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A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer
Open accessAbstract
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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“These functions normally contribute to tissue repair under homeostatic conditions, but sustained activation in chronic liver diseases drives fibrosis, especially in MASH (41) where they are detectable by expression of desmin and alpha smooth muscle actin (αSMA) using immunofluorescence, and by conservation of gene expression based on single-cell RNA-seq (42-46).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [45]
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In the citing paper
“the FAT-MASH model was used, as this model reproducibly recapitulates the stages of progression of human MASH that include advanced fibrosis and tumors along with changes in the gut microbiome.14,33,34”
From EHBP1 suppresses liver fibrosis in metabolic dysfunction-associated steatohepatitis (2025) · cites this paper as [14]
Experimental — accuracy not yet measuredIn the citing paper
“Our laboratory uses a simple rodent model of MASH, the “FAT-MASH” mouse, which robustly develops Fibrosis and Tumors, features of advanced disease, after 24 weeks of a Western diet combined with a small weekly dose of the liver toxin CCl4 (45).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [45]
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The Molecular Signatures Database Hallmark Gene Set Collection
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Design and validation of a histological scoring system for nonalcoholic fatty liver disease†
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A scaling normalization method for differential expression analysis of RNA-seq data
Robinson, M. D., & Oshlack, A. (2010) · Genome Biology · doi:10.1186/gb-2010-11-3-r25 · Cited by 7,876
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A lipidomic analysis of nonalcoholic fatty liver disease
Puri, P., Baillie, R. A., Wiest, M. M., Mirshahi, F., Choudhury, J., Cheung, O., Sargeant, C., Contos, M. J., & Sanyal, A. J. (2007) · Hepatology · doi:10.1002/hep.21763 · Cited by 1,338
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Cited by
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Mechanisms of NAFLD development and therapeutic strategies
Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M., & Sanyal, A. J. (2018) · Nature Medicine · doi:10.1038/s41591-018-0104-9 · Cited by 4,354
Self-citationFrom NASH to HCC: current concepts and future challenges
Anstee, Q. M., Reeves, H. L., Kotsiliti, E., Govaere, O., & Heikenwalder, M. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0145-7 · Cited by 1,392
Past, present and future perspectives in nonalcoholic fatty liver disease
Sanyal, A. J. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0144-8 · Cited by 522
The Power of Plasticity—Metabolic Regulation of Hepatic Stellate Cells
Trivedi, P., Wang, S., & Friedman, S. L. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2020.10.026 · Cited by 427
Self-citationNAFLD: Mechanisms, Treatments, and Biomarkers
Nassir, F. (2022) · Biomolecules · doi:10.3390/biom12060824 · Cited by 452
Metadata
- Authors
- Tsuchida, T., Lee, Y. A., Fujiwara, N., Ybanez, M., Allen, B., Martins, S., Fiel, M. I., Goossens, N., Chou, H.-I., Hoshida, Y., & Friedman, S. L.
- Affiliations
- Tanabe Pharma Corporation (Japan) (JP)
- Icahn School of Medicine at Mount Sinai (US)
- Mount Sinai Hospital (US)
- Corresponding author
- Friedman, Scott L.
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2018-08
- Volume
- 69
- Issue
- 2
- Pages
- 385-395
- ISSN
- 0168-8278 (ISSN-L)
- PMC
- PMC6054570
- OpenAlex
- W2790198401
- Cited by
- 583
- References
- 56
- Citations by year
- 2026: 65 · 2025: 86 · 2024: 90 · 2023: 91 · 2022: 93 · 2021: 62 · 2020: 52 · 2019: 34 · 2018: 10
- FWCI
- 30.84
- Type
- journal article
- Language
- en
- Update notices
- erratum (2018-10-01)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Hepatology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- NIH
- NIDDK (DK099558)
- European Commission (ERC-2014-AdG-671231)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, mouse model, Western diet, carbon tetrachloride, liver fibrosis, hepatocellular carcinoma, liver transcriptome, immune abnormalities, preclinical drug testing
- MeSH terms
- Animals, Carbon Tetrachloride, Disease Models, Animal, Fatty Liver, Inflammation, Liver Cirrhosis, Liver Neoplasms, Mice, Inbred C57BL, Reproducibility of Results, Disease Progression, Gene Expression Profiling, Mice, Diet, Western
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