Background & Aims: The transcription factor nuclear factor-eythroid 2-related factor 2 (Nrf2-/-) is essential for protecting cells against xenobiotic and oxidative stress. Increased oxidative stress has been implicated in the pathophysiology of many diseases including ethanol-induced liver disease. Therefore, the role of Nrf2-/- in ethanol-induced liver injury was investigated. Methods: Wild-type and Nrf2-/- mice were fed with the ethanol diet, followed by examination of liver pathology, mortality, and ethanol metabolism. Results: Nrf2-/- mice displayed a dramatically increased mortality associated with liver failure when fed doses of ethanol that were tolerated by WT mice. Nrf2-/- mice showed a significantly reduced ability to detoxify acetaldehyde, leading to an accumulation of the toxic metabolite. Loss of Nrf2-/- caused a marked steatosis in livers of ethanol-fed mice, and Srebp1 was identified as a candidate transcription factor responsible for lipogenic enzyme induction. Furthermore, ethanol consumption led to a progressive depletion of total and mitochondrial reduced glutathione, which was associated with more pronounced structural and functional changes to mitochondria of Nrf2-/- mice. In addition, ethanol feeding elicited an aggravated inflammatory response mediated by Kupffer cells in Nrf2-/- mice as shown by an increased tumor necrosis factor-α secretion and activation of the interleukin-6/Stat-3 pathway. Together these changes lead to a vicious cycle of accumulating hepatocellular damage, ultimately leading to liver failure and death of Nrf2-/- mice. Conclusions: Our data establish a central role for Nrf2-/- in the protection against ethanol-induced liver injury.
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