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

Abstract

Liver injury during cholestasis reflects a balance between the effects of toxic and nontoxic bile acids. However, the critical distinction between a toxic and nontoxic bile acid remains subtle and unclear. For example, the glycine conjugate of chenodeoxycholate (GCDC) induces hepatocyte apoptosis, whereas the taurine conjugate (TCDC) does not. We hypothesized that the dissimilar cellular responses may reflect differential activation of a phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway. In the bile acid-transporting McNtcp.24 rat hepatoma cell line, TCDC, but not GCDC, stimulated PI3K activity. Consistent with this observation, inhibition of PI3K rendered TCDC cytotoxic, and constitutive activation of PI3K rendered GCDC nontoxic. Both Akt and the atypical protein kinase C isoform ζ (PKCζ) have been implicated in PI3K-dependent survival signaling. However, TCDC activated PKCζ, but not Akt. Moreover, inhibition of PKCζ converted TCDC into a cytotoxic agent, whereas overexpression of wild-type PKCζ blocked GCDC-induced apoptosis. We also demonstrate that TCDC activated nuclear factor κB (NF-κB) in a PI3K- and PKCζ-dependent manner. Moreover, inhibition of NF-κB by an IκB super-repressor rendered TCDC cytotoxic, suggesting that NF-κB is also necessary to prevent the cytotoxic effects of TCDC. Collectively, these data suggest that some hydrophobic bile acids such as TCDC activate PI3K-dependent survival pathways, which prevent their otherwise inherent toxicity.