Synergistic Interaction of Light Alcohol Administration in the Presence of Mild Iron Overload in a Mouse Model of Liver Injury: Involvement of Triosephosphate Isomerase Nitration and Inactivation.
Synergistic Interaction of Light Alcohol Administration in the Presence of Mild Iron Overload in a Mouse Model of Liver Injury: Involvement of Triosephosphate Isomerase Nitration and Inactivation.
复制标题
在小鼠肝损伤模型中存在轻度铁过载的情况下，轻质酒精给药的协同相互作用：磷酸丙糖异构酶硝化和失活的参与
DOI：
10.1371/journal.pone.0170350
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Gao W;Zhao J;Gao Z;Li H
众所周知，铁超载促进酒精性肝损伤，但研究中使用的铁或酒精剂量通常能够独立地诱导肝损伤。很少有人注意到低酒精消费和轻度铁超载的共存，当它们中的任何一个都不足以引起明显的肝损伤时，尽管这种情况在一些人中很常见。我们研究了低剂量铁和酒精对小鼠肝损伤的相互作用及其机制。48只雄性昆明种小鼠随机分为4组：对照组、铁（右旋糖酐铁300 mg/kg，i. p.）酒精（2g/kg/天乙醇，i.g.四周），铁加酒精组。治疗4周后，处死小鼠，收集血液和肝脏用于生化分析。采用免疫沉淀法和Western blot法测定肝组织蛋白质硝化水平。虽然铁超载和饮酒在我们的测试剂量下都不会引起严重的肝损伤，但发现相同剂量的酒精和铁共同给药会导致肝损伤和肝功能障碍，伴随着NADH/NAD+比值升高，抗氧化能力降低，氧化应激增加，随后蛋白质硝化水平升高。进一步的研究表明，磷酸丙糖异构酶是一种重要的糖酵解酶，它是被氧化和硝化的目标之一，这是导致其失活的原因。这些数据表明，即使在低酒精摄入下，一定量的铁超载也会引起明显的肝脏氧化损伤，磷酸丙糖异构酶的修饰可能是肝功能损害的重要基础机制。
It is well known that iron overload promotes alcoholic liver injury, but the doses of iron or alcohol used in studies are usually able to induce liver injury independently. Little attention has been paid to the coexistence of low alcohol consumption and mild iron overload when either of them is insufficient to cause obvious liver damage, although this situation is very common among some people. We studied the interactive effects and the underlining mechanism of mild doses of iron and alcohol on liver injury in a mouse model. Forty eight male Kunming mice were randomly divided into four groups: control, iron (300 mg/kg iron dextran, i.p.), alcohol (2 g/kg/day ethanol for four weeks i.g.), and iron plus alcohol group. After 4 weeks of treatment, mice were sacrificed and blood and livers were collected for biochemical analysis. Protein nitration level in liver tissue was determined by immunoprecipitation and Western blot analysis. Although neither iron overload nor alcohol consumption at our tested doses can cause severe liver injury, it was found that co-administration of the same doses of alcohol and iron resulted in liver injury and hepatic dysfunction, accompanied with elevated ratio of NADH/NAD+, reduced antioxidant ability, increased oxidative stress, and subsequent elevated protein nitration level. Further study revealed that triosephosphate isomerase, an important glycolytic enzyme, was one of the targets to be oxidized and nitrated, which was responsible for its inactivation. These data indicate that even under low alcohol intake, a certain amount of iron overload can cause significant liver oxidative damage, and the modification of triosephosphate isomerasemight be the important underlining mechanism of hepatic dysfunction.