Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, ranging from simple steatosis to the necro-inflammatory disease, non-alcoholic steatohepatitis (NASH). Development of NASH subsequently increases risk of hepatocellular carcinomas (HCC). Alongside the impact on the liver, NASH is associated with other clinical features, including insulin resistance, hyperlipidaemia and sarcopaenia. We demonstrate that mice fed the American lifestyle induced obesity syndrome diet (ALIOS) recapitulate many of the clinical characteristics of human NAFLD and NASH, making it a robust model for studying the condition. Male and female C57BL/6 mice were fed either normal chow (NC) or ALIOS (45% fat [30% trans-fat], 55% fructose: 45% glucose in H2O; n=15 in each group) for 52 weeks. ALIOS fed mice had increased body mass and were insulin resistant. Relative quadriceps mass was decreased in ALIOS fed mice, mirroring sarcopaenia observed in NAFLD patients. In addition, metabolic caging revealed that ALIOS fed males were more sedentary than females. Plasma cholesterol, AST and ALT progressively increased in mice fed ALIOS in both sexes over the duration of the study. Whilst the ALIOS diet initially increased hepatic triglyceride content, by 52 weeks, hepatic triglyceride decreased (Males; NC: 21.7±1.2, ALIOS: 16.7±1.1 mg/g. Females; NC: 18.5±0.7, ALIOS: 13.2±0.8 mg/g, P<0.05). ALIOS induced liver inflammation in both sexes and was associated with increased hepatic fibrosis (Male; NC: 3.2±0.5, ALIOS; 5.4±0.9%. Female; NC: 2.7±0.8, ALIOS: 5.9±1.1%, P<0.05). Advanced fibrotic liver disease increases the risk of HCC; ALIOS fed male mice were more prone to tumour development (NC: 7.7%, ALIOS: 22.2%, P<0.05), while there was no incidence of macroscopic tumours in females. The ALIOS diet in mice recapitulates many of the clinical features of NAFLD and represents a robust and reproducible model for investigating the pathogenesis of NAFLD and its progression to NASH and HCC.