Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice

Autores
Atorrasagasti, Maria Catalina; Peixoto, Estanislao; Aquino, Jorge Benjamin; Kippes, Néstor Fabián; Malvicini, Mariana; Alaniz, Laura Daniela; Garcia, Mariana Gabriela; Piccioni, Flavia Valeria; Fiore, Esteban Juan; Bayo, Juan; Bataller, Ramón; Guruceaga, Elizabeth; Corrales, Fernando; Podhajcer, Osvaldo Luis; Mazzolini Rizzo, Guillermo Daniel
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Introduction Secreted Protein, Acidic and Rich in Cysteine (SPARC) is a matricellular protein involved in many biological processes and found over-expressed in cirrhotic livers. By mean of a genetic approach we herein provide evidence from different in vivo liver disease models suggesting a profibrogenic role for SPARC. Methods Two in vivo models of liver fibrosis, based on TAA administration and bile duct ligation, were developed on SPARC wild-type (SPARC+/+) and knock-out (SPARC−/−) mice. Hepatic SPARC expression was analyzed by qPCR. Fibrosis was assessed by Sirius Red staining, and the maturation state of collagen fibers was analyzed using polarized light. Necroinflammatory activity was evaluated by applying the Knodell score and liver inflammatory infiltration was characterized by immunohistochemistry. Hepatic stellate cell activation was assessed by α-SMA immunohistochemistry. In addition, pro-fibrogenic genes and inflammatory cytokines were measured by qPCR and/or ELISA. Liver gene expression profile was analyzed in SPARC−/− and SPARC+/+ mice using Affymetrix Mouse Gene ST 1.0 array. Results SPARC expression was found induced in fibrotic livers of mouse and human. SPARC−/− mice showed a reduction in the degree of inflammation, mainly CD4+ cells, and fibrosis. Consistently, collagen deposits and mRNA expression levels were decreased in SPARC−/− mice when compared to SPARC+/+ mice; in addition, MMP-2 expression was increased in SPARC−/− mice. A reduction in the number of activated myofibroblasts was observed. Moreover, TGF-β1 expression levels were down-regulated in the liver as well as in the serum of TAA-treated knock-out animals. Ingenuity Pathway Analysis (IPA) analysis suggested several gene networks which might involve protective mechanisms of SPARC deficiency against liver fibrogenesis and a better established machinery to repair DNA and detoxify from external chemical stimuli. Conclusions Overall our data suggest that SPARC plays a significant role in liver fibrogenesis. Interventions to inhibit SPARC expression are suggested as promising approaches for liver fibrosis treatment.
Fil: Atorrasagasti, Maria Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Peixoto, Estanislao. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Aquino, Jorge Benjamin. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Kippes, Néstor Fabián. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Alaniz, Laura Daniela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Garcia, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Piccioni, Flavia Valeria. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Fiore, Esteban Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Bayo, Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Bataller, Ramón. University of North Carolina. Department of Medicine and Nutrition; Estados Unidos
Fil: Guruceaga, Elizabeth. Universidad de Navarra. Centro de Investigación Médica Aplicada; España
Fil: Corrales, Fernando. Universidad de Navarra. Centro de Investigación Médica Aplicada; España
Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina
Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
SPARC
Collagen
TGFB1
Inflammation
Liver chirrosis
Microarray
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/4039
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/4039
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network_name_str CONICET Digital (CONICET)
spelling Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in MiceAtorrasagasti, Maria CatalinaPeixoto, EstanislaoAquino, Jorge BenjaminKippes, Néstor FabiánMalvicini, MarianaAlaniz, Laura DanielaGarcia, Mariana GabrielaPiccioni, Flavia ValeriaFiore, Esteban JuanBayo, JuanBataller, RamónGuruceaga, ElizabethCorrales, FernandoPodhajcer, Osvaldo LuisMazzolini Rizzo, Guillermo DanielSPARCCollagenTGFB1InflammationLiver chirrosisMicroarrayhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Introduction Secreted Protein, Acidic and Rich in Cysteine (SPARC) is a matricellular protein involved in many biological processes and found over-expressed in cirrhotic livers. By mean of a genetic approach we herein provide evidence from different in vivo liver disease models suggesting a profibrogenic role for SPARC. Methods Two in vivo models of liver fibrosis, based on TAA administration and bile duct ligation, were developed on SPARC wild-type (SPARC+/+) and knock-out (SPARC−/−) mice. Hepatic SPARC expression was analyzed by qPCR. Fibrosis was assessed by Sirius Red staining, and the maturation state of collagen fibers was analyzed using polarized light. Necroinflammatory activity was evaluated by applying the Knodell score and liver inflammatory infiltration was characterized by immunohistochemistry. Hepatic stellate cell activation was assessed by α-SMA immunohistochemistry. In addition, pro-fibrogenic genes and inflammatory cytokines were measured by qPCR and/or ELISA. Liver gene expression profile was analyzed in SPARC−/− and SPARC+/+ mice using Affymetrix Mouse Gene ST 1.0 array. Results SPARC expression was found induced in fibrotic livers of mouse and human. SPARC−/− mice showed a reduction in the degree of inflammation, mainly CD4+ cells, and fibrosis. Consistently, collagen deposits and mRNA expression levels were decreased in SPARC−/− mice when compared to SPARC+/+ mice; in addition, MMP-2 expression was increased in SPARC−/− mice. A reduction in the number of activated myofibroblasts was observed. Moreover, TGF-β1 expression levels were down-regulated in the liver as well as in the serum of TAA-treated knock-out animals. Ingenuity Pathway Analysis (IPA) analysis suggested several gene networks which might involve protective mechanisms of SPARC deficiency against liver fibrogenesis and a better established machinery to repair DNA and detoxify from external chemical stimuli. Conclusions Overall our data suggest that SPARC plays a significant role in liver fibrogenesis. Interventions to inhibit SPARC expression are suggested as promising approaches for liver fibrosis treatment.Fil: Atorrasagasti, Maria Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; ArgentinaFil: Peixoto, Estanislao. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; ArgentinaFil: Aquino, Jorge Benjamin. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Kippes, Néstor Fabián. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; ArgentinaFil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; ArgentinaFil: Alaniz, Laura Daniela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garcia, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Piccioni, Flavia Valeria. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; ArgentinaFil: Fiore, Esteban Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; ArgentinaFil: Bayo, Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; ArgentinaFil: Bataller, Ramón. University of North Carolina. Department of Medicine and Nutrition; Estados UnidosFil: Guruceaga, Elizabeth. Universidad de Navarra. Centro de Investigación Médica Aplicada; EspañaFil: Corrales, Fernando. Universidad de Navarra. Centro de Investigación Médica Aplicada; EspañaFil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaPublic Library of Science2013-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/4039Atorrasagasti, Maria Catalina; Peixoto, Estanislao; Aquino, Jorge Benjamin; Kippes, Néstor Fabián; Malvicini, Mariana; et al.; Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice; Public Library of Science; Plos One; 8; 2; 2-2013; e54962-e549621932-6203enginfo:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054962info:eu-repo/semantics/altIdentifier/url/http://dx.doi.org/10.1371%2Fjournal.pone.0054962info:eu-repo/semantics/altIdentifier/doi/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:24:43Zoai:ri.conicet.gov.ar:11336/4039instacron: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:34982025-10-22 11:24:43.609CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice
title Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice
spellingShingle Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice
Atorrasagasti, Maria Catalina
SPARC
Collagen
TGFB1
Inflammation
Liver chirrosis
Microarray
title_short Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice
title_full Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice
title_fullStr Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice
title_full_unstemmed Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice
title_sort Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice
dc.creator.none.fl_str_mv Atorrasagasti, Maria Catalina
Peixoto, Estanislao
Aquino, Jorge Benjamin
Kippes, Néstor Fabián
Malvicini, Mariana
Alaniz, Laura Daniela
Garcia, Mariana Gabriela
Piccioni, Flavia Valeria
Fiore, Esteban Juan
Bayo, Juan
Bataller, Ramón
Guruceaga, Elizabeth
Corrales, Fernando
Podhajcer, Osvaldo Luis
Mazzolini Rizzo, Guillermo Daniel
author Atorrasagasti, Maria Catalina
author_facet Atorrasagasti, Maria Catalina
Peixoto, Estanislao
Aquino, Jorge Benjamin
Kippes, Néstor Fabián
Malvicini, Mariana
Alaniz, Laura Daniela
Garcia, Mariana Gabriela
Piccioni, Flavia Valeria
Fiore, Esteban Juan
Bayo, Juan
Bataller, Ramón
Guruceaga, Elizabeth
Corrales, Fernando
Podhajcer, Osvaldo Luis
Mazzolini Rizzo, Guillermo Daniel
author_role author
author2 Peixoto, Estanislao
Aquino, Jorge Benjamin
Kippes, Néstor Fabián
Malvicini, Mariana
Alaniz, Laura Daniela
Garcia, Mariana Gabriela
Piccioni, Flavia Valeria
Fiore, Esteban Juan
Bayo, Juan
Bataller, Ramón
Guruceaga, Elizabeth
Corrales, Fernando
Podhajcer, Osvaldo Luis
Mazzolini Rizzo, Guillermo Daniel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv SPARC
Collagen
TGFB1
Inflammation
Liver chirrosis
Microarray
topic SPARC
Collagen
TGFB1
Inflammation
Liver chirrosis
Microarray
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Introduction Secreted Protein, Acidic and Rich in Cysteine (SPARC) is a matricellular protein involved in many biological processes and found over-expressed in cirrhotic livers. By mean of a genetic approach we herein provide evidence from different in vivo liver disease models suggesting a profibrogenic role for SPARC. Methods Two in vivo models of liver fibrosis, based on TAA administration and bile duct ligation, were developed on SPARC wild-type (SPARC+/+) and knock-out (SPARC−/−) mice. Hepatic SPARC expression was analyzed by qPCR. Fibrosis was assessed by Sirius Red staining, and the maturation state of collagen fibers was analyzed using polarized light. Necroinflammatory activity was evaluated by applying the Knodell score and liver inflammatory infiltration was characterized by immunohistochemistry. Hepatic stellate cell activation was assessed by α-SMA immunohistochemistry. In addition, pro-fibrogenic genes and inflammatory cytokines were measured by qPCR and/or ELISA. Liver gene expression profile was analyzed in SPARC−/− and SPARC+/+ mice using Affymetrix Mouse Gene ST 1.0 array. Results SPARC expression was found induced in fibrotic livers of mouse and human. SPARC−/− mice showed a reduction in the degree of inflammation, mainly CD4+ cells, and fibrosis. Consistently, collagen deposits and mRNA expression levels were decreased in SPARC−/− mice when compared to SPARC+/+ mice; in addition, MMP-2 expression was increased in SPARC−/− mice. A reduction in the number of activated myofibroblasts was observed. Moreover, TGF-β1 expression levels were down-regulated in the liver as well as in the serum of TAA-treated knock-out animals. Ingenuity Pathway Analysis (IPA) analysis suggested several gene networks which might involve protective mechanisms of SPARC deficiency against liver fibrogenesis and a better established machinery to repair DNA and detoxify from external chemical stimuli. Conclusions Overall our data suggest that SPARC plays a significant role in liver fibrogenesis. Interventions to inhibit SPARC expression are suggested as promising approaches for liver fibrosis treatment.
Fil: Atorrasagasti, Maria Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Peixoto, Estanislao. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Aquino, Jorge Benjamin. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Kippes, Néstor Fabián. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Alaniz, Laura Daniela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Garcia, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Piccioni, Flavia Valeria. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Fiore, Esteban Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Bayo, Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Bataller, Ramón. University of North Carolina. Department of Medicine and Nutrition; Estados Unidos
Fil: Guruceaga, Elizabeth. Universidad de Navarra. Centro de Investigación Médica Aplicada; España
Fil: Corrales, Fernando. Universidad de Navarra. Centro de Investigación Médica Aplicada; España
Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina
Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description Introduction Secreted Protein, Acidic and Rich in Cysteine (SPARC) is a matricellular protein involved in many biological processes and found over-expressed in cirrhotic livers. By mean of a genetic approach we herein provide evidence from different in vivo liver disease models suggesting a profibrogenic role for SPARC. Methods Two in vivo models of liver fibrosis, based on TAA administration and bile duct ligation, were developed on SPARC wild-type (SPARC+/+) and knock-out (SPARC−/−) mice. Hepatic SPARC expression was analyzed by qPCR. Fibrosis was assessed by Sirius Red staining, and the maturation state of collagen fibers was analyzed using polarized light. Necroinflammatory activity was evaluated by applying the Knodell score and liver inflammatory infiltration was characterized by immunohistochemistry. Hepatic stellate cell activation was assessed by α-SMA immunohistochemistry. In addition, pro-fibrogenic genes and inflammatory cytokines were measured by qPCR and/or ELISA. Liver gene expression profile was analyzed in SPARC−/− and SPARC+/+ mice using Affymetrix Mouse Gene ST 1.0 array. Results SPARC expression was found induced in fibrotic livers of mouse and human. SPARC−/− mice showed a reduction in the degree of inflammation, mainly CD4+ cells, and fibrosis. Consistently, collagen deposits and mRNA expression levels were decreased in SPARC−/− mice when compared to SPARC+/+ mice; in addition, MMP-2 expression was increased in SPARC−/− mice. A reduction in the number of activated myofibroblasts was observed. Moreover, TGF-β1 expression levels were down-regulated in the liver as well as in the serum of TAA-treated knock-out animals. Ingenuity Pathway Analysis (IPA) analysis suggested several gene networks which might involve protective mechanisms of SPARC deficiency against liver fibrogenesis and a better established machinery to repair DNA and detoxify from external chemical stimuli. Conclusions Overall our data suggest that SPARC plays a significant role in liver fibrogenesis. Interventions to inhibit SPARC expression are suggested as promising approaches for liver fibrosis treatment.
publishDate 2013
dc.date.none.fl_str_mv 2013-02
dc.type.none.fl_str_mv info:eu-repo/semantics/article
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info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/4039
Atorrasagasti, Maria Catalina; Peixoto, Estanislao; Aquino, Jorge Benjamin; Kippes, Néstor Fabián; Malvicini, Mariana; et al.; Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice; Public Library of Science; Plos One; 8; 2; 2-2013; e54962-e54962
1932-6203
url http://hdl.handle.net/11336/4039
identifier_str_mv Atorrasagasti, Maria Catalina; Peixoto, Estanislao; Aquino, Jorge Benjamin; Kippes, Néstor Fabián; Malvicini, Mariana; et al.; Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice; Public Library of Science; Plos One; 8; 2; 2-2013; e54962-e54962
1932-6203
dc.language.none.fl_str_mv eng
language eng
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publisher.none.fl_str_mv Public Library of Science
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reponame_str CONICET Digital (CONICET)
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