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Studies on apoptosis of hepatocyte and carcinogenesis in Fah.deficiency

Fah缺乏症肝细胞凋亡与癌变的研究

基本信息

批准号：
09672313
负责人：
ENDO Fumio
金额：
$ 1.98万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672313/
关键词：
apoptosis liver failure tyrosinemia mitochondria cytochrome c gene transfer hepatocellular carcinomas 化学発がん

项目摘要

Hereditary tyrosinemia 1(HT1) is due to mutations in the fumarylacetoacetate hydrolase gene FAH, encoding the last enzyme in the tyrosine catabolic pathway. HT1 patients have severe liver damage and hepatocellular carcinomas, hence liver transplantation has to be done for such children. We developed double mutant mice in which the phenotype of the primary homozygous defect (FAH-/-) is completely concealed by another homozygous mutant allele (HPD-/-). In this model, the inherent defect can be reconstituted by in vivo gene transfer or by a metabolic procedure. These approaches facilitated investigations on the early process of hepatocyte injury, and it became clear that the hepatocyte death was due to apoptosis. Apoptosis of hepatocytes was induced and an acute onset of liver failure occurred following administration of homogentisic acid (HGA), the intermediate metabolite between HPD and FAH.Cytochrome c was released from mitochondria prior to liver failure in the Fah^<-/-> Hpd^<-/-> double mutant mice following the administration of HGA.We also found that caspase inhibitors were highly effective in preventing the liver failure induced by HGA in the double mutant mice. It is highly likely that fumarylacetoacetate apparently induces the release of cytochrome c which in turn triggers activation of the caspase cascade in hepatocytes of subjects with hereditary tyrosinemia type 1.These knowledge on the hepatic injury in HT1 will facilitate understanding of carcinogenesis in FAH deficiency.

遗传性酪氨酸血症1（HT1）是由富马酰乙酸水解酶基因FAH突变引起的，该基因编码酪氨酸分解代谢途径中的最后一种酶。HT1患者有严重的肝损伤和肝细胞癌，因此必须对这类儿童进行肝移植。我们开发了双突变小鼠，其中原发性纯合缺陷（FAH-/-）的表型完全被另一个纯合突变等位基因（HPD-/-）掩盖。在这种模型中，固有缺陷可以通过体内基因转移或代谢过程来重建。这些方法有助于研究肝细胞损伤的早期过程，并明确肝细胞死亡是由于细胞凋亡。均质酸（HGA）是介于HPD和FAH之间的中间代谢物，可诱导肝细胞凋亡并导致急性肝衰竭。在给予HGA的Fah^<-/-> Hpd^<-/->双突变小鼠中，细胞色素c在肝衰竭前从线粒体中释放。我们还发现caspase抑制剂在预防HGA引起的双突变小鼠肝功能衰竭方面非常有效。很可能是富马酰乙酸明显诱导细胞色素c的释放，进而触发遗传性1型酪氨酸血症患者肝细胞中caspase级联的激活。这些关于HT1肝损伤的知识将有助于了解FAH缺乏症的致癌作用。