title: The bile acid-activated phosphatidylinositol 3-kinase pathway inhibits Fas apoptosis upstream of bid in rodent hepatocytes.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Takikawa
authors.forename: H
authors.initials: H
authors.lastname: Miyoshi
authors.forename: C
authors.initials: C
authors.lastname: Rust
authors.forename: P
authors.initials: P
authors.lastname: Roberts
authors.forename: R
authors.initials: R
authors.lastname: Siegel
authors.forename: P K
authors.initials: PK
authors.lastname: Mandal
authors.forename: R E
authors.initials: RE
authors.lastname: Millikan
authors.forename: G J
authors.initials: GJ
authors.lastname: Gores
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002779:Cholestasis / Q000209:etiology; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein; D005999:Glycochenodeoxycholic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D013657:Taurodeoxycholic Acid / Q000494:pharmacology*; D019014:fas Receptor / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D002352:Carrier Proteins; D003574:Cytochrome c Group; D004792:Enzyme Precursors; C505534:Fadd protein, mouse; C505535:Fadd protein, rat; D053200:Fas-Associated Death Domain Protein; D019014:fas Receptor; D013657:Taurodeoxycholic Acid; D005999:Glycochenodeoxycholic Acid; D019869:Phosphatidylinositol 3-Kinases; C505526:Casp8 protein, mouse; C505528:Casp8 protein, rat; C506434:Casp9 protein, mouse; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases