Nagao, H.; Kofuji, S.; Danzaki, K.; Suzuki, A.; Nishina, H.

Within hours of injury to the liver, signals from damaged hepatocytes activate Kupffer cells, inducing the production of inflammatory cytokines and proliferation of quiescent hepatocytes to regenerate the liver. In humans, liver regenerative capacity declines with age. However, the nature of the initial signals of liver regeneration and how they are affected during aging remain unclear. In this study, we leveraged ''neuro-aging mice'', in which neuronal function declines with age, and discovered an essential role for intrahepatic sympathetic nerves in the early phase of liver regeneration. Upon liver injury in wild-type mice, there was a rapid, transient production of noradrenaline (NA) in the liver. This was abolished in neuro-aging mice who instead exhibited decreased metabolic capacity and fatal liver regeneration failure. NA coordinated the activity of multiple cell types by inducing expression of acute-response genes in hepatocytes and stimulating production of inflammatory cytokines such as IL-6 in Kupffer cells. These results identify a crucial role for the sympathetic nervous system and NA in liver regeneration. Further, they suggest that aging-related loss of this sympathetic nerve-NA regulatory axis reduces liver regenerative capacity.