The bile acid taurochenodexoycholate activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade

Liver injury during cholestasis reflects a balance between the effects of t oxic and nontoxic bile acids. However, the critical distinction between a t oxic and nontoxic bile acid remains subtle and unclear. For example, the gl ycine conjugate of chenodeoxycholate (GCDC) induces hepatocyte apoptosis, w hereas the taurine conjugate (TCDC) does not. We hypothesized that the diss imilar cellular responses may reflect differential activation of a phosphat idylinositol 3-kinase (PI3K)-dependent signaling pathway. In the bile acid- transporting McNtcp.24 rat hepatoma cell line, TCDC, but not GCDC, stimulat ed PI3K activity. Consistent with this observation, inhibition of PI3K rend ered TCDC cytotoxic, and constitutive activation of PI3K rendered GCDC nont oxic. Both Akt and the atypical protein kinase C isoform zeta (PKC zeta) ha ve been implicated in PI3K-dependent survival signaling. However, TCDC acti vated PKC zeta, but not Akt, Moreover, inhibition of PKC zeta converted TCD C into a cytotoxic agent, whereas overexpression of wild-type PKC zeta bloc ked GCDC-induced apoptosis, We also demonstrate that TCDC activated nuclear factor kappa B (NF-kappa B) in a PI3K- and PKC zeta-dependent manner. More over, inhibition of NF-kappa B by an I kappa B super-repressor rendered TCD C cytotoxic, suggesting that NF-kappa B is also necessary to prevent the cy totoxic effects of TCDC, Collectively, these data suggest that some hydroph obic bile acids such as TCDC activate PI3K-dependent survival pathways, whi ch prevent their otherwise inherent toxicity.