Cholesterol overload in the liver aggravates oxidative stressmediated DNA damage and accelerates hepatocarcinogenesis

Cristina Enríquez-Cortina, Oscar Bello-Monroy, Patricia Rosales-Cruz, Verónica Souza, Roxana U. Miranda, Rafael Toledo-Pérez, Armando L. Luna-López, Arturo Simoni-Nieves, Rogelio Hernández-Pando, María Concepción Gutiérrez-Ruiz, Diego F. Calvisi, Jens U. Marquardt, Leticia Bucio, Luis Enrique Gomez-Quiroz*

*Corresponding author for this work
18 Citations (Scopus)


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.

Original languageEnglish
Issue number61
Pages (from-to)104136-104148
Number of pages13
Publication statusPublished - 2017


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