Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice

Autores
Motiño, Omar; Agra, Noelia; Brea Contreras, Rocío; Domínguez Moreno, Marina; García Monzón, Carmelo; Vargas Castrillón, Javier; Carnovale, Cristina Ester; Boscá, Lisardo; Casado, Marta; Mayoral, Rafael; Valdecantos, M. Pilar; Valverde, Ángela M.; Frances, Daniel Eleazar Antonio; Martin Sanz, Paloma
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Cyclooxygenase-2 (COX-2) is involved in different liver diseases but little is known about the significance of COX-2 in the development and progression of non-alcoholic steatohepatitis (NASH). This study was designed to elucidate the role of COX-2 expression in hepatocytes in the pathogenesis of steatohepatitis and hepatic fibrosis. In the present work, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were either fed methionine-and-choline deficient (MCD) diet to establish an experimental non-alcoholic steatohepatitis (NASH) model or injected with carbon tetrachloride (CCl4) to induce liver fibrosis. In our animal model, hCOX-2-Tg mice fed MCD diet showed lower grades of steatosis, ballooning and inflammation than Wt mice, in part by reduced recruitment and infiltration of hepatic macrophages, with a corresponding decrease in serum levels of pro-inflammatory cytokines. Furthermore, hCOX-2-Tg mice showed a significant attenuation of the MCD diet-induced increase in oxidative stress and hepatic apoptosis observed in Wt mice. Even more, hCOX-2-Tg mice treated with CCl4 had significantly lower stages of fibrosis and less hepatic content of collagen, hydroxyproline and pro-fibrogenic markers than Wt controls. Collectively, our data indicates that constitutive hepatocyte COX-2 expression ameliorates NASH and liver fibrosis development in mice by reducing inflammation, oxidative stress and apoptosis and by modulating activation of hepatic stellate cells, respectively, suggesting a possible protective role for COX-2 induction in NASH/NAFLD progression.
Fil: Motiño, Omar. Consejo Superior de Investigaciones Científicas; España
Fil: Agra, Noelia. Consejo Superior de Investigaciones Científicas; España
Fil: Brea Contreras, Rocío. Consejo Superior de Investigaciones Científicas; España
Fil: Domínguez Moreno, Marina. Consejo Superior de Investigaciones Científicas; España
Fil: García Monzón, Carmelo. Instituto de Investigación Sanitaria Princesa; España
Fil: Vargas Castrillón, Javier. Instituto de Investigación Sanitaria Princesa; España
Fil: Carnovale, Cristina Ester. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Boscá, Lisardo. Consejo Superior de Investigaciones Científicas; España
Fil: Casado, Marta. Instituto de Biomedicina de Valencia; España. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Mayoral, Rafael. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España. University of California at San Diego; Estados Unidos
Fil: Valdecantos, M. Pilar. Consejo Superior de Investigaciones Científicas; España
Fil: Valverde, Ángela M.. Consejo Superior de Investigaciones Científicas; España. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas; España
Fil: Frances, Daniel Eleazar Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Martin Sanz, Paloma. Consejo Superior de Investigaciones Científicas; España. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Materia
Cox-2
Fibrosis
Inflammation
Liver
Steatohepatitis
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/52641
Acceder
id CONICETDig_686800e0828cbd7f47d9ae0e47f2801f
oai_identifier_str oai:ri.conicet.gov.ar:11336/52641
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in miceMotiño, OmarAgra, NoeliaBrea Contreras, RocíoDomínguez Moreno, MarinaGarcía Monzón, CarmeloVargas Castrillón, JavierCarnovale, Cristina EsterBoscá, LisardoCasado, MartaMayoral, RafaelValdecantos, M. PilarValverde, Ángela M.Frances, Daniel Eleazar AntonioMartin Sanz, PalomaCox-2FibrosisInflammationLiverSteatohepatitishttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Cyclooxygenase-2 (COX-2) is involved in different liver diseases but little is known about the significance of COX-2 in the development and progression of non-alcoholic steatohepatitis (NASH). This study was designed to elucidate the role of COX-2 expression in hepatocytes in the pathogenesis of steatohepatitis and hepatic fibrosis. In the present work, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were either fed methionine-and-choline deficient (MCD) diet to establish an experimental non-alcoholic steatohepatitis (NASH) model or injected with carbon tetrachloride (CCl4) to induce liver fibrosis. In our animal model, hCOX-2-Tg mice fed MCD diet showed lower grades of steatosis, ballooning and inflammation than Wt mice, in part by reduced recruitment and infiltration of hepatic macrophages, with a corresponding decrease in serum levels of pro-inflammatory cytokines. Furthermore, hCOX-2-Tg mice showed a significant attenuation of the MCD diet-induced increase in oxidative stress and hepatic apoptosis observed in Wt mice. Even more, hCOX-2-Tg mice treated with CCl4 had significantly lower stages of fibrosis and less hepatic content of collagen, hydroxyproline and pro-fibrogenic markers than Wt controls. Collectively, our data indicates that constitutive hepatocyte COX-2 expression ameliorates NASH and liver fibrosis development in mice by reducing inflammation, oxidative stress and apoptosis and by modulating activation of hepatic stellate cells, respectively, suggesting a possible protective role for COX-2 induction in NASH/NAFLD progression.Fil: Motiño, Omar. Consejo Superior de Investigaciones Científicas; EspañaFil: Agra, Noelia. Consejo Superior de Investigaciones Científicas; EspañaFil: Brea Contreras, Rocío. Consejo Superior de Investigaciones Científicas; EspañaFil: Domínguez Moreno, Marina. Consejo Superior de Investigaciones Científicas; EspañaFil: García Monzón, Carmelo. Instituto de Investigación Sanitaria Princesa; EspañaFil: Vargas Castrillón, Javier. Instituto de Investigación Sanitaria Princesa; EspañaFil: Carnovale, Cristina Ester. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Boscá, Lisardo. Consejo Superior de Investigaciones Científicas; EspañaFil: Casado, Marta. Instituto de Biomedicina de Valencia; España. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; EspañaFil: Mayoral, Rafael. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España. University of California at San Diego; Estados UnidosFil: Valdecantos, M. Pilar. Consejo Superior de Investigaciones Científicas; EspañaFil: Valverde, Ángela M.. Consejo Superior de Investigaciones Científicas; España. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas; EspañaFil: Frances, Daniel Eleazar Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Martin Sanz, Paloma. Consejo Superior de Investigaciones Científicas; España. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; EspañaElsevier Science2016-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/52641Motiño, Omar; Agra, Noelia; Brea Contreras, Rocío; Domínguez Moreno, Marina; García Monzón, Carmelo; et al.; Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice; Elsevier Science; Biochimica et Biophysica Acta - Molecular Basis of Disease; 1862; 9; 9-2016; 1710-17230925-4439CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.bbadis.2016.06.009info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S092544391630151Xinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:29:14Zoai:ri.conicet.gov.ar:11336/52641instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:29:14.884CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice
title Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice
spellingShingle Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice
Motiño, Omar
Cox-2
Fibrosis
Inflammation
Liver
Steatohepatitis
title_short Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice
title_full Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice
title_fullStr Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice
title_full_unstemmed Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice
title_sort Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice
dc.creator.none.fl_str_mv Motiño, Omar
Agra, Noelia
Brea Contreras, Rocío
Domínguez Moreno, Marina
García Monzón, Carmelo
Vargas Castrillón, Javier
Carnovale, Cristina Ester
Boscá, Lisardo
Casado, Marta
Mayoral, Rafael
Valdecantos, M. Pilar
Valverde, Ángela M.
Frances, Daniel Eleazar Antonio
Martin Sanz, Paloma
author Motiño, Omar
author_facet Motiño, Omar
Agra, Noelia
Brea Contreras, Rocío
Domínguez Moreno, Marina
García Monzón, Carmelo
Vargas Castrillón, Javier
Carnovale, Cristina Ester
Boscá, Lisardo
Casado, Marta
Mayoral, Rafael
Valdecantos, M. Pilar
Valverde, Ángela M.
Frances, Daniel Eleazar Antonio
Martin Sanz, Paloma
author_role author
author2 Agra, Noelia
Brea Contreras, Rocío
Domínguez Moreno, Marina
García Monzón, Carmelo
Vargas Castrillón, Javier
Carnovale, Cristina Ester
Boscá, Lisardo
Casado, Marta
Mayoral, Rafael
Valdecantos, M. Pilar
Valverde, Ángela M.
Frances, Daniel Eleazar Antonio
Martin Sanz, Paloma
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cox-2
Fibrosis
Inflammation
Liver
Steatohepatitis
topic Cox-2
Fibrosis
Inflammation
Liver
Steatohepatitis
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Cyclooxygenase-2 (COX-2) is involved in different liver diseases but little is known about the significance of COX-2 in the development and progression of non-alcoholic steatohepatitis (NASH). This study was designed to elucidate the role of COX-2 expression in hepatocytes in the pathogenesis of steatohepatitis and hepatic fibrosis. In the present work, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were either fed methionine-and-choline deficient (MCD) diet to establish an experimental non-alcoholic steatohepatitis (NASH) model or injected with carbon tetrachloride (CCl4) to induce liver fibrosis. In our animal model, hCOX-2-Tg mice fed MCD diet showed lower grades of steatosis, ballooning and inflammation than Wt mice, in part by reduced recruitment and infiltration of hepatic macrophages, with a corresponding decrease in serum levels of pro-inflammatory cytokines. Furthermore, hCOX-2-Tg mice showed a significant attenuation of the MCD diet-induced increase in oxidative stress and hepatic apoptosis observed in Wt mice. Even more, hCOX-2-Tg mice treated with CCl4 had significantly lower stages of fibrosis and less hepatic content of collagen, hydroxyproline and pro-fibrogenic markers than Wt controls. Collectively, our data indicates that constitutive hepatocyte COX-2 expression ameliorates NASH and liver fibrosis development in mice by reducing inflammation, oxidative stress and apoptosis and by modulating activation of hepatic stellate cells, respectively, suggesting a possible protective role for COX-2 induction in NASH/NAFLD progression.
Fil: Motiño, Omar. Consejo Superior de Investigaciones Científicas; España
Fil: Agra, Noelia. Consejo Superior de Investigaciones Científicas; España
Fil: Brea Contreras, Rocío. Consejo Superior de Investigaciones Científicas; España
Fil: Domínguez Moreno, Marina. Consejo Superior de Investigaciones Científicas; España
Fil: García Monzón, Carmelo. Instituto de Investigación Sanitaria Princesa; España
Fil: Vargas Castrillón, Javier. Instituto de Investigación Sanitaria Princesa; España
Fil: Carnovale, Cristina Ester. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Boscá, Lisardo. Consejo Superior de Investigaciones Científicas; España
Fil: Casado, Marta. Instituto de Biomedicina de Valencia; España. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Mayoral, Rafael. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España. University of California at San Diego; Estados Unidos
Fil: Valdecantos, M. Pilar. Consejo Superior de Investigaciones Científicas; España
Fil: Valverde, Ángela M.. Consejo Superior de Investigaciones Científicas; España. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas; España
Fil: Frances, Daniel Eleazar Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Martin Sanz, Paloma. Consejo Superior de Investigaciones Científicas; España. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
description Cyclooxygenase-2 (COX-2) is involved in different liver diseases but little is known about the significance of COX-2 in the development and progression of non-alcoholic steatohepatitis (NASH). This study was designed to elucidate the role of COX-2 expression in hepatocytes in the pathogenesis of steatohepatitis and hepatic fibrosis. In the present work, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were either fed methionine-and-choline deficient (MCD) diet to establish an experimental non-alcoholic steatohepatitis (NASH) model or injected with carbon tetrachloride (CCl4) to induce liver fibrosis. In our animal model, hCOX-2-Tg mice fed MCD diet showed lower grades of steatosis, ballooning and inflammation than Wt mice, in part by reduced recruitment and infiltration of hepatic macrophages, with a corresponding decrease in serum levels of pro-inflammatory cytokines. Furthermore, hCOX-2-Tg mice showed a significant attenuation of the MCD diet-induced increase in oxidative stress and hepatic apoptosis observed in Wt mice. Even more, hCOX-2-Tg mice treated with CCl4 had significantly lower stages of fibrosis and less hepatic content of collagen, hydroxyproline and pro-fibrogenic markers than Wt controls. Collectively, our data indicates that constitutive hepatocyte COX-2 expression ameliorates NASH and liver fibrosis development in mice by reducing inflammation, oxidative stress and apoptosis and by modulating activation of hepatic stellate cells, respectively, suggesting a possible protective role for COX-2 induction in NASH/NAFLD progression.
publishDate 2016
dc.date.none.fl_str_mv 2016-09
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/52641
Motiño, Omar; Agra, Noelia; Brea Contreras, Rocío; Domínguez Moreno, Marina; García Monzón, Carmelo; et al.; Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice; Elsevier Science; Biochimica et Biophysica Acta - Molecular Basis of Disease; 1862; 9; 9-2016; 1710-1723
0925-4439
CONICET Digital
CONICET
url http://hdl.handle.net/11336/52641
identifier_str_mv Motiño, Omar; Agra, Noelia; Brea Contreras, Rocío; Domínguez Moreno, Marina; García Monzón, Carmelo; et al.; Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice; Elsevier Science; Biochimica et Biophysica Acta - Molecular Basis of Disease; 1862; 9; 9-2016; 1710-1723
0925-4439
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bbadis.2016.06.009
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S092544391630151X
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier Science
publisher.none.fl_str_mv Elsevier Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.22299

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