Hepatitis C as a Metabolic Disease : Pathogenesis for liver cancer and lifestyle-related diseases

除了与肝细胞癌（HCC）的发展有关外，丙型肝炎病毒（HCV）感染还与几种肝脏和肝外表现有关。肝脂肪变性在慢性丙型肝炎发病机制中的作用已被证明，这意味着丙型肝炎是一种代谢性疾病。此外，最近的流行病学研究表明胰岛素抵抗和慢性HCV感染之间存在联系。除了表明慢性丙型肝炎患者队列中存在脂质代谢紊乱和胰岛素抵抗的数据外，我们还发现了一系列证据，表明这两种情况与HCV感染之间存在关联，使用HCV核心基因转基因小鼠。这些小鼠在肝脂肪变性和胰岛素抵抗阶段之后在生命后期发展HCC。蛋白酶体激活因子28 g基因缺失的HCV核心基因转基因小鼠中脂肪变性和肝癌均未出现，提示脂质代谢紊乱与肝癌发生密切相关。此外，核心蛋白显示与类视黄醇X受体（RXR）-a结合，导致一些脂质代谢酶包括细胞视黄醇结合蛋白II和酰基辅酶A氧化酶的上调。此外，最近在HCV核心基因转基因小鼠的肝脏中发现了过氧化物酶体增殖物激活受体（peroxisome proliferator activated receptor，PPAR-a）的持续激活，产生脂质代谢和肝细胞增殖（包括HCC发展）的显著变化。这些结果为进一步了解脂质代谢在HCV感染的肝损伤和肝癌发生中的作用提供了线索。

In addition to the link with development of hepatocellular carcinoma (HCC), hepatitis C virus (HCV) infection is associated with several hepatic and extrahepatic manifestations. A role of hepatic steatosis in the pathogenesis of chronic hepatitis C has been shown, implying hepatitis C as a metabolic disease. Furthermore, recent epidemiological studies have suggested a linkage between insulin resistance and chronic HCV infection. Besides the data indicating the presence of lipid metabolism disturbance and insulin resistance in the cohort of chronic hepatitis C patients, we found a series of evidence showing the association between these two conditions and HCV infection using mice transgenic for the HCV core gene. These mice develop HCC late in life after the phase of hepatic steatosis and insulin resistance. The nonappearance of both steatosis and HCC in HCV core gene transgenic mice that are null for the proteasome activator 28g, implies a close relationship between lipid metabolism disturbance and hepatocarcinogenesis. Also, the core protein is shown to bind with retinoid X receptor (RXR)-a, resulting in the up-regulation of some lipid metabolism enzymes including cellular retinol binding protein II and acyl-CoA oxidase. In addition, the persistent activation of peroxisome proliferator activated receptor (PPAR)-a has recently been found in the liver of HCV core gene transgenic mice, yielding dramatic changes in the lipid metabolism and hepatocyte proliferation including HCC development. These results would provide a clue for further understanding of the role of lipid metabolism in pathogenesis of HCV infection including liver injury and hepatocarcinogenesis.