TY - JOUR TI - Key features of the environment promoting liver cancer in the absence of cirrhosis AU - Zaki, Marco Youssef William AU - Mahdi, Ahmed Khairallah AU - Patman, AU - Gillian Lucinda AU - Whitehead, Anna AU - Mauricio, Joao Pais AU - McCain, AU - Misti Vanette AU - Televantou, Despina AU - Abou-Beih, Sameh and AU - Ramon-Gil, Erik AU - Watson, Robyn AU - Cox, Charlotte AU - Leslie, Jack AU - and Wilson, Caroline AU - Govaere, Olivier AU - Lunec, John AU - Mann, AU - Derek Austin AU - Nakjang, Sirintra AU - Oakley, Fiona AU - Shukla, Ruchi AU - and Anstee, Quentin Mark AU - Tiniakos, Dina AU - Reeves, Helen Louise JO - Scientific Reports PY - 2021 VL - 11 TODO - 1 SP - null PB - NATURE PORTFOLIO SN - 2045-2322 TODO - 10.1038/s41598-021-96076-2 TODO - null TODO - The prevalence of obesity and non-alcoholic fatty liver disease (NAFLD) associated hepatocellular carcinoma (HCC) is rising, even in the absence of cirrhosis. We aimed to develop a murine model that would facilitate further understanding of NAFLD-HCC pathogenesis. A total of 144 C3H/He mice were fed either control or American lifestyle (ALIOS) diet, with or without interventions, for up to 48 weeks of age. Gross, liver histology, immunohistochemistry (IHC) and RNA-sequencing data were interpreted alongside human datasets. The ALIOS diet promoted obesity, elevated liver weight, impaired glucose tolerance, non-alcoholic fatty liver disease (NAFLD) and spontaneous HCC. Liver weight, fasting blood glucose, steatosis, lobular inflammation and lipogranulomas were associated with development of HCC, as were markers of hepatocyte proliferation and DNA damage. An antioxidant diminished cellular injury, fibrosis and DNA damage, but not lobular inflammation, lipogranulomas, proliferation and HCC development. An acquired CD44 phenotype in macrophages was associated with type 2 diabetes and NAFLD-HCC. In this diet induced NASH and HCC (DINAH) model, key features of obesity associated NAFLD-HCC have been reproduced, highlighting roles for hepatic steatosis and proliferation, with the acquisition of lobular inflammation and CD44 positive macrophages in the development of HCC-even in the absence of progressive injury and fibrosis. ER -