The bile acid-activated phosphatidylinositol 3-kinase pathway inhibits Fas apoptosis upstream of Bid in rodent hepatocytes

Yasuhiro Takikawa, Hideyuki Miyoshi, Christian Rust, Patricia Roberts, Richard Siegel, Pijus K. Mandal, Randal E. Millikan, Gregory J. Gores

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

Backgrounds & Aims: Bile acids differentially modulate hepatocyte injury in cholestasis. Although glycochenode-oxycholate (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.

Original languageEnglish (US)
Pages (from-to)1810-1817
Number of pages8
JournalGastroenterology
Volume120
Issue number7
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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