Figure 1.

Bile acid (BA)-induced apoptotic and prosurvival signaling. Internalized toxic (more hydrophobic) bile acids, such as glycine-conjugated form of chenodeoxycholic acid (GCDC), trigger death-receptor-mediated apoptosis. BA stimulate microtubule-dependent trafficking of Fas from the Golgi compartment to the plasma membrane, increasing Fas density on the cell surface and promoting spontaneous Fas oligomerization independent of FasL. This results in activation of caspase 8, which, in turn, cleaves Bid, whose truncated form translocates to mitochondria and cooperates with Bax to induce mitochondrial outer membrane permeabilization (MOMP). Following MOMP, several apoptogenic factors, such as cytochrome c, apoptosis-inducing factor and second mitochondrial activator of caspases, are released into the cytosol, which ultimately promote the activation of effector caspases-3, 6, and 7, and cell death. Moreover, BA activate c-jun N-terminal kinase, resulting in activation of the transcription factor Sp1 (specificity protein 1), which, in turn, upregulates death receptor 5 sensitizing the hepatocytes also to TRAIL-induced apoptosis. Nontoxic BA, such as tauro-conjugate of chenodeoxycholic acid and ursodeoxycholic acid, can also trigger plasma membrane trafficking and activation of Fas. However, the simultaneous activation of cytoprotective pathways which prevent activation of key players such as caspase 8, Bid, or Bax, blocks the apoptotic cascade and inhibits cell death.