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

Lookup NU author(s): Marco Zaki, Dr Ahmed Mahdi, Dr Gillian Patman, Anna Whitehead, Joao Mauricio, Misti McCainORCiD, Dr Despoina Televantou, Erik Ramon Gil, Robyn Watson, Charlotte Cox, Dr Olivier GovaereORCiD, Professor John LunecORCiD, Professor Derek Mann, Dr Sirintra Nakjang, Professor Fiona OakleyORCiD, Dr Ruchi ShuklaORCiD, Professor Quentin AnsteeORCiD, Dr Dina Tiniakos, Professor Helen ReevesORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2021, The Author(s).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.

Publication metadata

Author(s): Zaki MYW, Mahdi AK, Patman GL, Whitehead A, Mauricio JP, McCain MV, Televantou D, Abou-Beih S, Ramon-Gil E, Watson R, Cox C, Leslie J, Wilson C, Govaere O, Lunec J, Mann DA, Nakjang S, Oakley F, Shukla R, Anstee QM, Tiniakos D, Reeves HL

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2021

Volume: 11

Issue: 1

Print publication date: 01/12/2021

Online publication date: 18/08/2021

Acceptance date: 02/08/2021

Date deposited: 08/09/2021

ISSN (electronic): 2045-2322

Publisher: Nature Research


DOI: 10.1038/s41598-021-96076-2


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Funder referenceFunder name
and CR UK HUNTER Accelerator (C9380/A26813).
CR UK programme grant C18342/A23390
European Community’s Seventh Framework Programme (FP7/2010-2013) under grant agreement HEALTH-F2-2009-241762 for the project FLIP.
HR, AW, DT, RS, SN, DM, JLu and MM were supported by the CR UK Newcastle Experimental Cancer Medicine Center award (C9380/A18084),
OG, QMA, FO, HR and MYWZ were supported by the European Community’s Horizon 2020 Programme (EPoS Grant Agreement 634413)