Disrupting bile acid metabolism by suppressing Fxr causes hepatocellular carcinoma induced by YAP activation

Bile acid (BA) production is a critical metabolic function of the liver, and its disruption leads to various liver diseases including hepatocellular carcinoma (HCC). However, the underlying molecular mechanism remained elusive. Here, we report that BA metabolism is directly controlled by a previously unidentified repressor function of YAP, a transcriptional activator known to promote HCC formation. We show in hepatocytes, activated YAP suppressed Fxr, a BA-sensing nuclear receptor that critically regulates BA production and export. The repressor function of activated YAP induced cholestasis damaged the liver, and altered liver and serum BA concentrations and composition. Specifically, YAP activation inhibited expression of an Fxr target gene, Bsep (Abcb11), impairing BA exportation and injuring hepatocytes. Elevated BA in the blood due to hepatocyte injury further activated hepatic YAP, resulting in a vicious cycle leading to HCC. In both mouse liver and human HCC patient samples, transcriptomic analysis negatively correlated YAP and Fxr activities. Mechanistically, Fxr was found to bind Teads in a DNA-binding-independent manner; and Teads recruited YAP to epigenetically reprogram Fxr by replacing the histone acetyltransferase, P300, with the histone deacetylase, HDAC1. Importantly, alleviating YAP repressor function in BA metabolism by activating Fxr with its agonist GW4064, inhibiting HDAC1 with Entinostat, or overexpressing Bsep, reduced cholestatic phenotypes including hepatic injury, fibrosis, and inflammation, alleviating the HCC caused by YAP activation. Our results identify Yap's transcriptional repressor role as a key driver of Yap-induced HCC and BA metabolism as a potential therapeutic target for HCC.