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.

中文翻译：

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雌性小鼠的酒精性肝炎和代谢紊乱：比 Nrf2-/- 动物更容易处理的模型。

酒精性肝炎 (AH) 是酒精性肝病的严重急性表现，严重病例 28 天死亡率为 15%。由于缺乏可在国际不同监管框架下运行的有效且可重复的小鼠模型，对 AH 的研究受到了阻碍。液体 Lieber-deCarli (LdC) 饮食已被用作随意输送酒精的一种方式，但在没有额外伤害的情况下，它会导致相对轻微的肝损伤。转录因子核因子-红细胞 2 相关因子 2 ( Nrf2 ) 可防止氧化应激，并且表明缺乏该分子的小鼠对酒精引起的损伤更加敏感。^{我们在小鼠中建立了一种新的 AH 模型，并比较了 C57/BL6 野生型与 Nrf2 -/-}小鼠的肝损伤性质。我们的数据显示，当暴露于饮食和乙醇时，WT 和Nrf2 -/- 小鼠均表现出强劲的体重减轻、血清转氨酶增加、脂肪变性和肝脏炎症。这伴随着外周血和肝髓细胞群、纤维化反应和代偿性肝细胞再生的增加。我们还注意到肝脏碳水化合物和脂质代谢的特征性紊乱。重要的是，使用Nrf2 -/- 小鼠并没有增加我们手中的肝损伤反应，并且雌性野生型小鼠表现出更可重复的反应。因此，我们已经证明，这种简单的 AH 小鼠模型可用于诱导损伤，重现酒精性肝炎的许多关键人类特征，而无需进行具有挑战性的外科手术来施用乙醇。这对于了解 AH 的发病机制、测试新的治疗方法或设计代谢方法来管理接受医疗护理的患者非常有价值。