Investigation in the mechanisms involved in the development of nonalcoholic steatohepatitis and its clinical application

非酒精性脂肪性肝炎发生机制的探讨及其临床应用

基本信息

批准号：
16590600
负责人：
SAIBARA Toshiji
金额：
$ 2.62万
依托单位：
Kochi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590600/
关键词：
NASH ANIMAL MODEL OBESITY MTP NASH インスリン抵抗性脂肪肝酸化ストレス

项目摘要

1.Identification of NASH-related genesWe analyzed 240 loci of microsatellites in NASH patients and 4 loci were identified to be involved in the development of NASH. In 3 of the 4 loci, we succeeded in identifying functional single nucleotide polymorphisms of genes in disequilibrium with these microsatellites. All of these functional single nucleotide polymorphisms are frequent in Japanese. These observations could partially explain why NASH is very frequent among Japanese population.2.Functional analysis of microsomal triglyceride transfer proteinOne functional single nucleotide polymorphism was identified to be located in the microsomal triglyceride transfer protein gene that encodes an enzyme involved in conjugating triglycerides with apolipoprotein B. As homozygotes of variant form of this enzyme are impaired in secretion of very low density lipoprotein, they are susceptible to massive hepatic steatosis. Therefore, knockout mouse of microsomal triglyceride transfer protein was developed, but there was no obvious fat deposition in the liver High fat diet also failed to accelerate fat deposition in the liver possibly due to impaired triglyceride uptake in enterocytes since this enzyme is expressed not only in hepatocytes but also in enterocytes. On the contrary, intravenous administration of triglyceride easily induced massive hepatic deposition and provided a useful tool for investigating the mechanism of the development of nonalcoholic steatohepatitis.

1.NASH相关基因的鉴定我们分析了NASH患者的240个微卫星位点，鉴定出4个位点参与NASH的发生发展。在 4 个基因座中的 3 个中，我们成功地鉴定了与这些微卫星不平衡的基因的功能性单核苷酸多态性。所有这些功能性单核苷酸多态性在日语中都很常见。这些观察结果可以部分解释为什么NASH在日本人群中非常常见。2.微粒体甘油三酯转移蛋白的功能分析在微粒体甘油三酯转移蛋白基因中发现一个功能性单核苷酸多态性，该基因编码参与甘油三酯与载脂蛋白B结合的酶由于这种酶的变异形式的纯合子极低密度脂蛋白的分泌受到损害，因此它们容易发生严重的肝脂肪变性。因此，开发了微粒体甘油三酯转移蛋白的敲除小鼠，但肝脏中没有明显的脂肪沉积。高脂肪饮食也未能加速肝脏中的脂肪沉积，可能是由于肠上皮细胞对甘油三酯的摄取受损，因为这种酶不仅在肝脏中表达，肝细胞，但也存在于肠细胞中。相反，静脉注射甘油三酯很容易引起大量肝脏沉积，为研究非酒精性脂肪性肝炎的发生机制提供了有用的工具。

项目成果

期刊论文数量（78）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NASH の治療

NASH 的治疗

DOI：
发表时间：
2005
期刊：
消化器内視鏡 17
影响因子：
0
作者：
Lin T;Sakata H;Ootani A;Fujise T;Tsunada S;Amemori S;Danjo A;Yokoyama F;Sakata Y;Iwakiri R;Toda S;Fujimoto K.;Togashi T;西原利治
通讯作者：
西原利治