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dc.contributor.authorRomualdo, Guilherme Ribeiro [UNESP]
dc.contributor.authorDa Silva, Tereza Cristina
dc.contributor.authorde Albuquerque Landi, Marina Frota
dc.contributor.authorMorais, Juliana Ávila
dc.contributor.authorBarbisan, Luis Fernando [UNESP]
dc.contributor.authorVinken, Mathieu
dc.contributor.authorOliveira, Cláudia Pinto
dc.contributor.authorCogliati, Bruno
dc.identifier.citationEnvironmental Toxicology.
dc.description.abstractNon-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.en
dc.relation.ispartofEnvironmental Toxicology
dc.subjectantifibrotic therapy
dc.subjectfatty hepatocytes
dc.subjecthepatic stellate cells
dc.subjectnon-alcoholic steatohepatitis
dc.subjecttridimensional cell culture
dc.titleSorafenib reduces steatosis-induced fibrogenesis in a human 3D co-culture model of non-alcoholic fatty liver diseaseen
dc.contributor.institutionUniversidade Estadual Paulista (UNESP)
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionVrije Universiteit Brussel
dc.description.affiliationDepartment of Structural and Functional Biology Biosciences Institute São Paulo State University (UNESP)
dc.description.affiliationDepartment of Pathology School of Veterinary Medicine and Animal Science University of São Paulo (USP)
dc.description.affiliationDepartment of in vitro Toxicology and Dermato-Cosmetology Faculty of Medicine and Pharmacy Vrije Universiteit Brussel
dc.description.affiliationDepartment of Gastroenterology (LIM07) School of Medicine University of São Paulo (USP)
dc.description.affiliationUnespDepartment of Structural and Functional Biology Biosciences Institute São Paulo State University (UNESP)
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