Investigating the Role of Obesity and Obstructive Sleep Apnea in Hepatocellular Carcinoma Progression

Abstract

Primary liver cancer is the seventh most common cancer worldwide and the second highest cause of cancer mortality. The incidence of hepatocellular carcinoma (HCC) has increased 80% in the past two decades and now comprises 85% of all primary liver cancer. Obesity increases the risk of developing HCC two-fold in women and five-fold in men. Co-morbidities common to obesity including non-alcoholic steatohepatitis (NASH), hepatic inflammation, and lipid accumulation increase the risk of developing HCC. Obstructive sleep apnea (OSA), a state of chronic intermittent hypoxia which is common in obese individuals, also increases the incidence of NASH. With a U.S. population that is approximately 33% obese, having OSA at 30-50%, we estimate the co-incidence of obesity and OSA is 10-16.5% of the entire U.S. population. Diet-induced obesity or intermittent hypoxia induces hepatic lipid accumulation and diet-induced obesity was recently shown to promote HCC tumor development. Whether obesity, chronic intermittent hypoxia, and their combination hasten hepatic lipid accumulation and HCC tumor progression remains unclear. In our studies, we monitored tumor development utilizing micro-computed tomography imaging and discovered that tumors developed fastest in mice that consumed a high fat diet. Upon further investigation, these mice also tended to have higher serum levels of AST and ALT and gained more weight than their counterparts. However, the addition of hypoxia lead to a decrease in weight gained, as well as a reduction in hepatic lipid accumulation and tumor formation. Extraction of mRNA from mouse livers revealed an up-regulation HIF-1α in mice fed a high fat diet without treatment with hypoxia that correlated strongly with tumorigenesis. Remarkably, hypoxia was found in mice treated with hypoxia as well as the mice that were fed a high fat diet only. These findings suggest that hepatic lipid accumulation produces endogenous hepatic hypoxia which associates with increased hepatic HIF-1α expression that correlates with tumorigenesis. Collectively, these data reveal a mechanism that potentially explains progression from early liver disease to HCC.