Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
Food Chem Toxicol. 2018 Nov;121:495-503. doi: 10.1016/j.fct.2018.09.042. Epub 2018 Sep 21.
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.
binge 饮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风险因素。氧化应激在急性酒精中毒的发病机制中起着关键作用。核因子红细胞 2 样 2（NRF2）是细胞对氧化应激适应性反应的主要调节剂。然而，NRF2 在急性酒精中毒和相关病理中的作用仍不清楚。我们发现，与野生型小鼠相比，Nrf2 敲除（Nrf2-KO）小鼠在 binge 乙醇暴露后表现出明显的低血糖和低体温，死亡率增加。这种表型部分通过提供温暖的环境和/或葡萄糖给药得到挽救。急性高剂量乙醇暴露导致 Nrf2-KO 小鼠的肝和胰腺损伤明显加重。重要的是，Nrf2 的缺失允许在 binge 乙醇暴露期间发生严重的胰腺炎和胰腺β细胞损伤，导致胰岛素分泌增加和/或渗漏，从而导致低血糖。相比之下，一种临床使用的 NRF2 激活剂二甲基富马酸（DMF）可预防急性乙醇暴露引起的低血糖和致死。此外，Nrf2-KO 小鼠可能存在肝乙醛代谢缺陷。总之，NRF2 对急性 binge 酒精引起的肝和胰腺损伤具有重要的保护作用，这可能部分归因于其在抗氧化反应中的主要调节作用及其对乙醇代谢的影响。
