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

1. NASH相关基因的鉴定我们对NASH患者的240个微卫星位点进行了分析，发现4个位点与NASH的发生有关。在4个位点中的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本人中是常见的。这些观察结果可以部分解释NASH在日本人群中非常常见的原因。2.微粒体甘油三酯转移蛋白的功能分析一个功能性单核苷酸多态性被确定位于微粒体甘油三酯转移蛋白基因，该基因编码一种参与甘油三酯与载脂蛋白B结合的酶。由于这种酶的变体形式的纯合子在极低密度脂蛋白的分泌中受损，因此它们容易发生大量的肝脂肪变性。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。高脂饮食也未能加速肝脏中的脂肪沉积，这可能是由于肠细胞中甘油三酯摄取受损，因为这种酶不仅在肝细胞中表达，而且在肠细胞中表达。相反，静脉注射甘油三酯容易引起大量的肝脏沉积，并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。

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.