Hepatitis C virus core protein induces spontaneous and persistent activation of peroxisome proliferator-activated receptor α in transgenic mice: Implications for HCV-associated hepatocarcinogenesis
✍ Scribed by Naoki Tanaka; Kyoji Moriya; Kendo Kiyosawa; Kazuhiko Koike; Toshifumi Aoyama
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- French
- Weight
- 493 KB
- Volume
- 122
- Category
- Article
- ISSN
- 0020-7136
No coin nor oath required. For personal study only.
✦ Synopsis
Abstract
Persistent infection of hepatitis C virus (HCV) can lead to a high risk for hepatocellular carcinoma (HCC). HCV core protein plays important roles in HCV‐related hepatocarcinogenesis, because mice carrying the core protein exhibit multicentric HCCs without hepatic inflammation and fibrosis. However, the precise mechanism of hepatocarcinogenesis in these transgenic mice remains unclear. To evaluate whether the core protein modulates hepatocyte proliferation and apoptosis in vivo, we examined these parameters in 9‐ and 22‐month‐old transgenic mice. Although the numbers of apoptotic hepatocytes and hepatic caspase 3 activities were similar between transgenic and nontransgenic mice, the numbers of proliferating hepatocytes and the levels of numerous proteins such as cyclin D1, cyclin‐dependent kinase 4 and c‐Myc, were markedly increased in an age‐dependent manner in the transgenic mice. This increase was correlated with the activation of peroxisome proliferator‐activated receptor α (PPARα). In these transgenic mice, spontaneous and persistent PPARα activation occurred heterogeneously, which was different from that observed in mice treated with clofibrate, a potent peroxisome proliferator. We further demonstrated that stabilization of PPARα through a possible interaction with HCV core protein and an increase in nonesterified fatty acids, which may serve as endogenous PPARα ligands, in hepatocyte nuclei contributed to the core protein‐specific PPARα activation. In conclusion, these results offer the first suggestion that HCV core protein induces spontaneous, persistent, age‐dependent and heterogeneous activation of PPARα in transgenic mice, which may contribute to the age‐dependent and multicentric hepatocarcinogenesis mediated by the core protein. © 2007 Wiley‐Liss, Inc.