Role of Nrf2 in preventing ethanol-induced oxidative stress and lipid accumulation
Role of Nrf2 in preventing ethanol-induced oxidative stress and lipid accumulation
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DOI：
10.1016/j.taap.2012.05.010
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发表时间：
2012-08-01
影响因子：
3.8
通讯作者：
Klaassen, Curtis D.
中科院分区：
文献类型：
--
作者：
Wu, Kai Connie;Liu, Jie;Klaassen, Curtis D.
氧化应激和脂质蓄积在酒精性肝损伤中起重要作用。先前的报道表明，在核因子红细胞2相关因子2（Nrf 2）激活小鼠的肝脏中，参与抗氧化防御的基因被诱导，而参与脂质生物合成的基因被抑制。为了研究Nrf 2在乙醇诱导的肝脏改变中的作用，用乙醇（5 g/kg，po）处理Nrf 2缺失小鼠、野生型小鼠、Nrf 2增强的kelch样ECH相关蛋白1敲除（Keap 1-KD）小鼠和Nrf 2最大活化的Keap 1肝细胞敲除（Keap 1-HKO）小鼠。6 h后采集血液和肝脏样品。乙醇增加了Nrf 2缺失小鼠和野生型小鼠血清中的丙氨酸氨基转移酶和乳酸脱氢酶活性以及硫代巴比妥酸反应物质，但在Nrf 2增强小鼠中则不然。乙醇给药后，线粒体谷胱甘肽浓度显着降低Nrf 2基因敲除小鼠，但在Nrf 2基因增强小鼠。从四种基因型小鼠分离的原代肝细胞的H（2）DCFDA染色表明，与野生型细胞相比，Nrf 2缺失细胞中的氧化应激较高，而Nrf 2增强细胞中的氧化应激较低。乙醇增加Nrf 2基因敲除小鼠的血清甘油三酯和肝脏游离脂肪酸，而这些增加在Nrf 2基因增强小鼠中减弱。此外，基础的mRNA和核蛋白水平的固醇调节元件结合蛋白1（Srebp-1）与分级Nrf 2激活下降。乙醇在Nrf 2缺失小鼠中进一步诱导Srebp-1 mRNA，但在Nrf 2增强小鼠中不诱导。总之，Nrf 2激活通过增加参与抗氧化防御的基因和减少参与脂肪生成的基因来防止酒精诱导的氧化应激和肝脏中游离脂肪酸的积累。(C)2012 Elsevier Inc. All rights reserved.
Oxidative stress and lipid accumulation play important roles in alcohol-induced liver injury. Previous reports showed that, in livers of nuclear factor erythroid 2-related factor 2 (Nrf2)-activated mice, genes involved in antioxidant defense are induced, whereas genes involved in lipid biosynthesis are suppressed. To investigate the role of Nrf2 in ethanol-induced hepatic alterations, Nrf2-null mice, wild-type mice, kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum Nrf2 activation, were treated with ethanol (5 g/kg, po). Blood and liver samples were collected 6 h thereafter. Ethanol increased alanine aminotransferase and lactate dehydrogenase activities as well as thiobarbituric acid reactive substances in serum of Nrf2-null and wild-type mice, but not in Nrf2-enhanced mice. After ethanol administration, mitochondrial glutathione concentrations decreased markedly in Nrf2-null mice but not in Nrf2-enhanced mice. H(2)DCFDA staining of primary hepatocytes isolated from the four genotypes of mice indicates that oxidative stress was higher in Nrf2-null cells, and lower in Nrf2-enhanced cells than in wild-type cells. Ethanol increased serum triglycerides and hepatic free fatty acids in Nrf2-null mice, and these increases were blunted in Nrf2-enhanced mice. In addition, the basal mRNA and nuclear protein levels of sterol regulatory element-binding protein 1(Srebp-1) were decreased with graded Nrf2 activation. Ethanol further induced Srebp-1 mRNA in Nrf2-null mice but not in Nrf2-enhanced mice. In conclusion, Nrf2 activation prevented alcohol-induced oxidative stress and accumulation of free fatty acids in liver by increasing genes involved in antioxidant defense and decreasing genes involved in lipogenesis. (C) 2012 Elsevier Inc. All rights reserved.