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.

该研究项目由两项独立研究组成，两项研究都通过公共介体，过氧化物体增生剂激活的受体α（PPARα）（核受体）密切相互关联。前一项研究描述的如下：过氧化物体增殖物激活的受体α（PPARα）null小鼠被喂食含有4％（w/v）乙醇的液体饮食。饮食六个月后，所有小鼠患有严重的肝异常。在这些小鼠的生活中观察到的特征，例如肝脂肪变性，感染，凋亡，纤维化，肝肿大和线粒体吞咽，类似于人类酒精肝损伤的特征。这项研究中使用的小鼠似乎构成了酒精损害的非常有用的实验模型。这项研究的结果表明，由于乙醛或氧化应激的增加以及肝细胞增殖的促进和其他现象，由于生长因子或细胞周期调节剂的表达改变而引起的肝细胞增殖和其他现象，肝脏异常的发作与细胞损伤有关。另一方面，后来的研究描述为：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HCV核心基因的小鼠，后者发展了肝脂肪变性和肝细胞癌。过氧化物组激活的受体A在肝细胞核中激活的受体A含量通过与HCV核心蛋白的相互作用而增加。此外，其功能性激活发生在某些特定的肝细胞中，刺激了癌基因产物和细胞周期调节剂的功能，随后引起异常细胞的发生，参与了PPAR的未来积累，细胞周期蛋白D1等在核心中。这些异常。细胞增殖，并具有依赖年龄依赖性的质塑料簇的趋势。这些结果表明，在持续性HCV INFEDION期间，通过PPARα的多中心肝癌发生了一种新的机制。