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Hepatocyte‐specific YAP deletion suppresses hepatocyte proliferation and hepatomegaly induced by CAR agonist, TCPOBOP (1,4‐Bis [2‐(3,5‐Dichloropyridyloxy)] benzene), in mice

TCPOBOP (1,4‐Bis [2‐(3,5‐Dichloropyridyloxy)] benzene) is a direct ligand of constitutive androstane receptor (CAR), which induces robust hepatocyte proliferation and hepatomegaly in mice without any liver injury or tissue loss. Organ size including that of liver is known to be tightly controlled by transcriptional regulator, yes‐associated protein (YAP). Recent studies have indicated potential interaction of CAR and YAP. Here, we directly investigated role of YAP in TCPOBOP‐induced proliferative response using hepatocyte‐specific YAP‐KO strategy. Hepatocyte‐specific YAP deletion was achieved by administering AAV8‐TBG‐CRE vector to YAP‐floxed mice. TCBOPOP treatment in control mice caused rapid activation and nuclear translocation of YAP along with decreased phosphorylation (inactive form) of YAP concomitant to proliferative response. YAP deletion neither altered protein expression of CAR nor its activation. However, YAP deletion significantly reduced TCPOBOP‐induced hepatomegaly and hepatocyte proliferation. TCPOBOP‐driven cell cycle activation was disrupted in YAP‐KO mice due to impaired protein and gene expression of cyclin D1 and decreased phosphorylation of retinoblastoma (Rb) protein. YAP regulated these cell cycle proteins via alerting expression of cMyc and FOXM1, two critical transcriptional regulators of TCPOBOP‐mediated hepatocyte proliferation. In conclusion, our study revealed an important role of YAP signaling in hepatomegaly and hepatocyte proliferation induced by TCPOBOP.