Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury.
OBJECTIVE
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-alpha 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.
Lamlé
Jutta
J
Department of Hepatology, Gastroenterology and Endocrinology, Hannover, Germany.
Marhenke
Silke
S
Borlak
Jürgen
J
von Wasielewski
Reinhard
R
Eriksson
C J Peter
CJ
Geffers
Robert
R
Manns
Michael P
MP
Yamamoto
Masayuki
M
Vogel
Arndt
A
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D015153:Blotting, Western; D002492:Central Nervous System Depressants / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D000431:Ethanol / Q000633:toxicity; D005500:Follow-Up Studies; D015870:Gene Expression; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007527:Isoenzymes; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008104:Liver Cirrhosis, Alcoholic / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000627:therapeutic use*; D018384:Oxidative Stress; D012313:RNA / Q000235:genetics; D050697:Retinal Dehydrogenase; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000096:biosynthesis / Q000235:genetics; D000637:Transaminases / Q000378:metabolism
D002492:Central Nervous System Depressants; D007527:Isoenzymes; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D000431:Ethanol; D012313:RNA; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D000637:Transaminases