Key features of the environment promoting liver cancer in the absence of cirrhosis

Marco Youssef William Zaki, Ahmed Khairallah Mahdi, Gillian Lucinda Patman, Anna Whitehead, João Pais Maurício, Misti Vanette McCain, Despina Televantou, Sameh Abou-Beih, Erik Ramon-Gil, Robyn Watson, Charlotte Cox, Jack Leslie, Caroline Wilson, Olivier Govaere, John Lunec, Derek Austin Mann, Sirintra Nakjang, Fiona Oakley, Ruchi Shukla, Quentin Mark AnsteeDina Tiniakos, Helen Louise Reeves*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)
18 Downloads (Pure)


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.

Original languageEnglish
Article number16727
Pages (from-to)1-17
Number of pages17
JournalScientific Reports
Issue number1
Early online date18 Aug 2021
Publication statusPublished - 1 Dec 2021
Externally publishedYes


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