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

本课题由两项独立研究组成，两项研究通过共同的介质——核受体过氧化物酶体增殖体激活受体α (PPARα)密切相关。前者的研究内容如下：过氧化物酶体增殖物激活受体α (PPARα)缺失小鼠喂食含有4% （w/v）乙醇的液体饲料。这种饮食6个月后，所有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。在这项研究中使用的老鼠似乎构成了一个非常有用的酒精损伤实验模型。本研究的结果表明，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引起的肝细胞增殖和其他现象有关。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HCV核心基因的小鼠，这些小鼠发生肝脂肪变性和肝细胞癌。过氧化物酶体增殖物激活受体a通过与丙型肝炎病毒核心蛋白的相互作用而稳定，其在肝细胞核中的含量增加。此外，它的功能性激活发生在男性特异性的一些特定肝细胞中，刺激癌基因产物和细胞周期调节因子的功能，导致异常细胞的发生，并伴随PPAR、cyclin D1等在细胞核内的显著积累。这些异常。细胞增殖并有形成肿瘤前簇的倾向，这与年龄有关。这些结果提示PPARα在持续HCV感染期间通过多中心肝癌发生的新机制。

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.