Chronic oxidative stress sensitizes hepatocytes to death from 4-hydroxynonenal by JNK/c-Jun overactivation
Chronic oxidative stress sensitizes hepatocytes to death from 4-hydroxynonenal by JNK/c-Jun overactivation
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DOI：
10.1152/ajpgi.00151.2009
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发表时间：
2009-11-01
影响因子：
4.5
通讯作者：
Czaja, Mark J.
中科院分区：
文献类型：
--
作者：
Singh, Rajat;Wang, Yongjun;Czaja, Mark J.
王勇，王勇，王勇。慢性氧化应激通过JNK/c-Jun过度激活使4-羟基壬烯醛致肝细胞死亡。[J] .中国生物医学工程学报，2009,31(2):557 - 557。2009年9月17日首次出版；doi: 10.1152 / ajpgi.00151.2009。c-Jun nh2末端激酶（JNK）信号通路的持续激活介导实验性饮食诱导的非酒精性脂肪性肝病（NAFLD）的发生和进展。因此，描述脂肪肝中JNK过度激活的机制对于理解NAFLD的病理生理至关重要。人类和实验NAFLD都与氧化应激和由此产生的脂质过氧化有关，这被认为介导了这种疾病从单纯脂肪变性到脂肪性肝炎的进展。氧化剂和脂质过氧化产物4-羟基壬烯醛（HNE）激活JNK信号的能力表明，这两个因素可能协同作用，引发JNK过度激活。因此，在慢性氧化应激下的细胞中，通过过度表达促氧化酶细胞色素P450 2E1 (CYP2E1)，研究了HNE对肝细胞损伤和JNK激活的影响，这种情况发生在NAFLD中。cyp2e1产生的氧化应激使大鼠肝细胞系从正常无毒浓度的HNE中致敏死亡。由于γ -谷氨酰半胱氨酸合成酶活性降低而继发的HNE， cyp2e1过表达的细胞经历了更深刻的谷胱甘肽（GSH）消耗。GSH耗竭导致JNK/c-Jun信号在丝裂原活化蛋白激酶激酶4水平上过度激活，从而诱导细胞死亡。氧化应激和脂质过氧化产物HNE在肝细胞中引起JNK/c-Jun信号通路的协同过度激活，表明HNE可能不仅仅是肝氧化应激的被动生物标志物，而是通过影响JNK信号传导而成为肝细胞损伤的主动介质。
Singh R, Wang Y, Schattenberg JM, Xiang Y, Czaja MJ. Chronic oxidative stress sensitizes hepatocytes to death from 4-hydroxynonenal by JNK/c-Jun overactivation. Am J Physiol Gastrointest Liver Physiol 297: G907-G917, 2009. First published September 17, 2009; doi:10.1152/ajpgi.00151.2009.-Sustained activation of the c-Jun NH2-terminal kinase (JNK) signaling pathway mediates the development and progression of experimental diet-induced nonalcoholic fatty liver disease (NAFLD). Delineating the mechanism of JNK overactivation in the setting of a fatty liver is therefore essential to understanding the pathophysiology of NAFLD. Both human and experimental NAFLD are associated with oxidative stress and resultant lipid peroxidation, which have been proposed to mediate the progression of this disease from simple steatosis to steatohepatitis. The ability of oxidants and the lipid peroxidation product 4-hydroxynonenal (HNE) to activate JNK signaling suggested that these two factors may act synergistically to trigger JNK overactivation. The effect of HNE on hepatocyte injury and JNK activation was therefore examined in cells under chronic oxidant stress from overexpression of the prooxidant enzyme cytochrome P450 2E1 (CYP2E1), which occurs in NAFLD. CYP2E1-generated oxidant stress sensitized a rat hepatocyte cell line to death from normally nontoxic concentrations of HNE. CYP2E1-overexpressing cells underwent a more profound depletion of glutathione (GSH) in response to HNE secondary to decreased gamma-glutamylcysteine synthetase activity. GSH depletion led to overactivation of JNK/c-Jun signaling at the level of mitogen-activated protein kinase kinase 4 that induced cell death. Oxidant stress and the lipid peroxidation product HNE cause synergistic overactivation of the JNK/c-Jun signaling pathway in hepatocytes, demonstrating that HNE may not be just a passive biomarker of hepatic oxidant stress but rather an active mediator of hepatocellular injury through effects on JNK signaling.