权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Elucidation of mechanisms of steatosis and inflammation by alcohol ingestion or HCV core protein

阐明酒精摄入或 HCV 核心蛋白引起的脂肪变性和炎症机制

基本信息

批准号：
11470040
负责人：
AOYAMA Toshifumi
金额：
$ 9.28万
依托单位：
Shinshu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470040/
关键词：
PPARα Mitochondria swelling Hepatitis C virus core protein Fatty liver Cu Zu SOD Oxidative stress βOxidation enzymes Fibrosis

项目摘要

This research project is composed of two independent studies, both of which closely relate each other through the common mediator, peroxisome proliferator-activated receptor alpha (PPARα), a nuclear receptor. The former study describes as follows : Peroxisome proliferator-activated receptor alpha (PPARα)-null mice were fed a liquid diet containing 4% (w/v) ethanol. After 6 months of this diet, all the mice suffered from severe hepatic abnormalities. The features observed in the livers of these mice, e.g., hepatic steatosis, inflammation, apoptosis, fibrosis, hepatomegaly and mitochondrial swelling, resembled the features of alcoholic liver injury in humans. The mice used in this study would seem to constitute a very useful experimental model of alcoholic damage. The results of this study suggest that the onset of hepatic abnormalities is associated with cell damage due to increases in acetaldehyde or oxidative stresses, and with the promotion of hepatocyte proliferation and other phenomena due to altered expression in growth factors or cell cycle regulators. On the other hand, the latter study describes as follows : To clarify the role of hepatitis C virus in hepatocarcinogenesis, we analyzed mice carrying the HCV core gene, which developed hepatic steatosis and hepatocellular carcinoma. The peroxisome proliferator activated receptor a content in hepatocyte nuclei increased due to its stabilization through an interaction with HCV core protein. Additionally, its functiotnal activation occurred in some particular hepatocytes male-specifically, which stimulated functions of oncogene products and cell cycle regulators, and subsequently caused occurrence of aberrant cells, accompanying outstanding accumulation of PPAR, cyclin D1 and so on in nucleus. These aberrant. cells proliferated and had a tendency to form preneoplastic clusters age-dependently. These results suggest a novel mechanism of multicentric hepatocarcinogenesis through PPARα during persistent HCV infedion.

本研究项目由两项独立的研究组成，两项研究都通过共同的介导物--核受体--过氧化物酶体增殖物激活受体α(PPARα)而密切相关。前者描述如下：PPARα基因缺失的小鼠喂饲含4%(w/v)乙醇的液体饲料。6个月后，所有的小鼠都出现了严重的肝脏异常。在这些小鼠的肝脏中观察到的特征，如肝脏脂肪变性、炎症、细胞凋亡、纤维化、肝肿大和线粒体肿胀，与人类酒精性肝损伤的特征相似。这项研究中使用的小鼠似乎构成了一个非常有用的酒精损伤的实验模型。本研究结果提示，肝脏异常的发生与乙醛或氧化应激增加引起的细胞损伤有关，与生长因子或细胞周期调节因子表达改变导致的肝细胞增殖促进等现象有关。另一方面，后一项研究描述如下：为了阐明丙型肝炎病毒在肝癌发生中的作用，我们分析了携带丙型肝炎病毒核心基因的小鼠，这些小鼠发生了肝脏脂肪变性和肝细胞癌。肝细胞核中的过氧化物酶体增殖物激活受体a的含量增加，这是因为它通过与丙型肝炎病毒核心蛋白的相互作用而稳定。此外，它的功能性激活发生在某些特定的男性特异性肝细胞中，刺激癌基因产物和细胞周期调节因子的功能，从而导致异常细胞的出现，并伴有PPAR、细胞周期蛋白D1等在细胞核内的显著积聚。这些反常现象。随着年龄的增长，细胞增殖，并有形成癌前簇的趋势。这些结果提示了一种新的机制，即在丙型肝炎病毒持续感染期间通过PPARα发生多中心肝癌。