Carvedilol improves ethanol‐induced liver injury via modifying the interaction between oxidative stress and sympathetic hyperactivity in rats

Oxidative stress is a major pathway mediating ethanol hepatotoxicity and liver injury. We previously found that carvedilol, which can block the sympathetic nervous system via β1-, β2- and α1-adrenoreceptors, modifies ethanol-induced production of lipogenesis- and fibrogenesis-related mediators from hepatic stellate cells (HSC). In the present study, we assessed the effects of carvedilol on ethanol-induced liver injury, hepatic insulin resistance, and the interaction between oxidative stress and sympathetic hyperactivity in rats with alcoholic fatty liver disease (AFLD).Male Wistar rats were pair-fed for 49 days and divided into four groups: control and ethanol liquid-diet-fed rats with and without 7-day carvedilol treatment. Rats' sympathetic activity, hepatic oxidative stress, hepatic insulin resistance and liver injury were evaluated based on biochemical analysis, enzyme-linked immunosorbent assay, fluorescence immunohistochemistry, western blot and reverse transcriptase polymerase chain reaction.Forty-nine days of ethanol consumption induced the increases in circulating noradrenaline metabolite (3-methoxy-4-hydroxyphenylglycol), hepatic noradrenaline and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, the downregulation of hepatic insulin receptor substrate-1 gene expression, and the accumulation of fatty droplets within hepatocytes with the increased hepatic triglyceride and blood alanine aminotransferase levels. All of these changes were modified by carvedilol treatment. 8-OHdG was detected in activated HSC and suppressed by carvedilol treatment based on fluorescence immunohistochemical double-staining analysis.Carvedilol may modify the interaction between the oxidative stress and the sympathetic hyperactivity, and then contribute to attenuating the development of AFLD in rats. Additionally, oxidative stress may be responsible for the activation of HSC during the early stage of alcoholic liver disease.