Constitutive androstane receptor promoted- hepatomegaly and liver
regeneration is partially via yes-associated protein activation
Abstract
Background & Purpose: The constitutive androstane receptor (CAR)
belongs to nuclear receptor superfamily. The administration of CAR
agonist TCPOBOP to mice leads to hepatomegaly but the mechanism is
unclear. Yes-associated protein (YAP) is a downstream factor of Hippo
signaling pathway, which is a potent regulator of organ size and tissue
homeostasis. This study examined the role of YAP in CAR-promoted
hepatomegaly and liver regeneration. Experimental Approach: The effect
of CAR on liver enlargement and liver regeneration was evaluated in
wild-type (WT) mice, liver-specific YAP-deficient mice, and partial
hepatectomy (PHx) mice. KI67 and CTNNB1 staining were performed to
evaluate the proliferation response and hepatocytes size. The protein
levels of YAP and its downstream targets were measured and Co-IP was
conducted to explore the protein-protein interaction between CAR and
YAP. Key Results: The results suggested TCPOBOP increases the liver/body
weight ratio in WT mice and PHx mice. Hepatocytes enlargement occurred
around the central vein area, while the number of KI67+ cells increased
around portal vein area. The translocation of YAP was induced and its
downstream targets were upregulated after CAR activation via TCPOBOP.
Co-IP results revealed a potential protein-protein interaction between
CAR and YAP. However, CAR-induced hepatomegaly was still observed in
Yap-/- mice. Conclusion and Implications: CAR activation promotes
hepatomegaly and liver regeneration in part by inducing nuclear
translocation of YAP and interaction with YAP pathway, which provides
new insights for understanding the physiological functions of CAR, and
suggests the potential for manipulation of liver size.