β(2)-adrenergic receptor promotes liver regeneration partially through crosstalk with c-met

The β(2)-adrenergic receptor (β(2)AR) is a G protein-coupled receptor (GPCR) that mediates the majority of cellular responses to external stimuli. Aberrant expression of β(2)AR 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 β(2)AR in liver regeneration. Here, we found that β(2)AR was upregulated during liver regeneration induced by 70% PH. Deletion of β(2)AR 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 β(2)AR in hepatocytes accelerated the regeneration process and increased target gene expression. Mechanistically, β(2)AR 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 β(2)AR overexpression-induced hepatocyte proliferation. Our findings revealed that β(2)AR might act as a critical mediator regulating liver regeneration by crosstalk with c-met and activation of ERK signaling.