Alcohol increases tumor necrosis factor α and decreases nuclear factor-κB to activate hepatic apoptosis in genetically obese mice

Both obesity and alcohol can cause oxidative stress, cytokine induction, and steatohepatitis. To determine the consequences of their combination, we compared the hepatic effects of moderate ethanol binges in lean and obese ob/ob mice. Mice received water or ethanol (2.5 g/kg) by gastric intubation daily for 4 days, and were killed 2 hours after the last administration. Some obese mice also received pentoxifylline, an inhibitor of tumor necrosis factor-a (TNF-alpha) production, before each ethanol administration. In lean mice, these moderate ethanol doses did not increase plasma TNF-a and hepatic caspase-3 activity, but triggered some apoptotic hepatocytes. Naive ob/ob mice had a few necrotic and apoptotic hepatocytes, but exhibited little oxidative stress, possibly because of adaptive increases in manganese superoxide dismutase, heat shock protein 70 (Hsp70), mitochondrial cytochrome c, and mitochondrial DNA. Alcohol administration to ob/ob mice did not increase oxidative stress despite increased CYP2E1, but increased plasma TNF-a, further increased Hsp70, and profoundly decreased p65 nuclear factor kappa B (NF-kappa B) protein and DNA-binding activity in nuclear extracts. Caspase-3 was activated, and more apoptotic hepatocytes were found in intoxicated obese mice than naive obese mice. In intoxicated obese mice, pentoxifylline fully prevented the increase in plasma TNF-a the decrease in nuclear NF-kappa B activity, and the increase in hepatic caspase-3, and it also decreased hepatic triglycerides. In conclusion, obese mice develop adaptations that may limit oxidative stress. Moderate ethanol intoxication does not increase oxidative stress in obese mice, but increases TNF-a and also decreases nuclear NF-kappa B activity, thus unleashing the apoptotic effects of TNF-a. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).