The genetic background shapes disease susceptibility and reveal a specific role for mitochondrial dysfunction in the progression from NAFLD to NASH

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Non-alcoholic steatohepatitis (NASH) is a global health concern that has still no treatment. The challenge in finding effective therapies is partly due to the lack of good mouse models and the complexity of the disease, characterized by the interplay between environmental and genetics factors. We tested the susceptibility of 7 genetically diverse mouse strains to develop NASH, by feeding them a western diet and housing them at thermoneutrality. Each strain responded to the environmental challenges, but the severity of their clinical phenotype varied widely across strains. The wild-derived PWK/PhJ mice were the most prone to develop NASH, while CAST/EiJ mice were completely resistant to hepatic histological alterations. We show that our experimental design is more suited than high-fat diet and room temperature housing to model human NASH. Levels of transcripts and proteins present in the mitochondria as well as mitochondrial function were robustly reduced in the liver of PWK/PhJ mice, suggesting a central role of mitochondrial dysfunction in NASH progression. Importantly, among the 7 strains tested, the alterations in gene expression observed in PWK/PhJ mice were the closest to the human NASH. Our study exposes the limitations of using a single mouse genetic background in metabolic studies and describes a novel NASH mouse model that closely resembles the human disease.