Strain dependence of diet‐induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype
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Background & Aims: Obese Alms1 mutant (foz/foz) NOD.B10 mice develop diabetes and fibrotic NASH when fed high‐fat(HF) diet. To establish whether diabetes or obesity is more closely associated with NASH fibrosis, we compared diabetic foz/foz C57 BL 6/J with non‐diabetic foz/foz BALB/c mice. We also determined hepatic cytokines, growth factors and related profibrotic pathways. Methods: Male and female foz/foz BALB/c and C57 BL 6/J mice were fed HF or chow for 24 weeks before determining metabolic indices, liver injury, cytokines, growth factors, pathology/fibrosis and matrix deposition pathways. Results: All foz/foz mice were obese. Hepatomegaly, hyperinsulinemia, hyperglycaemia and hypoadiponectinaemia occurred only in foz/foz C57BL6/J mice, whereas foz/foz BALB/c formed more adipose. Serum ALT, steatosis, ballooning, liver inflammation and NAFLD activity score were worse in C57BL6/J mice. In HF‐fed mice, fibrosis was severe in foz/foz C57BL6/J, appreciable in WT C57BL6/J, but absent in foz/foz BALB/c mice. Hepatic mRNA expression of TNF‐α, IL‐12, IL‐4, IL‐10 was increased (but not IFN‐γ, IL‐1β, IL‐17A), and IL‐4:IFN‐γ ratio (indicating Th‐2 predominance) was higher in HF‐fed foz/foz C57BL6/J than BALB/c mice. In livers of HF‐fed foz/foz C57BL6/J mice, TGF‐β was unaltered but PDGFα and CTGF were increased in association with enhanced α‐SMA, CD147and MMP activity. Conclusions: In mice with equivalent genetic/dietary obesity, NASH development is linked to strain differences in hyperinsulinaemia and hyperglycaemia inversely related to lipid partitioning between adipose and liver. Diabetes‐mediated CTGF‐regulation of MMP s as well as cytokines/growth factors (Th‐2 cytokine predominant, PDGF α, not TGF‐β) mobilized in the resultant hepatic necroinflammatory change may contribute to strain differences in NASH fibrosis.
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The Oz mouse harbors a spontaneous Alms1 mutation similar to Alstrom syndrome; combined with a Western diet on a C57BL/6 background, it leads to obesity and diabetes, then MASH with advanced fibrosis by 12 weeks of age.
“The Oz mouse harbors a spontaneous mutation within the Alstrom syndrome 1 (Alms1) gene, similar to patients with Alstrom syndrome, which, when combined with a Western diet on a C57BL/6 background, leads to obesity and diabetes, then MASH, with advanced fibrosis by 12 weeks of age (43, 229, 230).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [229]
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“Alms1 mutated mice (also known as fat Aussie or Foz/Foz) are hyperphagic, have reduced physical activity, and on a high-caloric diet develop NASH accompanied by obesity, diabetes, and hypercholesterolemia.(8,9) Restriction of Foz/Foz mice to a diet equivalent to the average daily food intake of a normal-weight mouse r…”
BackgroundMethodNon-alcoholic fatty liver disease: pathogenesis and models
Zhong, H. (2024) · American Journal of Translational Research · doi:10.62347/kmsa5983 · Cited by 37 · see citing works
- Authors
- Farrell, G. C., Mridha, A. R., Yeh, M. M., Arsov, T., Van Rooyen, D. M., Brooling, J., Nguyen, T., Heydet, D., Delghingaro‐Augusto, V., Nolan, C. J., Shackel, N. A., McLennan, S. V., Teoh, N. C., & Larter, C. Z.
- Affiliations
- Australian National University (AU)
- University of Washington (US)
- Liver Research Group Australian National University Medical School at The Canberra Hospital Garran ACT Australia
- Canberra Hospital (AU)
- Centenary Institute (AU)
- Royal Prince Alfred Hospital (AU)
- Corresponding author
- Farrell, Geoffrey C.
- ORCID
- Venue
- Liver International
- Publisher
- Wiley
- Published
- 2013-10-25
- Volume
- 34
- Issue
- 7
- Pages
- 1084-1093
- ISSN
- 0106-9543 (ISSN-L)
- 1478-3223
- 1478-3231
- OpenAlex
- W1970253621
- Cited by
- 85
- References
- 38
- Citations by year
- 2025: 6 · 2024: 10 · 2023: 6 · 2022: 7 · 2021: 8 · 2020: 10 · 2019: 9 · 2018: 8 · 2017: 5 · 2016: 7 · 2015: 7 · 2014: 1
- FWCI
- 3.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Liver International (publishedVersion)
- PubMed (publishedVersion)
- University of Canberra Research Portal (submittedVersion)
- ANU Open Research (Australian National University) (submittedVersion)
- Funders
- NHMRC Project Grant (102818, 585411, 1042288)
- NHMRC Australian Postdoctoral Training Fellowship (525473)
- NHMRC Scholarship (585539)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- nonalcoholic steatohepatitis, liver fibrosis, obesity, diabetes mellitus, strain differences, high-fat diet, liver inflammation, Th2 cytokines, IFN-γ/IL-4 ratio, connective tissue growth factor, matrix metalloproteinases, TGF-beta
- MeSH terms
- Analysis of Variance, Animals, Diabetes Mellitus, Type 2, DNA-Binding Proteins, Female, Fluorescent Antibody Technique, Liver, Liver Cirrhosis, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Species Specificity, Cytokines, Mice, Inbred NOD, Cell Cycle Proteins, Matrix Metalloproteinases, Intercellular Signaling Peptides and Proteins, Mice, Diet, High-Fat, Non-alcoholic Fatty Liver Disease
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