMJ Publishing Group
publisher.none.fl_str_mv BMJ Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Medicina)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869411606194028544
score 15,300724

Similares en LA Referencia