NRF2 mitigates acute alcohol-induced hepatic and pancreatic injury in mice

Jing Sun, Jingqi Fu, Yang Zhong, Lu Li, Chengjie Chen, Xiaolei Wang, Linlin Wang, Yongyong Hou, Huihui Wang, Rui Zhao, Xixuan Zhang, Masayuki Yamamoto, Yuanyuan Xu, Jingbo Pi

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)495-503
Number of pages9
JournalFood and Chemical Toxicology
Volume121
DOIs
Publication statusPublished - 2018 Nov

Keywords

  • Alcohol
  • Alcoholism
  • Hepatic injury
  • NRF2
  • Pancreatic injury

ASJC Scopus subject areas

  • Food Science
  • Toxicology

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