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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.
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
URL: https://doi.org/10.1038/s41598-021-96076-2
DOI: 10.1038/s41598-021-96076-2
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