| Budget Amount *help |
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 2000: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 1999: ¥10,300,000 (Direct Cost: ¥10,300,000)
|
|---|
| Research Abstract |
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.
|
