Mode of Oral Ethanol Feeding Affects Liver Oxidative Stress Levels and Methylation Status: Study on NS5A-Transgenic Mice.

ABSTRACT

Alcohol consumption accelerates the progression and worsens the outcomes of hepatitis C viral (HCV) infection in heavy and moderate drinkers. Our aim was to investigate the effects of two modes of oral ethanol feeding on induction of oxidative stress, impaired methylation status and downstream changes in proteasome activity in livers of NS5A-transgenic (Tg) mice. Methods: Ethanol was administered either in water (chow fed mice given 20% ethanol in water; designated chow-EtOH) or fed in Lieber De Carli 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. However, LCD diet by itself triggered lipid peroxidation. Conclusion: We conclude that both modes of oral ethanol feeding (chow and LCDbased) 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.