Insulin resistance enhances binge ethanol-induced liver injury through promoting oxidative stress and up-regulation CYP2E1

Alcoholic liver disease (ALD) has caused a serious burden on public and personal health in crowd with ethanol abuse. The effects of insulin resistance (IR) on ALD and the mechanisms underlying these responses are still not well understood. In this study, we investigated the changes of liver injury, inflammation, apoptosis, mitochondrial dysfunction and CYP2E1 changes in liver of mice exposed to ethanol with IR or not. We found IR increased the sensitivity of liver injury in mice exposed to ethanol, manifested as the increase serum activities of AST and ALT, the accumulation of triglycerides, the deterioration of liver pathology and increase of inflammatory factors. IR also exacerbated apoptosis and mitochondrial dysfunction in liver of mice exposed to ethanol. The increase of oxidative stress and the decrease of antioxidant defense ability might be responsible for the sensitizing effects of IR on ethanol-induced liver injury, supported by the increase of MDA levels and the decline of GSH/GSSG, the inactivation of antioxidant enzymes SOD, GR through the inhibition of Nrf-2 pathway. The activation of CYP2E1 might be also involved in the sensitizing effects of IR on ethanol induced liver injury in mice. These results demonstrated that IR exhibited a significant pro-oxidative and pro-apoptosis effects to aggravate alcoholic liver injury. Our study helped us to better understand the sensitive role of IR on ALD and suggested that alcohol intake may be more harmful for people with IR.