Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury
Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury
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DOI：
10.1053/j.gastro.2008.01.011
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发表时间：
2008-04-01
期刊：
影响因子：
29.4
通讯作者：
Vogel, Arndt
中科院分区：
文献类型：
--
作者：
Lamle, Jutta;Marhenke, Silke;Vogel, Arndt
背景和目标：转录因子核因子-类红细胞2相关因子2（Nrf 2（-/-））对于保护细胞免受外源性和氧化应激是必需的。氧化应激增加与许多疾病的病理生理学有关，包括乙醇诱导的肝病。因此，研究了Nrf 2（-/-）在乙醇诱导的肝损伤中的作用。方法：野生型和Nrf 2（-/-）小鼠用乙醇饮食喂养，然后检查肝脏病理学、死亡率和乙醇代谢。结果如下：当喂食WT小鼠耐受的乙醇剂量时，Nrf 2（-/-）小鼠显示出与肝衰竭相关的死亡率显著增加。Nrf 2（-/-）小鼠表现出明显降低的乙醛解毒能力，导致有毒代谢物的积累。Nrf 2（-/-）的缺失导致了乙醇喂养小鼠肝脏中显著的脂肪变性，Srebp 1被鉴定为负责脂肪生成酶诱导的候选转录因子。此外，乙醇消耗导致总还原型谷胱甘肽和线粒体还原型谷胱甘肽的逐渐耗尽，这与Nrf 2（-/-）小鼠线粒体更明显的结构和功能变化相关。此外，乙醇喂养引起Nrf 2（-/-）小鼠中枯否细胞介导的炎症反应加重，如肿瘤坏死因子-a分泌增加和白细胞介素-6/Stat-3途径激活所示。这些变化共同导致肝细胞损伤累积的恶性循环，最终导致肝衰竭和Nrf 2（-/-）小鼠死亡。结论：我们的数据确立了Nrf 2（-/-）在保护乙醇诱导的肝损伤中的核心作用。
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.