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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Sorafenib reduces steatosis-induced fibrogenesis in a human3Dco-culture model of non-alcoholic fatty liver disease

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Author(s):
Romualdo, Guilherme Ribeiro [1] ; Da Silva, Tereza Cristina [2] ; de Albuquerque Landi, Marina Frota [2] ; Morais, Juliana Avila [2] ; Barbisan, Luis Fernando [1] ; Vinken, Mathieu [3] ; Oliveira, Claudia Pinto [4] ; Cogliati, Bruno [2]
Total Authors: 8
Affiliation:
[1] Sao Paulo State Univ UNESP, Biosci Inst, Dept Struct & Funct Biol, Botucatu, SP - Brazil
[2] Univ Sao Paulo, Sch Vet Med & Anim Sci, Dept Pathol, Ave Prof Dr Orlando Marques de Paiva 87, Sao Paulo - Brazil
[3] Vrije Univ Brussel, Fac Med & Pharm, Dept Vitro Toxicol & Dermatocosmetol, Brussels - Belgium
[4] Univ Sao Paulo, Sch Med, Dept Gastroenterol LIM07, Sao Paulo - Brazil
Total Affiliations: 4
Document type: Journal article
Source: ENVIRONMENTAL TOXICOLOGY; v. 36, n. 2 SEP 2020.
Web of Science Citations: 0
Abstract

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 mu M) for 72 hours reduced fatty spheroid viability, and upregulated the expression of lipid oxidation- and hydrolysis-related genes,CPT1andLIPC, respectively. Sorafenib also inhibited steatosis-induced fibrogenesis by downregulatingCOL1A1,TGFB1,PDGF, andTIMP1and by decreasing protein levels of IL-6, TGF-beta 1, and TNF-alpha 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. (AU)

FAPESP's process: 12/17084-0 - Molecular aspects of cellular spheroids in an in vitro 3D model of nonalcoholic fatty liver disease (NAFLD)
Grantee:Juliana Ávila Morais
Support type: Scholarships in Brazil - Scientific Initiation
FAPESP's process: 11/18954-5 - 3D co-culture of fatty hepatocytes and stellate cells: evaluation of fibrogenesis induced by steatosis in a new in vitro model of nonalcoholic fatty liver disease
Grantee:Bruno Cogliati
Support type: Regular Research Grants
FAPESP's process: 11/18461-9 - Morphologic and ultrastructural evaluation of cellular spheroids in an in vitro 3D model of nonalcoholic fatty liver disease
Grantee:Marina Frota de Albuquerque Landi
Support type: Scholarships in Brazil - Scientific Initiation