Abstract
Primary liver cancers represent the second leading cause of cancer-related deaths worldwide. Diverse etiological factors include chronic viral hepatitis, aflatoxin and alcohol exposure as well as aberrant liver lipid overload. Cholesterol has been identified as a key inducer of metabolic impairment, oxidative stress and promoter of cellular dysfunction. The aim of this work was to address the oxidative stress-mediated DNA damage induced by cholesterol overload, and its role in the development of hepatocellular carcinoma.C57BL/6 male mice were fed with a high cholesterol diet, followed by a single dose of N-diethylnitrosamine (DEN, 10 μg/g, ip). Reactive oxygen species generation, DNA oxidation, antioxidant and DNA repair proteins were analyzed at different time points. Diet-induced cholesterol overload caused enhanced oxidative DNA damage in the liver and was associated with a decrease in key DNA repair genes as early as 7 days. Interestingly, we found a cell survival response, induced by cholesterol, judged by a decrement in Bax to Bcl2 ratio. Importantly, N-acetyl-cysteine supplementation significantly prevented DNA oxidation damage. Furthermore, at 8 months after DEN administration, tumor growth was significantly enhanced in mice under cholesterol diet in comparison to control animals. Together, these results suggest that cholesterol overload exerts an oxidative stress-mediated effects and promotes the development of liver cancer.
Highlights
Aberrant lipogenesis has a major effect on many diseases, in addition to well-known metabolic disorders such as obesity and/or metabolic syndrome, lipid disorders have crucial impact on tumor development
Free cholesterol is increased in liver tissue from patients with nonalcoholic steatohepatitis (NASH), and this is associated to an increment in the expression of the sterol regulatory element binding protein (SREBP) 2 and steroidogenic acute regulatory protein (StAR) [9], both critically linked to Hepatocellular carcinoma (HCC) development and progression [10]
high cholesterol (HC) fed mice displayed a transient increase in AST serum levels starting two days under the treatment, peaking at 7 days when compared with animals under the CW diet and treated with damage inducers such as N-nitrosodiethylamine (DEN) (DCW, Figure 1A)
Summary
Aberrant lipogenesis has a major effect on many diseases, in addition to well-known metabolic disorders such as obesity and/or metabolic syndrome, lipid disorders have crucial impact on tumor development. HCC aggressiveness is directly associated to the levels of lipogenic enzymes, related to fatty acid and cholesterol synthesis. Recent evidence supports the notion that exogenous free fatty acids play a major role in liver cancer development [8], the relevance of excessive dietary cholesterol in this context is less well understood. Free cholesterol is increased in liver tissue from patients with nonalcoholic steatohepatitis (NASH), and this is associated to an increment in the expression of the sterol regulatory element binding protein (SREBP) 2 and steroidogenic acute regulatory protein (StAR) [9], both critically linked to HCC development and progression [10]
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