A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer

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art_TSUCHIDA_A_simple_diet_and_chemicalinduced_murine_NASH_model_2018.PDF (4.12 MB)
Citações na Scopus
313
Tipo de produção
article
Data de publicação
2018
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
ELSEVIER SCIENCE BV
Autores
TSUCHIDA, Takuma
LEE, Youngmin A.
FUJIWARA, Naoto
YBANEZ, Maria
ALLEN, Brittany
FIEL, M. Isabel
GOOSSENS, Nicolas
CHOU, Hsin-I.
HOSHIDA, Yujin
Citação
JOURNAL OF HEPATOLOGY, v.69, n.2, p.385-395, 2018
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Background and Aims: Although the majority of patients with non-alcoholic fatty liver disease (NAFLD) have only steatosis without progression, a sizeable fraction develop non-alcoholic steatohepatitis (NASH), which can lead to cirrhosis and hepatocellular carcinoma (HCC). Many established diet-induced mouse models for NASH require 24-52 weeks, which makes testing for drug response costly and time consuming. Methods: We have sought to establish a murine NASH model with rapid progression of extensive fibrosis and HCC by using a western diet (WD), which is high-fat, high-fructose and highcholesterol, combined with low weekly dose of intraperitoneal carbon tetrachloride (CCl4), which serves as an accelerator. Results: C57BL/6J mice were fed a normal chow diet +/- CCl4 or WD +/- CCl4 for 12 and 24 weeks. Addition of CCl4 exacerbated histological features of NASH, fibrosis, and tumor development induced by WD, which resulted in stage 3 fibrosis at 12 weeks and HCC development at 24 weeks. Furthermore, whole liver transcriptomic analysis indicated that dysregulated molecular pathways in WD/CCl4 mice and immunologic features were similar to those of human NASH. Conclusions: Our mouse NASH model exhibits rapid progression of advanced fibrosis and HCC, and mimics histological, immunological and transcriptomic features of human NASH, suggesting that it will be a useful experimental tool for preclinical drug testing. Lay summary: A carefully characterized model has been developed in mice that recapitulates the progressive stages of human fatty liver disease, from simple steatosis, to inflammation, fibrosis and cancer. The functional pathways of gene expression and immune abnormalities in this model closely resemble human disease. The ease and reproducibility of this model make it ideal to study disease pathogenesis and test new treatments.
Palavras-chave
NAFLD, NASH, Steatohepatitis, Fatty liver disease models, Hepatic stellate cells, Fibrosis, Hepatocellular carcinoma, Insulin resistance
URI
https://observatorio.fm.usp.br/handle/OPI/28300
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Coleções
Artigos e Materiais de Revistas Científicas - FM/Outros
Artigos e Materiais de Revistas Científicas - LIM/14
Artigos e Materiais de Revistas Científicas - ODS/03