CAR-induced hepatomegaly is partially due to YAP signaling.
To further explore the role of YAP in TCPOBOP-induced hepatomegaly,Yap -/- mice were used and treated with TCPOBOP for 10 days (Figure 4A). The liver/body weight ratio still showed an increase in TCPOBOP treated Yap -/- mice, but decreased compared with TCPOBOP-treated WT mice, which suggested that YAP is only partially involved in CAR activation-induced hepatomegaly (Figure 4B). A slight shrinkage of liver was noted inYap -/- mice in the treated group compared with the counterpart in WT mice (Figure 4C).
Serum ALT, AST and ALP indicated no significant difference between the treatment and vehicle group (Figure S4A). The YAP protein and its downstream targets together with proliferation-related proteins were also measured (Figure S4B and S4C). YAP was totally depleted inYap -/- mice, YAP downstream targets CTGF, ANKRD1 and proliferation-related protein CCND1 were upregulated in TCPOBOP-treated group both in WT and Yap -/-mice.
Immunohistochemical staining of CTNNB1 and KI67 was conducted revealing that hepatocyte size in the CV area was still enlarged (Figure 4E and 4F), while the number of KI67+ cells was increased in the PV area in TCPOBOP-treated Yap -/- mice (Figure 4G and 4H), but the effect was weaker compared with TCPOBOP-treated WT mice. CTNNB1 staining in the PV area and KI67 staining in the CV area are shown in Figure S4D and S4E.