Alcoholic hepatitis and metabolic disturbance in female mice : a more tractable model than Nrf2-/- animals

Abstract

Alcoholic hepatitis (AH) is the dramatic acute presentation of alcoholic liver disease, with a 28-day mortality of 15% in severe cases. Research into AH has been hampered by the lack of effective and reproducible murine models that can be operated under different regulatory frameworks internationally. The liquid Lieber-deCarli (LdC) diet has been used as a means of ad libitum delivery of alcohol, but without an additional insult, it is associated with relatively mild liver injury. The transcription factor Nuclear factor-erythroid 2-related factor 2 (Nrf2) protects against oxidative stress and mice deficient in this molecule are suggested to be more sensitive to alcohol-induced injury. We have established a novel model of AH in mice and compared the nature of liver injury in C57/BL6 wild type versus Nrf2−/- mice. Our data show that both WT and Nrf2-/- mice demonstrate a robust weight loss, increase in serum transaminase, steatosis and hepatic inflammation when exposed to diet and ethanol. This is accompanied by an increase in peripheral blood and hepatic myeloid cell populations, fibrogenic response and compensatory hepatocyte regeneration. We also noted characteristic disturbances in hepatic carbohydrate and lipid metabolism. Importantly use of Nrf2-/- mice did not increase hepatic injury responses in our hands and female wild type mice exhibited a more reproducible response. Thus, we have demonstrated that this simple murine model of AH can be used to induce an injury that recreates many of the key human features of alcoholic hepatitis, without the need for challenging surgical procedures to administer ethanol. This will be valuable for understanding of the pathogenesis of AH, for testing new therapeutic treatments or devising metabolic approaches to manage patients whilst under medical care.