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An unbiased ranking of murine dietary models based on their proximity to human metabolic dysfunction-associated steatotic liver disease (MASLD)
Univ Cambridge, England; Univ Bari Aldo Moro, Italy; Roger Williams Inst Hepatol, England.
Univ Cambridge, England; European Bioinformat Inst EMBL EBI, England.
Novo Nordisk AS, Denmark; Novo Nordisk, Denmark.
Newcastle Univ, England.
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2024 (English)In: Nature Metabolism, E-ISSN 2522-5812, Vol. 6, no 6, p. 1178-+Article in journal (Refereed) Published
Abstract [en]

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, encompasses steatosis and metabolic dysfunction-associated steatohepatitis (MASH), leading to cirrhosis and hepatocellular carcinoma. Preclinical MASLD research is mainly performed in rodents; however, the model that best recapitulates human disease is yet to be defined. We conducted a wide-ranging retrospective review (metabolic phenotype, liver histopathology, transcriptome benchmarked against humans) of murine models (mostly male) and ranked them using an unbiased MASLD 'human proximity score' to define their metabolic relevance and ability to induce MASH-fibrosis. Here, we show that Western diets align closely with human MASH; high cholesterol content, extended study duration and/or genetic manipulation of disease-promoting pathways are required to intensify liver damage and accelerate significant (F2+) fibrosis development. Choline- deficient models rapidly induce MASH-fibrosis while showing relatively poor translatability. Our ranking of commonly used MASLD models, based on their proximity to human MASLD, helps with the selection of appropriate in vivo models to accelerate preclinical research.
Place, publisher, year, edition, pages
NATURE PORTFOLIO , 2024. Vol. 6, no 6, p. 1178-+
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:liu:diva-209103DOI: 10.1038/s42255-024-01043-6ISI: 001287307700001PubMedID: 38867022Scopus ID: 2-s2.0-85195930089OAI: oai:DiVA.org:liu-209103DiVA, id: diva2:1910770
Note

Funding Agencies|multi-center study aiming to evaluate NAFLD biomarkers; Innovative Medicines Initiative 2 (IMI2) Joint Undertaking [777377]; European Union's Horizon 2020 research and innovation program; European Federation of Pharmaceutical Industries and Associations (EFPIA); European Bioinformatics Institute (EMBL-EBI); EMBL-EBI; Medical Research Council (MRC); University of Bari [S06-miRNASH]; Foundation for Liver Research; Associazione Italiana Ricerca sul Cancro [IG2022, 27521]; Ministry of University and Research on Next Generation EU Funds [P202222FCC, H53D23009960001, DD MUR 1366, 01-09-2023, H93C22000630001, DD MUR 1550, CN00000041, H93C22000430007, H93C22000450007]; MRC Metabolic Diseases Unit [(MC_UU_00014/5)]; UK MRC program [MR/K0019494/1, MR/R023026/1]; Fundacao para a Ciencia e Tecnologia [PTDC/MED-FAR/3492/2021]; La Caixa Foundation [LCF/PR/HR21/52410028]; Newcastle NIHR Biomedical Research Centre; National Institutes of Health (NIH) [NIH R01 DK128289, NCI 5P30CA196521-08, R01 DK136016]

Available from: 2024-11-05 Created: 2024-11-05 Last updated: 2025-04-30

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Ekstedt, MattiasKechagias, Stergios

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Ekstedt, MattiasKechagias, Stergios
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Division of Diagnostics and Specialist MedicineFaculty of Medicine and Health SciencesMag- tarmmedicinska kliniken
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