The bile acid–activated phosphatidylinositol 3-kinase pathway inhibits Fas apoptosis upstream of bid in rodent hepatocytes
| Autor: | Patricia J. Roberts, Hideyuki Miyoshi, Yasuhiro Takikawa, Christian Rust, Pijus K. Mandal, Gregory J. Gores, R. E. Millikan, Richard M. Siegel |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Male
Fas-Associated Death Domain Protein Apoptosis Cytochrome c Group Caspase 8 Fas ligand Wortmannin Mice Phosphatidylinositol 3-Kinases chemistry.chemical_compound Glycochenodeoxycholic Acid Animals fas Receptor FADD Phosphatidylinositol Adaptor Proteins Signal Transducing Enzyme Precursors Taurodeoxycholic Acid Cholestasis Hepatology biology Cytochrome c Gastroenterology Caspase 9 Mitochondria Cell biology Enzyme Activation Mice Inbred C57BL chemistry Biochemistry Caspases Death-inducing signaling complex biology.protein Carrier Proteins BH3 Interacting Domain Death Agonist Protein |
| Zdroj: | Gastroenterology. 120:1810-1817 |
| ISSN: | 0016-5085 |
| DOI: | 10.1053/gast.2001.24835 |
| Popis: | Backgrounds & 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. GASTROENTEROLOGY 2001;120:1810-1817 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|