Bile acids activate YAP to promote liver carcinogenesis

Area of Science:

• Hepatology
• Molecular Biology
• Oncology

Background:

• Elevated bile acids are linked to hepatocellular carcinoma (HCC) through poorly understood mechanisms.
• Nuclear receptors like Farnesoid X Receptor (FXR) and Small Heterodimer Partner (SHP) are crucial for bile acid homeostasis.

Purpose of the Study:

• To elucidate the role of bile acid homeostasis in liver tumorigenesis.
• To investigate the molecular pathways linking bile acids to liver growth and cancer development.

Main Methods:

• Utilized mouse models with severe defects in bile acid homeostasis (FXR and SHP loss).
• Analyzed liver phenotype, progenitor cell proliferation, and Yes-associated protein (YAP) activation.
• Investigated the involvement of IQ motif-containing GTPase-activating protein 1 (IQGAP1) in bile acid- YAP signaling.
• Examined IQGAP1 and nuclear YAP expression in human patients with biliary dysfunction.

Main Results:

• Loss of FXR and SHP in mice resulted in enlarged livers, progenitor cell proliferation, YAP activation, and spontaneous liver tumors.
• The observed phenotype mimicked that of mice with disrupted Hippo kinase signaling or YAP overexpression.
• Bile acids were identified as upstream regulators of YAP, mediated by IQGAP1 induction.
• Patients with biliary dysfunction showed increased IQGAP1 and nuclear YAP expression.

Conclusions:

• Bile acids regulate liver growth and tumorigenesis via the Hippo pathway.
• IQGAP1 acts as a key mediator in the bile acid- YAP signaling axis.
• This study reveals a novel mechanism connecting bile acid metabolism to liver cancer development.