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

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 7 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 NASH, while CAST/EiJ mice were completely resistant. 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, 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.