Sorafenib reduces steatosis-induced fibrogenesis in a human 3D co-culture model of non-alcoholic fatty liver disease
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1002/tox.23021 http://hdl.handle.net/11449/202093 |
Resumo: | Non-alcoholic fatty liver disease (NAFLD) affects around 25% of the worldwide population. Non-alcoholic steatohepatitis (NASH), the more progressive variant of NAFLD, is characterized by steatosis, cellular ballooning, lobular inflammation, and may culminate on hepatic stellate cell (HSC) activation, thus increasing the risk for fibrosis, cirrhosis, and HCC development. Conversely, the antifibrotic effects of sorafenib, an FDA-approved drug for HCC treatment, have been demonstrated in 2D cell cultures and animal models, but its mechanisms in a NAFLD-related microenvironment in vitro requires further investigation. Thus, a human 3D co-culture model of fatty hepatocytes and HSC was established by culturing hepatoma C3A cells, pre-treated with 1.32 mM oleic acid, with HSC LX-2 cells. The fatty C3A/LX-2 spheroids showed morphological and molecular hallmarks of altered lipid metabolism and steatosis-induced fibrogenesis, similarly to the human disease. Sorafenib (15 μM) for 72 hours reduced fatty spheroid viability, and upregulated the expression of lipid oxidation- and hydrolysis-related genes, CPT1 and LIPC, respectively. Sorafenib also inhibited steatosis-induced fibrogenesis by downregulating COL1A1, TGFB1, PDGF, and TIMP1 and by decreasing protein levels of IL-6, TGF-β1, and TNF-α in fatty spheroids. The demonstration of the antifibrotic properties of sorafenib on steatosis-induced fibrogenesis in a 3D in vitro model of NAFLD supports its clinical use as a therapeutic agent for the treatment of NAFLD/NASH patients. |
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Sorafenib reduces steatosis-induced fibrogenesis in a human 3D co-culture model of non-alcoholic fatty liver diseaseantifibrotic therapyfatty hepatocyteshepatic stellate cellsnon-alcoholic steatohepatitistridimensional cell cultureNon-alcoholic fatty liver disease (NAFLD) affects around 25% of the worldwide population. Non-alcoholic steatohepatitis (NASH), the more progressive variant of NAFLD, is characterized by steatosis, cellular ballooning, lobular inflammation, and may culminate on hepatic stellate cell (HSC) activation, thus increasing the risk for fibrosis, cirrhosis, and HCC development. Conversely, the antifibrotic effects of sorafenib, an FDA-approved drug for HCC treatment, have been demonstrated in 2D cell cultures and animal models, but its mechanisms in a NAFLD-related microenvironment in vitro requires further investigation. Thus, a human 3D co-culture model of fatty hepatocytes and HSC was established by culturing hepatoma C3A cells, pre-treated with 1.32 mM oleic acid, with HSC LX-2 cells. The fatty C3A/LX-2 spheroids showed morphological and molecular hallmarks of altered lipid metabolism and steatosis-induced fibrogenesis, similarly to the human disease. Sorafenib (15 μM) for 72 hours reduced fatty spheroid viability, and upregulated the expression of lipid oxidation- and hydrolysis-related genes, CPT1 and LIPC, respectively. Sorafenib also inhibited steatosis-induced fibrogenesis by downregulating COL1A1, TGFB1, PDGF, and TIMP1 and by decreasing protein levels of IL-6, TGF-β1, and TNF-α in fatty spheroids. The demonstration of the antifibrotic properties of sorafenib on steatosis-induced fibrogenesis in a 3D in vitro model of NAFLD supports its clinical use as a therapeutic agent for the treatment of NAFLD/NASH patients.Department of Structural and Functional Biology Biosciences Institute São Paulo State University (UNESP)Department of Pathology School of Veterinary Medicine and Animal Science University of São Paulo (USP)Department of in vitro Toxicology and Dermato-Cosmetology Faculty of Medicine and Pharmacy Vrije Universiteit BrusselDepartment of Gastroenterology (LIM07) School of Medicine University of São Paulo (USP)Department of Structural and Functional Biology Biosciences Institute São Paulo State University (UNESP)Universidade Estadual Paulista (Unesp)Universidade de São Paulo (USP)Vrije Universiteit BrusselRomualdo, Guilherme Ribeiro [UNESP]Da Silva, Tereza Cristinade Albuquerque Landi, Marina FrotaMorais, Juliana ÁvilaBarbisan, Luis Fernando [UNESP]Vinken, MathieuOliveira, Cláudia PintoCogliati, Bruno2020-12-12T02:49:36Z2020-12-12T02:49:36Z2020-01-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1002/tox.23021Environmental Toxicology.1522-72781520-4081http://hdl.handle.net/11449/20209310.1002/tox.230212-s2.0-85090757688Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengEnvironmental Toxicologyinfo:eu-repo/semantics/openAccess2021-10-23T05:43:27Zoai:repositorio.unesp.br:11449/202093Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462021-10-23T05:43:27Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Sorafenib reduces steatosis-induced fibrogenesis in a human 3D co-culture model of non-alcoholic fatty liver disease |
title |
Sorafenib reduces steatosis-induced fibrogenesis in a human 3D co-culture model of non-alcoholic fatty liver disease |
spellingShingle |
Sorafenib reduces steatosis-induced fibrogenesis in a human 3D co-culture model of non-alcoholic fatty liver disease Romualdo, Guilherme Ribeiro [UNESP] antifibrotic therapy fatty hepatocytes hepatic stellate cells non-alcoholic steatohepatitis tridimensional cell culture |
title_short |
Sorafenib reduces steatosis-induced fibrogenesis in a human 3D co-culture model of non-alcoholic fatty liver disease |
title_full |
Sorafenib reduces steatosis-induced fibrogenesis in a human 3D co-culture model of non-alcoholic fatty liver disease |
title_fullStr |
Sorafenib reduces steatosis-induced fibrogenesis in a human 3D co-culture model of non-alcoholic fatty liver disease |
title_full_unstemmed |
Sorafenib reduces steatosis-induced fibrogenesis in a human 3D co-culture model of non-alcoholic fatty liver disease |
title_sort |
Sorafenib reduces steatosis-induced fibrogenesis in a human 3D co-culture model of non-alcoholic fatty liver disease |
author |
Romualdo, Guilherme Ribeiro [UNESP] |
author_facet |
Romualdo, Guilherme Ribeiro [UNESP] Da Silva, Tereza Cristina de Albuquerque Landi, Marina Frota Morais, Juliana Ávila Barbisan, Luis Fernando [UNESP] Vinken, Mathieu Oliveira, Cláudia Pinto Cogliati, Bruno |
author_role |
author |
author2 |
Da Silva, Tereza Cristina de Albuquerque Landi, Marina Frota Morais, Juliana Ávila Barbisan, Luis Fernando [UNESP] Vinken, Mathieu Oliveira, Cláudia Pinto Cogliati, Bruno |
author2_role |
author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (Unesp) Universidade de São Paulo (USP) Vrije Universiteit Brussel |
dc.contributor.author.fl_str_mv |
Romualdo, Guilherme Ribeiro [UNESP] Da Silva, Tereza Cristina de Albuquerque Landi, Marina Frota Morais, Juliana Ávila Barbisan, Luis Fernando [UNESP] Vinken, Mathieu Oliveira, Cláudia Pinto Cogliati, Bruno |
dc.subject.por.fl_str_mv |
antifibrotic therapy fatty hepatocytes hepatic stellate cells non-alcoholic steatohepatitis tridimensional cell culture |
topic |
antifibrotic therapy fatty hepatocytes hepatic stellate cells non-alcoholic steatohepatitis tridimensional cell culture |
description |
Non-alcoholic fatty liver disease (NAFLD) affects around 25% of the worldwide population. Non-alcoholic steatohepatitis (NASH), the more progressive variant of NAFLD, is characterized by steatosis, cellular ballooning, lobular inflammation, and may culminate on hepatic stellate cell (HSC) activation, thus increasing the risk for fibrosis, cirrhosis, and HCC development. Conversely, the antifibrotic effects of sorafenib, an FDA-approved drug for HCC treatment, have been demonstrated in 2D cell cultures and animal models, but its mechanisms in a NAFLD-related microenvironment in vitro requires further investigation. Thus, a human 3D co-culture model of fatty hepatocytes and HSC was established by culturing hepatoma C3A cells, pre-treated with 1.32 mM oleic acid, with HSC LX-2 cells. The fatty C3A/LX-2 spheroids showed morphological and molecular hallmarks of altered lipid metabolism and steatosis-induced fibrogenesis, similarly to the human disease. Sorafenib (15 μM) for 72 hours reduced fatty spheroid viability, and upregulated the expression of lipid oxidation- and hydrolysis-related genes, CPT1 and LIPC, respectively. Sorafenib also inhibited steatosis-induced fibrogenesis by downregulating COL1A1, TGFB1, PDGF, and TIMP1 and by decreasing protein levels of IL-6, TGF-β1, and TNF-α in fatty spheroids. The demonstration of the antifibrotic properties of sorafenib on steatosis-induced fibrogenesis in a 3D in vitro model of NAFLD supports its clinical use as a therapeutic agent for the treatment of NAFLD/NASH patients. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-12-12T02:49:36Z 2020-12-12T02:49:36Z 2020-01-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1002/tox.23021 Environmental Toxicology. 1522-7278 1520-4081 http://hdl.handle.net/11449/202093 10.1002/tox.23021 2-s2.0-85090757688 |
url |
http://dx.doi.org/10.1002/tox.23021 http://hdl.handle.net/11449/202093 |
identifier_str_mv |
Environmental Toxicology. 1522-7278 1520-4081 10.1002/tox.23021 2-s2.0-85090757688 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Environmental Toxicology |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
_version_ |
1803649661989289984 |