MECHANISMS OF OBESITY-RELATED HEPATOCARCINOGENSIS

Abstract

Nearly a third of the US population is currently obese. The recent rise in liver cancer prevalence correlates with the obesity epidemic and non-alcoholic fatty liver disease (NAFLD). The underlying mechanisms behind the increased risk of liver cancer in the obese population remain to be elucidated. My hypothesis is that NAFLD causes elevated levels of the promutagenic lipid peroxidation (LPO)-derived cyclic adduct γ-hydroxy-1,N2-propano-2′-deoxyguanosine (γ-OHPdG), which may initiate hepatocarcinogenesis. Immunohistochemistry (IHC) of γ-OHPdG in human liver samples representing the disease stages of steatosis, fibrosis, cirrhosis and hepatocellular carcinoma (HCC) was used to discern if there was a correlation between adduct formation and disease progression. γ-OHPdG formation in these samples was elevated in early stages of liver disease, suggesting it may be a source of mutagenic DNA damage. Furthermore, I propose that Theaphenon E (TE), a formulated green tea extract, can prevent γ-OHPdG formation. Using a C57Bl/6J bioassay, mice were subjected to a high fat (HFD), low fat (LFD) and high fat with 2% TE (HFD+TE) diet in order to investigate γ-OHPdG formation and HCC prevention through TE. HFD+TE mice maintained a healthy body weight, liver to body weight ratio and low levels of alanine aminotransferase and aspartate aminotransferase, enzymes commonly elevated in liver disease. TE also effectively prevented lipid accumulation in human and mouse liver cell lines treated with fatty acids (FAs). Additionally, increased CD4+ T cell survival and apoptosis in HFD+TE mice may be responsible for prevention of liver damage from lipid accumulation. The overall incidence of HCC in the bioassay was 15% in LFD, 33% in HFD and none in HFD+TE mice. Levels of γ-OHPdG were significantly lower between the HFD+TE mice compared to both HFD and LFD at the final timepoint indicating that TE may have a preventative role in γ-OHPdG formation. A significant decrease was also found in the number of G>T mutations between HFD and HFD+TE liver tissue, a mutation that is common in HCC as well as γ-OHPdG-related DNA modifications. The relationships characterized in this research between γ-OHPdG formation and HCC will contribute to a better understanding of its role in obesity-related hepatocarcinogenesis.