Dietary α- and γ-tocopherol supplementation attenuates lipopolysaccharide-induced oxidative stress and inflammatory-related responses in an obese mouse model of nonalcoholic steatohepatitis

Oxidative stress contributes towards the development of nonalcoholic steatohepatitis (NASH). Thus, antioxidants may decrease oxidative stress and ameliorate the events contributing to NASH. We hypothesized that alpha- or gamma-tocopherol would protect against lipopolysaccharide (LPS)-triggered NASH in an obese (ob/ob) mouse model. Five-week-old obese mice (n=18/dietary treatment) were provided 15 mg/kg each of alpha- and gamma-tocopherol or 500 mg/kg of alpha- or gamma-tocopherol for 5-weeks. Then, all mice were injected ip once with LPS (250 mu g/kg) before being sacrificed at 0, 1.5 or 6 h. Body weight and hepatic steatosis were unaffected by tocopherols and LPS. Hepatic alpha- and gamma-tocopherol increased (P<.05) similar to 9.8- and 10-fold in respective tocopherol supplemented mice and decreased in response to LPS. LPS increased serum alanine aminotransferase (ALT) by 86% at 6 h and each tocopherol decreased this response by 29-31%. By 6 h, LPS increased hepatic malondialdehyde (MDA) and tumor necrosis factor-alpha by 81% and 44%, respectively, which were decreased by alpha- or gamma-tocopherol. Serum ALT was correlated (P<.05) to hepatic tumor necrosis factor-cc (r=0.585) and MDA (r=0.592), suggesting that inflammation and lipid peroxidation contributed to LPS-triggered hepatic injury. alpha- and gamma-Tocopherol similarly attenuated LPS-triggered increases in serum free fatty acid, and alpha-tocopherol only maintained the LPS-triggered serum triacylglycerol responses at 6 h. These findings indicate that increasing hepatic alpha- or gamma-tocopherol protected against LPS-induced NASH by decreasing liver damage, lipid peroxidation, and inflammation without affecting body mass or hepatic steatosis. Further study is needed to define the mechanisms by which these tocopherols protected against LPS-triggered NASH. (C) 2010 Elsevier Inc. All rights reserved.