From this study, we have drawn the following conclusions: 1) Liver-specific RBPJ KO leads to abnormal development of the bile ducts during the perinatal period, causing the emergence of cholestasis and increased neonatal mortality; 2) The Notch–RBPJ signaling pathway is involved in liver regeneration, especially bile duct regeneration; 3) Notch–RBPJ regulates differentiation of HPCs by promoting a biliary fate; and 4) Notch–Hippo crosstalk involving RBPJ and YAP may represent a critical regulatory node in HPC differentiation. This evidence concerns the gene RBPJ and cholestasis.