Development of preventive measures of liver failures caused by HCV infection by clarification of the mechanisms of liver diseases

丙型肝炎病毒是导致包括慢性肝炎和肝细胞癌在内的各种肝功能衰竭的主要病原体。HCV感染的持续性是导致此类肝衰竭的主要问题之一。事实上，那些通过干扰素治疗而免于HCV感染的个体此后从HCV相关的肝衰竭中治愈。因此，开发有效的抗HCV药物是预防HCV相关肝病的目标之一。此外，阐明肝衰竭的发生机制有助于制定预防HCV相关疾病发作的措施。因此，本工作的目的是首先了解HCV增殖的详细机制，以获得开发抗HCV药物的知识的见解，其次，揭示肝衰竭的发展机制，这有助于制定预防肝病恶化的措施。在本研究中，我发现了以下证据：（1）环孢菌素A通过破坏亲环素的功能有效地抑制HCV基因组的复制;（2）发现了一种新的调节干扰素信号的泛素E3连接酶;（3）HCV感染引起脂质代谢和脂质转运机制的失调。这种失调对HCV的有效复制很重要。(4)脂质代谢和脂蛋白转运机制的失调可能导致肝功能衰竭的加重，因此，调节脂质代谢不仅可以预防肝脏疾病，而且可以防止HCV增殖。

Hepatitis C virus is a major causative agent for development of various liver failures including chronic hepatitis and hepatocellular carcinoma. One of the major problem of the developing such liver failures by HCV is persistent nature of HCV infection. In fact, those of individuals who became free from HCV infection by interferon treatment were cured from HCV associated liver failures thereafter. Thus, the development of efficient anti-HCV agents is one goal to prevent HCV related liver diseases. In addition, clarification of the mechanism of the development of liver failures contributes to establish preventive measures for onset of HCV-related diseases. Aims in this work are, therefore, firstly, to understand detail mechanisms of HCV proliferation to obtain insights of the knowledge to develop anti-HCV agents and, secondary, to reveal the mechanisms of the development of liver failure which contributes to develop measures to prevent exacerbation of liver diseases. In this work, I discovered following evidences; (1) Cyclosporin A inhibited HCV genome replication efficiently through impairing the function of cyclophilins, (2) a new ubiquitin E3 ligase which regulats interferon signaling was discovered, (3) HCV infection dys-regulated lipid metabolism as well as lipid transfer mechanism. And this dys-regulation is important for efficient replication of HCV. (4) Dys-regulation of lipid metabolisms and lipoprotein transfer mechanism may contribute to exacerbate of liver failure and, therefore, regulation of lipid metabolism will be therapeutics for not only prevent liver diseases but also prevent HCV proliferation.