Cholesterol overload in the liver aggravates oxidative stress-mediated DNA damage and accelerates hepatocarcinogenesis
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Cristina Enríquez-Cortina1,2, Oscar Bello-Monroy1,2, Patricia Rosales-Cruz1,2, Verónica Souza2, Roxana U. Miranda2, Rafael Toledo-Pérez1,2, Armando Luna-López3, Arturo Simoni-Nieves1,2, Rogelio Hernández-Pando4, María Concepción Gutiérrez-Ruiz2, Diego F. Calvisi5, Jens U. Marquardt6, Leticia Bucio2,* and Luis Enrique Gomez-Quiroz2,*
1Posgrado en Biología Experimental, DCBS, Universidad Autónoma Metropolitana Iztapalapa, México City, México
2Laboratorio de Fisiología Celular, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana Iztapalapa, México City, México
3Instituto Nacional de Geriatría, S.S., México City, México
4Departamento de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
5Institute of Pathology, University of Greifswald, Greifswald, Germany
61st Department of Medicine, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
*Shared senior authorship
Luis Enrique Gomez-Quiroz, email: [email protected]
Keywords: cholesterol; oxidative stress; ATM; DNA damage; carcinogenesis
Received: August 06, 2017 Accepted: September 20, 2017 Published: October 24, 2017
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.
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