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Comprehensive genome analysis using DNA microarray during liver regeneration after partial hepatectomy and living donor liver transplantation

在部分肝切除和活体肝移植后的肝再生过程中使用 DNA 微阵列进行全面的基因组分析

基本信息

批准号：
17591365
负责人：
HAKAMADA Kenichi
金额：
$ 2.37万
依托单位：
Hirosaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

Background. Liver damage with hyperbilirubinemia during regeneration of the small liver is the major hurdle to expand indications of adult living donor liver transplantation. We previously reported that decrease in multidrug resistance protein (MRP) 2 and expression of MRP3 during liver regeneration lead to conjugated hyperbilirubinemia after 90% hepatectomy in rats. However, the genetic control of these ATP binding cassette (ABC) transporters under comprehensive review of the gene expression profile during liver regeneration have not been performed yet.Methods. RNAs were prepared from three rat livers at each time point of 0,24,72, and 168 hr after 90% hepatectomy. Gene expression profile was analyzed by the Rat Genome 230 2.0 array with special references to ABC transporters. Those from rat livers treated with lipopolysaccharide after 70% hepatectomy were also analyzed.Results. Among 31,042 probes, 1587 reported genes were identified either up-or down-regulated, more than 2-fold. Among 16 ABC transporter genes, MRP2 and OATP1 were significantly down-regulated, while MRP1 and MRP3 tended to be expressed. These genetic changes were confirmed by real-time PCR. These changes were enhanced synergistically by adding lipopolysaccharide during liver regeneration.Conclusions. Microarray analysis demonstrated not only extensive gene expression profile in the regenerating liver but more specific molecular events related to bilirubin transport at the same time. Changes in expression pattern of ABC transporters, especially down-regulation of MRP2,seem the key event in liver failure during liver regeneration.

背景。小肝再生过程中肝损伤伴高胆红素血症是扩大成人活体肝移植适应症的主要障碍。我们之前报道过，大鼠肝切除90%后，肝脏再生过程中多药耐药蛋白（MRP） 2和MRP3表达的减少导致结合性高胆红素血症。然而，这些ATP结合盒（ABC）转运体在肝脏再生过程中基因表达谱的遗传控制尚未得到全面的综述。在90%肝切除术后0、24、72和168小时的每个时间点从3只大鼠肝脏中制备rna。通过大鼠基因组230 2.0阵列分析基因表达谱，并特别参考ABC转运蛋白。同时对肝切除70%后用脂多糖处理的大鼠肝脏组织进行了分析。在31,042个探针中，1587个已报道的基因被鉴定为上调或下调，超过2倍。16个ABC转运基因中，MRP2和OATP1显著下调，MRP1和MRP3趋于表达。这些遗传变化通过实时PCR证实。在肝再生过程中，添加脂多糖可协同增强这些变化。微阵列分析不仅显示了再生肝脏中广泛的基因表达谱，同时还显示了与胆红素运输相关的更具体的分子事件。ABC转运蛋白表达模式的改变，尤其是MRP2的下调，似乎是肝再生过程中肝衰竭的关键事件。