| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2003: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Research Abstract |
We studied that effects of bile acids on apoptosis and cell proliferation in hepatocytes through regulation of transcription factor such as NF-κB and farnesoid X receptor (FXR). NF-κB playd a pivotal role in anti-apoptosis and cell survival. In addition, FXR is an orphan nuclear transcription factor that has been identified as a negative regulator of cholesterol 7α-hydroxylase, the rate-limiting enzyme in the classic bile acid synthesis pathway. However, little is known about bile acid-modulated apoptosis and cell proliferation in human normal hepatocytes. First, we showed that high concentration of bile acids induced apoptosis in hepatocytes. Moreover, high dose-bile acids-induced apoptosis was inhibited by caspase-9 inhibitor, but not by caspases-8 inhibitor, suggesting that hepatocytes apoptosis induced by high doase-bile acids is via mitochondrial injury. In contrast, low dose-bile acids did not induce apoptosis and up-regulated anti-apoptotic protein such as IAP-1 through activation of NF-κB. Additionally, bile acids transactivated cyclin D1 gene and induced cell proliferation in hepatocytes. Next, we examined interaction between FXR and NF-κB. Luciferase assay showed that FXR transactivated NF-κB-driven gene expression in a dose dependent manner. In addition, we presented that bile acids phosphorylated IκB kinase. Moreover, DNA array analysis demonstrated that bile acid-targeted genes were PI3 kinase and protein kinase C in addition to anti-apoptotic protein IAP-1 and cell proliferative factor cyclin D1. Given these results, we found for the first time that bile acids, especially low-dose, induced anti-apoptotic and cell survival pathway through interaction between FXR and NF-κB.
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