The ALIOS diet in male and female rodents recapitulates the clinical and transcriptomic features of NAFLD and NASH.

BACKGROUND & AIMS The pathogenesis of non-alcoholic fatty liver disease (NAFLD) and the progression to non-alcoholic steatohepatitis (NASH) and increased risk of hepatocellular carcinoma (HCC), remain poorly understood. Additionally, there is increasing recognition of the extra-hepatic manifestations associated with NAFLD and NASH. We demonstrate that intervention with the American lifestyle induced obesity syndrome diet (ALIOS) in male and female mice recapitulates many of the clinical and transcriptomic features of human NAFLD and NASH. METHODS Male and female C57BL/6N mice were fed either normal chow (NC) or ALIOS from 11 to 52-weeks and underwent comprehensive metabolic analysis throughout the duration of the study. RESULTS From 26-weeks, ALIOS-fed mice developed features of hepatic steatosis, inflammation and fibrosis. ALIOS-fed mice also had an increased incidence of hepatic tumours at 52-weeks compared to those fed NC. Hepatic transcriptomic analysis revealed alterations in multiple genes associated with inflammation and tissue repair in ALIOS-fed mice. Ingenuity Pathway Analysis confirmed dysregulation of metabolic pathways as well as those associated with liver disease and cancer. In parallel the development of a robust hepatic phenotype, ALIOS-fed mice displayed many of the extra-hepatic manifestations of NAFLD including hyperlipidaemia, increased fat mass, sarcopaenia and insulin resistance. CONCLUSIONS The ALIOS diet in mice recapitulates many of the clinical features of NAFLD and therefore represents a robust and reproducible model for investigating the pathogenesis of NAFLD and its progression.