Ethanol Affects Liver Oxidative Stress and Methylation Status in HCV-infection: study on NS5A-Transgenic Mice

Ethanol Affects Liver Oxidative Stress and Methylation Status in HCV-infection: study on NS5A-Transgenic Mice

Background: Alcohol consumption accelerates the progression and worsens the outcomes of hepatitis C viral (HCV) infection in heavy and moderate drinkers. Non-structural NS5A protein is a known inducer of oxidative stress and carcinogenesis. Although alcohol consumption exacerbates the course of HCV-infection, the combined effects of NS5A protein and alcohol have not been studied and experimental animal HCV models as well as ways of ethanol administration to animals are not optimized.   Our aim was to investigate the effects of two modes of oral ethanol feeding on induction of oxidative stress, methylation status and changes in proteasome activity in livers of NS5A-transgenic (Tg) mice.

Methods: Ethanol was administered either in drinking water (chow- fed mice given 20% ethanol in water; designated chow-EtOH) or in Lieber DeCarli liquid diet (LCD-EtOH). Appropriate controls were used.  The mechanisms of alcohol and NS5A-induced changes in oxidative stress, liver methylation status and 20S proteasome activity were determined after 5 weeks of the feeding regimen.

Results: Ethanol administration using both feeding regimens induced oxidative stress and suppressed cytosolic proteasome activity. However, only LCD-EtOH diet induced fatty changes in the liver, which correlated with higher levels of oxidative stress, impaired methylation potential and reduced cytosolic and nuclear proteasome activity. Importantly, LCD diet administration by itself promoted lipid peroxidation in NS5A-expressing mice.

Conclusion: We conclude that both modes of oral ethanol feeding (chow and LCD-based) induce oxidative stress in NS5A-Tg mice that suppresses proteasome activity. Nonetheless, impaired methylation potential, higher level of oxidative stress and suppression of nuclear proteasome was observed only in LCD-EtOH mice.  However, the effects of LCD-control liquid diet in inducing lipid peroxidation in NS5A-Tg mice, in certain cases, tended to mask the effects of ethanol, indicating that fatty diet serves as a second hit for NS5A-protein-induced stress response of liver cells.

Author(s) Details

Natalia A. Osna [M.D., Ph.D.]
Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System Omaha, NE, USA and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE  68105, USA.

Murali Ganesan [Ph.D.]
Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System Omaha, NE, USA and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE  68105, USA.

Larisa Y. Poluektova [M.D., Ph.D.]
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE  68105, USA.

Kusum K. Kharbanda [Ph.D.]
Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System Omaha, NE, USA and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE  68105, USA and Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE  68105, USA.

View Volume: http://bp.bookpi.org/index.php/bpi/catalog/book/136

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