The bile acid-activated phosphatidylinositol 3-kinase pathway inhibits Fas apoptosis upstream of bid in rodent hepatocytes.
BACKGROUND & AIMS: Bile acids differentially modulate hepatocyte injury in cholestasis. Although glycochenodeoxycholate (GCDC) induces Fas-mediated hepatocyte apoptosis, taurochenodeoxycholate (TCDC) simultaneously activates a phosphatidylinositol 3-kinase (PI 3-K)-mediated survival pathway blocking Fas apoptosis. In this study, the mechanisms by which the TCDC/ PI 3-K survival signal disrupts Fas signaling were examined. METHODS: Studies were performed in primary cultures of mouse hepatocytes and the bile-salt-transporting McNtcp.24 rat hepatoma cell line. RESULTS: GCDC, but not TCDC, resulted in cytochrome c release demonstrating that TCDC blocked apoptosis upstream of mitochondria. In contrast, both GCDC and TCDC treatment resulted in Fas aggregation and recruitment of a dominant-negative FADD green fluorescent protein (GFP) and C360S procaspase 8-GFP to the plasma membrane. Despite recruitment of procaspase 8 to the plasma membrane by both bile acids, only GCDC resulted in increases of caspase 8 activity and Bid-GFP mitochondrial translocation. However, when PI-3K was inhibited with wortmannin or dominant-negative PI 3-K, TCDC-induced Bid-GFP mitochondrial translocation and cytochrome c release. CONCLUSIONS: The TCDC/ PI 3-K survival signal blocks Fas- mediated apoptosis by preventing caspase 8 activation and Bid mitochondrial translocation. Potentiation of this survival pathway in cholestasis has the potential to attenuate liver injury.[1]References
- The bile acid-activated phosphatidylinositol 3-kinase pathway inhibits Fas apoptosis upstream of bid in rodent hepatocytes. Takikawa, Y., Miyoshi, H., Rust, C., Roberts, P., Siegel, R., Mandal, P.K., Millikan, R.E., Gores, G.J. Gastroenterology (2001) [Pubmed]
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