The
constitutive androstane receptor (CAR, NR3I1) belongs to
nuclear receptor superfamily. It was reported that CAR agonist
TCPOBOP induces
hepatomegaly but the underlying mechanism remains largely unknown. Yes-associated
protein (YAP) is a potent regulator of organ size. The aim of this study is to explore the role of YAP in CAR activation-induced
hepatomegaly and liver regeneration.
TCPOBOP-induced CAR activation on
hepatomegaly and liver regeneration was evaluated in wild-type (WT) mice, liver-specific YAP-deficient mice, and partial
hepatectomy (PHx) mice. The results demonstrate that
TCPOBOP can increase the liver-to-
body weight ratio in wild-type mice and PHx mice. Hepatocytes enlargement around central vein (CV) area was observed, meanwhile hepatocytes proliferation was promoted as evidenced by the increased number of KI67+ cells around portal vein (PV) area. The
protein levels of YAP and its downstream targets were upregulated in
TCPOBOP-treated mice and YAP translocation can be induced by CAR activation. Co-immunoprecipitation results suggested a potential
protein-
protein interaction of CAR and YAP. However, CAR activation-induced
hepatomegaly can still be observed in liver-specific YAP-deficient (Yap -/-) mice. In summary, CAR activation promotes
hepatomegaly and liver regeneration partially by inducing YAP translocation and interaction with YAP signaling pathway, which provides new insights to further understand the physiological functions of CAR.