The genetic background shapes the susceptibility to mitochondrial dysfunction and NASH progression

Non-alcoholic steatohepatitis (NASH) is a global health concern without treatment. The challenge in finding effective therapies is due to the lack of good mouse models and the complexity of the disease, characterized by gene-environment interactions. We tested the susceptibility of seven mouse strai...

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Published in:The Journal of experimental medicine 2023-04, Vol.220 (4)
Main Authors: Benegiamo, Giorgia, von Alvensleben, Giacomo V G, Rodríguez-López, Sandra, Goeminne, Ludger J E, Bachmann, Alexis M, Morel, Jean-David, Broeckx, Ellen, Ma, Jing Ying, Carreira, Vinicius, Youssef, Sameh A, Azhar, Nabil, Reilly, Dermot F, D'Aquino, Katharine, Mullican, Shannon, Bou-Sleiman, Maroun, Auwerx, Johan
Format: Article
Language:English
Subjects:
Animals
Disease Models, Animal
Human Disease Genetics
Humans
Liver - metabolism
Liver Cirrhosis - metabolism
Metabolism
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
Mitochondria - genetics
Mitochondria - metabolism
Non-alcoholic Fatty Liver Disease - genetics
Non-alcoholic Fatty Liver Disease - metabolism
Non-alcoholic Fatty Liver Disease - pathology
Technical Advances and Resources
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Summary:Non-alcoholic steatohepatitis (NASH) is a global health concern without treatment. The challenge in finding effective therapies is due to the lack of good mouse models and the complexity of the disease, characterized by gene-environment interactions. We tested the susceptibility of seven mouse strains to develop NASH. The severity of the clinical phenotypes observed varied widely across strains. PWK/PhJ mice were the most prone to develop hepatic inflammation and the only strain to progress to NASH with extensive fibrosis, while CAST/EiJ mice were completely resistant. Levels of mitochondrial transcripts and proteins as well as mitochondrial function were robustly reduced specifically in the liver of PWK/PhJ mice, suggesting a central role of mitochondrial dysfunction in NASH progression. Importantly, the NASH gene expression profile of PWK/PhJ mice had the highest overlap with the human NASH signature. Our study exposes the limitations of using a single mouse genetic background in metabolic studies and describes a novel NASH mouse model with features of the human NASH.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20221738