Gao Wanxia, Zhao Jie, Gao Zhonghong, Li Hailing
School of Chemistry and Chemical Engineering, Huazhong University of Science & Technology, Wuhan, P. R. China.
Basis medical college, Hubei University of Science and Technology, Xianning, P. R. China.
PLoS One. 2017 Jan 19;12(1):e0170350. doi: 10.1371/journal.pone.0170350. eCollection 2017.
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.
众所周知，铁过载会促进酒精性肝损伤，但研究中使用的铁或酒精剂量通常能够独立诱导肝损伤。当低酒精摄入量和轻度铁过载共存时，尽管这种情况在某些人群中非常普遍，但由于它们各自都不足以引起明显的肝损伤，因此很少受到关注。我们在小鼠模型中研究了低剂量铁和酒精对肝损伤的交互作用及其潜在机制。48只雄性昆明小鼠被随机分为四组：对照组、铁组（腹腔注射300mg/kg葡聚糖铁）、酒精组（四周内每天灌胃2g/kg乙醇）和铁加酒精组。治疗4周后，处死小鼠并采集血液和肝脏进行生化分析。通过免疫沉淀和蛋白质印迹分析测定肝组织中的蛋白质硝化水平。尽管我们测试剂量的铁过载和酒精摄入均未导致严重肝损伤，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，同时伴有NADH/NAD+比值升高、抗氧化能力降低、氧化应激增加以及随后蛋白质硝化水平升高。进一步研究表明，磷酸丙糖异构酶是一种重要的糖酵解酶，是被氧化和硝化的靶点之一，这导致了其失活。这些数据表明，即使在低酒精摄入情况下，一定量的铁过载也会导致明显的肝脏氧化损伤，而磷酸丙糖异构酶的修饰可能是肝功能障碍的重要潜在机制。
