Journal
SCIENTIFIC REPORTS
Volume 11, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41598-021-96076-2
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Funding
- European Community [HEALTH-F2-2009-241762]
- CR UK Newcastle Experimental Cancer Medicine Center award [C9380/A18084]
- CR UK programme [C18342/A23390]
- CR UK HUNTER Accelerator [C9380/A26813]
- European Community's Horizon 2020 Programme [634413]
- MRC Confidence in Concept award
- Newton-Mosharafa Fund
- Iraqi ministry of higher education and scientific research
- Newcastle University Research Fellowship
- H2020 Societal Challenges Programme [634413] Funding Source: H2020 Societal Challenges Programme
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The study utilized a mouse model to reproduce key features of obesity associated NAFLD-HCC, highlighting the roles of hepatic steatosis and proliferation in HCC development, as well as emphasizing the importance of lobular inflammation and CD44 positive macrophages in HCC progression.
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.
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