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Cholesterol overload in the liver aggravates oxidative stress-mediated DNA damage and accelerates hepatocarcinogenesis
- Source :
- Oncotarget
- Publication Year :
- 2017
-
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.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
DNA repair
DNA damage
Oxidative phosphorylation
medicine.disease_cause
03 medical and health sciences
chemistry.chemical_compound
Internal medicine
medicine
oxidative stress
Cholesterol
business.industry
cholesterol
DNA oxidation
medicine.disease
030104 developmental biology
Endocrinology
Oncology
chemistry
ATM
Liver cancer
Carcinogenesis
business
carcinogenesis
Oxidative stress
Research Paper
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 8
- Issue :
- 61
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....ff708ab3d52eab813c5614368eeb52b0