Binge alcohol drinking is an important health concern and well-known risk factor for the development of numerous disorders. Oxidative stress plays a critical role in the pathogenesis of acute alcoholism. Nuclear factor erythroid 2 like 2 (NRF2) is a master regulator of cellular adaptive response to oxidative insults. However, the role of NRF2 in acute alcoholism and associated pathologies remains unclear. We found that Nrf2-knockout (Nrf2-KO) mice had exaggerated hypoglycemia and hypothermia and increased mortality compared to wildtype mice after binge ethanol exposure. This phenotype was partially rescued by providing warm environment and/or glucose administration. Acute high dose of alcohol exposure resulted in substantially worsened liver and pancreatic injuries in Nrf2-KO mice. Importantly, deficiency of Nrf2 allowed severe pancreatitis and pancreatic β-cell injury with increased insulin secretion and/or leaking during binge ethanol exposure, which contributed to hypoglycemia. In contrast, a clinically used NRF2 activator dimethyl fumarate (DMF) protected against hypoglycemia and lethality induced by acute ethanol exposure. Furthermore, Nrf2-KO mice likely had defective hepatic acetaldehyde metabolism. Taken together, NRF2 plays an important protective role against acute binge alcohol-induced hepatic and pancreatic damage, which may be partially attributable to its primary regulating role in antioxidant response and impact on ethanol metabolism.

酗酒是一个重要的健康问题，也是许多疾病发展的众所周知的危险因素。氧化应激在急性酒精中毒的发病机理中起着至关重要的作用。核因子类红细胞2样2（NRF2）是细胞对氧化损伤的适应性反应的主要调节因子。但是，NRF2在急性酒精中毒及相关病理中的作用仍不清楚。我们发现，Nrf2的敲除（Nrf2的-KO）小鼠有夸张的低血糖和低体温，并与无节制乙醇暴露后野生型小鼠的死亡率增加。通过提供温暖的环境和/或葡萄糖施用，部分挽救了该表型。急性高剂量酒精暴露导致肝脏和胰腺损伤大大加重。Nrf2- KO小鼠。重要的是，Nrf2的缺乏会导致严重的胰腺炎和胰腺β细胞损伤，并在暴饮乙醇期间增加胰岛素分泌和/或渗漏，从而导致低血糖症。相反，临床上使用的NRF2活化剂富马酸二甲酯（DMF）可以防止因急性乙醇暴露引起的低血糖和致死性。此外，Nrf2- KO小鼠肝乙醛代谢可能存在缺陷。两者合计，NRF2对急性暴饮酒引起的肝和胰腺损害起着重要的保护作用，这可能部分归因于其在抗氧化剂反应和对乙醇代谢的影响中的主要调节作用。