Bile Acids Activate YAP to Promote Liver Carcinogenesis

• Bile acids are upstream regulators of the Hippo pathway
• The signaling scaffold protein IQGAP1 is induced by bile acid overload
• IQGAP1 is sufficient to increase YAP expression
• BAs promote hepatocarcinogenesis via IQGAP1 induction and YAP activation

SummaryElevated bile acid levels increase hepatocellular carcinoma by unknown mechanisms. Here, we show that mice with a severe defect in bile acid homeostasis due to the loss of the nuclear receptors FXR and SHP have enlarged livers, progenitor cell proliferation, and Yes-associated protein (YAP) activation and develop spontaneous liver tumorigenesis. This phenotype mirrors mice with loss of hippo kinases or overexpression of their downstream target, YAP. Bile acids act as upstream regulators of YAP via a pathway dependent on the induction of the scaffold protein IQGAP1. Patients with diverse biliary dysfunctions exhibit enhanced IQGAP1 and nuclear YAP expression. Our findings reveal an unexpected mechanism for bile acid regulation of liver growth and tumorigenesis via the Hippo pathway.Video Abstract To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon belowHelp with MP4 filesOptionsDownload video (23955 K)

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