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

Takuma Tsuchida, Youngmin A. Lee, Naoto Fujiwara, Maria Ybanez, Brittany Allen, Sebastiao Martins, M. Isabel Fiel, Nicolas Goossens, Hsin I. Chou, Yujin Hoshida, Scott L. Friedman

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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 high-cholesterol, combined with low weekly dose of intraperitoneal carbon tetrachloride (CCl 4 ), which serves as an accelerator. Results: C57BL/6J mice were fed a normal chow diet ± CCl 4 or WD ± CCl 4 for 12 and 24 weeks. Addition of CCl 4 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/CCl 4 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.

Original languageEnglish (US)
Pages (from-to)385-395
Number of pages11
JournalJournal of Hepatology
Volume69
Issue number2
DOIs
StatePublished - Aug 2018
Externally publishedYes

Fingerprint

Fatty Liver
Liver Neoplasms
Fibrosis
Diet
Hepatocellular Carcinoma
Carbon Tetrachloride
Fructose
Inbred C57BL Mouse
Pharmaceutical Preparations
Liver Diseases
Neoplasms
Fats
Cholesterol
Inflammation
Gene Expression
Western Diet
Liver

Keywords

  • Fatty liver disease models
  • Fibrosis
  • Hepatic stellate cells
  • Hepatocellular carcinoma
  • Insulin resistance
  • NAFLD
  • NASH
  • Steatohepatitis

ASJC Scopus subject areas

  • Hepatology

Cite this

Tsuchida, T., Lee, Y. A., Fujiwara, N., Ybanez, M., Allen, B., Martins, S., ... Friedman, S. L. (2018). A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. Journal of Hepatology, 69(2), 385-395. https://doi.org/10.1016/j.jhep.2018.03.011

A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. / Tsuchida, Takuma; Lee, Youngmin A.; Fujiwara, Naoto; Ybanez, Maria; Allen, Brittany; Martins, Sebastiao; Fiel, M. Isabel; Goossens, Nicolas; Chou, Hsin I.; Hoshida, Yujin; Friedman, Scott L.

In: Journal of Hepatology, Vol. 69, No. 2, 08.2018, p. 385-395.

Research output: Contribution to journalArticle

Tsuchida, T, Lee, YA, Fujiwara, N, Ybanez, M, Allen, B, Martins, S, Fiel, MI, Goossens, N, Chou, HI, Hoshida, Y & Friedman, SL 2018, 'A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer', Journal of Hepatology, vol. 69, no. 2, pp. 385-395. https://doi.org/10.1016/j.jhep.2018.03.011
Tsuchida, Takuma ; Lee, Youngmin A. ; Fujiwara, Naoto ; Ybanez, Maria ; Allen, Brittany ; Martins, Sebastiao ; Fiel, M. Isabel ; Goossens, Nicolas ; Chou, Hsin I. ; Hoshida, Yujin ; Friedman, Scott L. / A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. In: Journal of Hepatology. 2018 ; Vol. 69, No. 2. pp. 385-395.
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abstract = "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 high-cholesterol, combined with low weekly dose of intraperitoneal carbon tetrachloride (CCl 4 ), which serves as an accelerator. Results: C57BL/6J mice were fed a normal chow diet ± CCl 4 or WD ± CCl 4 for 12 and 24 weeks. Addition of CCl 4 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/CCl 4 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.",
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AU - Fujiwara, Naoto

AU - Ybanez, Maria

AU - Allen, Brittany

AU - Martins, Sebastiao

AU - Fiel, M. Isabel

AU - Goossens, Nicolas

AU - Chou, Hsin I.

AU - Hoshida, Yujin

AU - Friedman, Scott L.

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N2 - 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 high-cholesterol, combined with low weekly dose of intraperitoneal carbon tetrachloride (CCl 4 ), which serves as an accelerator. Results: C57BL/6J mice were fed a normal chow diet ± CCl 4 or WD ± CCl 4 for 12 and 24 weeks. Addition of CCl 4 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/CCl 4 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.

AB - 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 high-cholesterol, combined with low weekly dose of intraperitoneal carbon tetrachloride (CCl 4 ), which serves as an accelerator. Results: C57BL/6J mice were fed a normal chow diet ± CCl 4 or WD ± CCl 4 for 12 and 24 weeks. Addition of CCl 4 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/CCl 4 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.

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KW - Steatohepatitis

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