Department of Surgery, Washington University in St Louis, School of Medicine, St Louis, MO, USA.
BMC Biochem. 2012 Sep 10;13:17. doi: 10.1186/1471-2091-13-17.
The molecular basis of the increased susceptibility of steatotic livers to warm ischemia/reperfusion (I/R) injury during transplantation remains undefined. Animal model for warm I/R injury was induced in obese Zucker rats. Lean Zucker rats provided controls. Two dimensional differential gel electrophoresis was performed with liver protein extracts. Protein features with significant abundance ratios (p < 0.01) between the two cohorts were selected and analyzed with HPLC/MS. Proteins were identified by Uniprot database. Interactive protein networks were generated using Ingenuity Pathway Analysis and GRANITE software.
The relative abundance of 105 proteins was observed in warm I/R injury. Functional grouping revealed four categories of importance: molecular chaperones/endoplasmic reticulum (ER) stress, oxidative stress, metabolism, and cell structure. Hypoxia up-regulated 1, calcium binding protein 1, calreticulin, heat shock protein (HSP) 60, HSP-90, and protein disulfide isomerase 3 were chaperonins significantly (p < 0.01) down-regulated and only one chaperonin, HSP-1 was significantly upregulated in steatotic liver following I/R.
Down-regulation of the chaperones identified in this analysis may contribute to the increased ER stress and, consequently, apoptosis and necrosis. This study provides an initial platform for future investigation of the role of chaperones and therapeutic targets for increasing the viability of steatotic liver allografts.
在移植过程中，脂肪肝对温热缺血/再灌注（I/R）损伤的易感性增加的分子基础仍未确定。使用肥胖型 Zucker 大鼠诱导温热 I/R 损伤的动物模型。 lean Zucker 大鼠作为对照。对肝蛋白提取物进行二维差异凝胶电泳。选择两组之间丰度比值有显著差异（p<0.01）的蛋白质特征，并进行 HPLC/MS 分析。通过 Uniprot 数据库鉴定蛋白质。使用 Ingenuity Pathway Analysis 和 GRANITE 软件生成交互式蛋白质网络。
在温热 I/R 损伤中观察到 105 种蛋白质的相对丰度。功能分组显示出四个重要类别：分子伴侣/内质网（ER）应激、氧化应激、代谢和细胞结构。缺氧上调 1、钙结合蛋白 1、钙网蛋白、热休克蛋白（HSP）60、HSP-90 和蛋白二硫键异构酶 3 是显著下调的伴侣素（p<0.01），只有一种伴侣素 HSP-1 在 I/R 后脂肪肝中显著上调。
本研究中鉴定的伴侣素下调可能导致 ER 应激增加，进而导致细胞凋亡和坏死。该研究为进一步研究伴侣素在增加脂肪肝同种异体移植物活力中的作用和治疗靶点提供了初步平台。
