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...

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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:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat: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
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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 Group2020202020162020info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion12 p.application/pdfhttps://hdl.handle.net/2445/160082Articles publicats en revistes (Medicina)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió 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:recercat.cat:2445/1600822026-05-29T05:05:01Z
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
2020
2020
2020
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 12 p.
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:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.81155

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