From bile acids to yes-associated protein: A bidirectional switch for cholangiocarcinoma therapy

Figure 1 Upper panel: Hydrophilic conjugated bile acids (taurocholic acid, glycocholic acid) and lower panel: Lipophilic unconjugated bile acids. The upper panel: Hydrophilic conjugated bile acid taurocholic acid activates nuclear yes-associated protein (YAP) via sphingosine-1-phosphate receptor 2/p38 mitogen-activated protein kinase to promote liver fibrosis. Glycocholic acid also promotes YAP translocation in hepatocytes, inducing connective tissue growth factor expression to activate hepatic stellate cells via paracrine signaling. The lower panel: Lipophilic unconjugated bile acids have dual roles. Chenodeoxycholic acid promotes hepatocellular carcinoma by upregulating IQ motif containing GTPase activating protein 1 to activate YAP. Ursodeoxycholic acid, deoxycholic acid, lithocholic acid activate Takeda G protein-coupled receptor 5/cyclic adenosine monophosphate/protein kinase A to inactivate YAP, inhibiting tumors and maintaining intestinal barrier integrity. BA: Bile acid; S1R2: Sphingosine-1-phosphate receptor 2; GCA: Glycocholic acid; TCA: Taurocholic acid; MAPK: Mitogen-activated protein kinase; YAP: Yes-associated protein; TEAD: Transcriptional enhanced associate domain; CDCA: Chenodeoxycholic acid; LCA: Lithocholic acid; UDCA: Ursodeoxycholic acid; TGR5: Takeda G protein-coupled receptor 5; cAMP: Cyclic adenosine monophosphate; PKA: Protein kinase A; LATS: Large tumor suppressor kinases; HCC: Hepatocellular carcinoma; MST2: Mammalian sterile 20-like kinase 2; IQGAP1: IQ motif containing GTPase activating protein 1.