β₂-adrenergic receptor promotes liver regeneration partially through crosstalk with c-met

The β₂-adrenergic receptor (β₂AR) is a G protein-coupled receptor (GPCR) that mediates the majority of cellular responses to external stimuli. Aberrant expression of β₂AR results in various pathophysiological disorders, including tumorigenesis, but little is known about its role in liver regeneration. This study aims to investigate the impact and the underlying mechanism of β₂AR in liver regeneration. Here, we found that β₂AR was upregulated during liver regeneration induced by 70% PH. Deletion of β₂AR in mice resulted in 62% mortality 2 days post-PH, decreased proliferative marker expression and impaired liver function throughout regeneration. Moreover, AAV8-mediated overexpression of β₂AR in hepatocytes accelerated the regeneration process and increased target gene expression. Mechanistically, β₂AR recruited G-protein-coupled receptor kinase 2 (GRK2) to the membrane and then formed a complex with c-met to transactivate c-met signaling, which triggered downstream extracellular regulated protein kinase (ERK) signaling activation and nuclear translocation. Inhibition of c-met with SU11274 or ERK with U0126 decreased β₂AR overexpression-induced hepatocyte proliferation. Our findings revealed that β₂AR might act as a critical mediator regulating liver regeneration by crosstalk with c-met and activation of ERK signaling.