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

• Published in: Scientific reports Vol. 11; no. 1; pp. 16727 - 17
• Main Authors: Zaki, Marco Youssef William, Mahdi, Ahmed Khairallah, Patman, Gillian Lucinda, Whitehead, Anna, Maurício, João Pais, McCain, Misti Vanette, Televantou, Despina, Abou-Beih, Sameh, Ramon-Gil, Erik, Watson, Robyn, Cox, Charlotte, Leslie, Jack, Wilson, Caroline, Govaere, Olivier, Lunec, John, Mann, Derek Austin, Nakjang, Sirintra, Oakley, Fiona, Shukla, Ruchi, Anstee, Quentin Mark, Tiniakos, Dina, Reeves, Helen Louise
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.08.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67/1504/1610/4029; 631/67/327; 631/67/70; 692/163/2743/137/773; 692/163/2743/393; 692/4020/1503/1607/2751; Aged; Animal models; Animals; Antioxidants; Carcinoma, Hepatocellular - epidemiology; Carcinoma, Hepatocellular - etiology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; CD44 antigen; Cirrhosis; Deoxyribonucleic acid; Diabetes Complications - epidemiology; Diabetes Complications - metabolism; Diabetes Complications - pathology; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - epidemiology; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diet; Diet, High-Fat - adverse effects; DNA; DNA damage; Fatty liver; Female; Fibrosis; Glucose tolerance; Hepatocellular carcinoma; Histology; Humanities and Social Sciences; Humans; Immunohistochemistry; Inflammation; Liver cancer; Liver cirrhosis; Liver Cirrhosis - complications; Liver Cirrhosis - epidemiology; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver diseases; Liver Neoplasms - epidemiology; Liver Neoplasms - etiology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Macrophages; Male; Mice; multidisciplinary; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - epidemiology; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Obesity; Phenotypes; Science; Science (multidisciplinary); Steatosis
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-96076-2

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.