Iron-Mediated Lysosomal Membrane Permeabilization in Ethanol-Induced Hepatic Oxidative Damage and Apoptosis: Protective Effects of Quercetin.
Iron-Mediated Lysosomal Membrane Permeabilization in Ethanol-Induced Hepatic Oxidative Damage and Apoptosis: Protective Effects of Quercetin.
复制标题
乙醇诱导的肝氧化损伤和细胞凋亡中铁介导的溶酶体膜透化：槲皮素的保护作用
DOI：
10.1155/2016/4147610
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发表时间：
2016
影响因子：
--
通讯作者：
Yao P
中科院分区：
文献类型：
--
作者：
Li Y;Chen M;Xu Y;Yu X;Xiong T;Du M;Sun J;Liu L;Tang Y;Yao P
游离态的铁能催化芬顿反应产生OH自由基，在酒精性肝病（ALD）的发病机制中起重要作用。由于含铁化合物的连续分解，溶酶体含有氧化还原活性铁池。为了研究溶酶体内铁在酒精性肝损伤中的重要作用和槲皮素的潜在保护作用，雄性C57 BL/6 J小鼠饲喂含乙醇的Lieber De Carli饲料，（总热量的30%）用槲皮素或去铁胺（DFO）共处理15周，乙醇孵育的小鼠原代肝细胞用FeCl 3，DFO，和巴弗洛霉素A1在它们的最佳浓度和暴露时间。慢性乙醇消耗引起溶酶体氧化还原活性铁伴随持续氧化损伤的明显增加。铁离子介导的活性氧可引发溶酶体膜透化（LMP）和随后的线粒体凋亡。肝毒性通过减少溶酶体铁而减弱，同时通过增加溶酶体铁而加重。槲皮素可通过降低溶酶体铁和改善铁介导的LMP，显著减轻酒精性肝损伤和细胞凋亡，为槲皮素抗ALD的应用提供了新的前景。
Iron, in its free ferrous states, can catalyze Fenton reaction to produce OH∙, which is recognized as a crucial role in the pathogenesis of alcoholic liver diseases (ALD). As a result of continuous decomposition of iron-containing compounds, lysosomes contain a pool of redox-active iron. To investigate the important role of intralysosomal iron in alcoholic liver injury and the potential protection of quercetin, male C57BL/6J mice fed by Lieber De Carli diets containing ethanol (30% of total calories) were cotreated by quercetin or deferoxamine (DFO) for 15 weeks and ethanol-incubated mice primary hepatocytes were pretreated with FeCl3, DFO, and bafilomycin A1 at their optimal concentrations and exposure times. Chronic ethanol consumption caused an evident increase in lysosomal redox-active iron accompanying sustained oxidative damage. Iron-mediated ROS could trigger lysosomal membrane permeabilization (LMP) and subsequent mitochondria apoptosis. The hepatotoxicity was attenuated by reducing lysosomal iron while being exacerbated by escalating lysosomal iron. Quercetin substantially alleviated the alcoholic liver oxidative damage and apoptosis by decreasing lysosome iron and ameliorating iron-mediated LMP, which provided a new prospective of the use of quercetin against ALD.