taurochenodeoxycholic-acid and Carcinogenesis

Dysregulated bile acids (BAs) are closely associated with liver diseases and attributed to altered gut microbiota. Here, we show that the intrahepatic retention of hydrophobic BAs including deoxycholate (DCA), taurocholate (TCA), taurochenodeoxycholate (TCDCA), and taurolithocholate (TLCA) were substantially increased in a streptozotocin and high fat diet (HFD) induced nonalcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) mouse model. Additionally chronic HFD-fed mice spontaneously developed liver tumors with significantly increased hepatic BA levels. Enhancing intestinal excretion of hydrophobic BAs in the NASH-HCC model mice by a 2% cholestyramine feeding significantly prevented HCC development. The gut microbiota alterations were closely correlated with altered BA levels in liver and feces. HFD-induced inflammation inhibited key BA transporters, resulting in sustained increases in intrahepatic BA concentrations. Our study also showed a significantly increased cell proliferation in BA treated normal human hepatic cell lines and a down-regulated expression of tumor suppressor gene CEBPα in TCDCA treated HepG2 cell line, suggesting that several hydrophobic BAs may collaboratively promote liver carcinogenesis.

Topics: Animals; Bile Acids and Salts; Carcinogenesis; Cell Line; Deoxycholic Acid; Diet, High-Fat; Female; Gastrointestinal Microbiome; Hep G2 Cells; Humans; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Pregnancy; Streptozocin; Taurochenodeoxycholic Acid; Taurocholic Acid; Taurolithocholic Acid

The role of the unfolded protein response (UPR) in tissue homeostasis remains largely unknown. Here we find that loss of Mst1/2, the mammalian Hippo orthologues, or their regulator WW45, leads to a remarkably enlarged endoplasmic reticulum (ER) size-associated UPR. Intriguingly, attenuation of the UPR by tauroursodeoxycholic acid (TUDCA) diminishes Mst1/2 mutant-driven liver overgrowth and tumorigenesis by promoting nuclear exit and degradation of Hippo downstream effector Yap. Yap is required for UPR activity and ER expansion to alleviate ER stress. During the adaptive stage of the UPR, PERK kinase-eIF2α axis activates Yap, while prolonged ER stress-induced Hippo signalling triggers assembly of the GADD34/PP1 complex in a negative feedback loop to inhibit Yap and promote apoptosis. Significantly, the deregulation of UPR signals associated with Yap activation is found in a substantial fraction of human hepatocellular carcinoma (HCC). Thus, we conclude Yap integrates Hippo and UPR signalling to control liver size and tumorigenesis.

Topics: Activating Transcription Factor 6; Adaptor Proteins, Signal Transducing; Animals; Blotting, Western; Carcinogenesis; Cell Cycle Proteins; Endoplasmic Reticulum; Hep G2 Cells; Hepatocyte Growth Factor; Hepatocytes; Humans; Liver; Liver Neoplasms; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Molecular Sequence Data; Mutation; Organ Size; Phosphoproteins; Poly(ADP-ribose) Polymerases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Serine-Threonine Kinase 3; Signal Transduction; Taurochenodeoxycholic Acid; Transcription, Genetic; Unfolded Protein Response; YAP-Signaling Proteins