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

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Abstract
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.