HP_A_217569 53..63

Nathan W Sweeney Cecil J Gomes Richard De Armond Sara M Centuori 3 Sairam Parthasarathy Jesse D Martinez 1Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, USA; 2University of Arizona Health Sciences Center for Sleep and Circadian Sciences, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Arizona, Tucson, AZ, USA; 3University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA; 4Department of Cellular and Molecular Medicine, Cell and Molecular Medicine, University of Arizona, Tucson, AZ, USA Purpose: Nonalcoholic fatty liver disease (NAFLD) is considered the most common form of silent liver disease in the United States and obesity is associated with increased risk of NAFLD. Obstructive sleep apnea (OSA) which is common in obese individuals is associated with a greater incidence of NAFLD, which in turn, increases the risk for hepatocellular carcinoma (HCC). It is unclear how obesity, OSA and NAFLD interrelate nor how they collectively contribute to an increased risk for developing HCC. Patients and methods: Male BALB/c mice were exposed to diethylnitrosamine and phenobarbital followed by 48 weeks of either standard chow diet (chow), chow with hypoxia, high-fat diet, or a combination of hypoxia and high-fat diet. We noninvasively monitored tumor development using micro-CT imaging. We tracked the total weight gained throughout the study. We evaluated liver histology, fat accumulation, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor 1-alpha (HIF-1α) expression, as well as, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Results: A high-fat diet without hypoxia led to the development of obesity that induced hepatic steatosis and promoted tumorigenesis. Animals on a high-fat diet and that were also exposed to hypoxia had lower total weight gain, lower steatosis, lower serum AST and ALT levels, and fewer number of hepatic adenomas than a high-fat diet without hypoxia. Conclusion: These findings suggest that hypoxia abrogates obesity, hepatic steatosis, and hepatic tumorigenesis related to a high-fat diet.