期刊
FOOD AND CHEMICAL TOXICOLOGY
卷 121, 期 -, 页码 495-503出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.fct.2018.09.042
关键词
NRF2; Alcohol; Hepatic injury; Pancreatic injury; Alcoholism
资金
- National Natural Science Foundation of China [81402635, 81573106, 81830099, 81573187]
- Liaoning Pandeng Scholar Program
- Liaoning Province Natural Science Foundation [20180530011]
- China Medical University Training Program for National Natural Science Fund for Excellent Young Scholars [YQ20170001]
- Program for Liaoning Innovative Research Team in University [LT2015028]
- China Medical University
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-K0 mice. Importantly, deficiency of Nrf2 allowed severe pancreatitis and pancreatic beta-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.
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