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Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury

 
: Lamle, J.; Marhenke, S.; Borlak, J.; Wasielewski, R. von; Eriksson, C.J.P.; Geffers, R.; Manns, M.P.; Yamamoto, M.; Vogel, A.

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Gastroenterology 134 (2008), Nr.4, S.1159-1168
ISSN: 0016-5085
Englisch
Zeitschriftenaufsatz
Fraunhofer ITEM ()
alcohol-induced liver disease; acetaldeyde; tumor necrosis factor; oxidative stress; rat hepatocytes; factor-alpha; HEPG2 cells; ethanol; polymerase chain reaction; glutathione

Abstract
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-a 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.

: http://publica.fraunhofer.de/dokumente/N-74093.html