Chenodeoxycholic acid and taurochenodexycholic acid induce anti‐apoptotic cIAP‐1 expression in human hepatocytes

Background and Aims:  Increased concentration of endogenous bile acids in the liver correlates with clinical features of cholestatic liver diseases. Recently, it was reported that non-toxic hydrophobic bile acid activated a survival signaling pathway via phosphatidylinositol 3 (PI3) kinase in hepatocytes. However, whether bile acid induces inhibitors of apoptosis protein (IAPs) directly in human hepatocytes remains unknown. This study investigated effects of bile acids on cIAP-1, cIAP-2 and XIAP expression in hepatocytes. Methods:  Human fetal hepatocytes and HepG2 cells were treated with free or conjugated chenodeoxycholic acid (CDCA) or ursodeoxycholic acid in the presence or absence of several inhibitors. Reverse transcriptase-polymerase chain reaction and Western blot analyses were performed for mRNA and protein expressions, respectively, of IAPs. Luciferase assay was used to investigate transcriptional activity of nuclear factor (NF)-κB. Results:  Chenodeoxycholic acid up-regulated both mRNA and protein expressions of cIAP-1. In particular, taurochenodeoxycholic acid (TCDCA), but not glycochenodeoxycholic acid (GCDCA), induced cIAP-1 mRNA expression. In contrast, cIAP-2 and XIAP mRNA expressions were not influenced by CDCA. Moreover, CDCA-induced cIAP-1 mRNA expression was inhibited completely by calphostin C and SB203580, but not by wortmannin. Luciferase assay showed that CDCA and TCDCA activated NF-κB-driven transcriptional activity. Conclusion:  It was shown that CDCA induced cIAP-1 expression in hepatocytes through protein kinase C- and p38 mitogen-activated protein kinase-mediated pathway. Especially, TCDCA, but not GCDCA, increased cIAP-1 mRNA expression and NF-κB-regulated transcriptional activity. Therefore, it is suggested that CDCA and TCDCA themselves have an inhibitory potential against apoptosis through the cIAP-1-survival signaling pathway, in addition to PI3 kinase-dependent pathway.