Improved hepatic γ-tocopherol status limits oxidative and inflammatory stress-mediated liver injury in db/db mice with nonalcoholic steatohepatitis

γ-Tocopherol (γ-T) and its physiological metabolite γ-carboxyethyl-hydroxychroman (γ-CEHC) exhibit antioxidant and anti-inflammatory activities. We hypothesized that improved hepatic γ-T status would protect against NASH in leptin-resistant db/db mice. Wild-type mice were fed a diet without γ-T, and db/db mice were fed the same diet supplemented with or without γ-T for 8 wk. Hepatic γ-T and γ-CEHC levels were increased (P < .05) compared with db/db controls. Serum ALT and insulin resistance, which were otherwise increased in db/db controls, were 33-38% lower in db/db mice fed γ-T. Increased hepatic lipid peroxidation in db/db mice was attenuated by dietary γ-T, which occurred without increasing hepatic Nrf2 mRNA expression. However, γ-T attenuated hepatic iNOS, MCP-1, TNF-α and CRP expression. Histological assessment showed γ-T-mediated improvements in overall hepatic architecture, specifically by limiting hepatic steatosis. These findings demonstrate that improvements in hepatic γ-T status protect against liver injury during NASH by reducing inflammation and oxidative stress.