Open AccessDisorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging
Author(s) -
Csaba Ádori,
Teresa Daraio,
Raoul Kuiper,
Swapnali Barde,
Ľubica Horváthová,
Takashi Yoshitake,
Robert Ihnatko,
Ismael ValladolidAcebes,
Pauline Vercruysse,
Ashley M Wellendorf,
Roberto Gramignoli,
Béla Bozóky,
Ján Kehr,
Elvar Theodorsson,
José A. Cancelas,
Boris Mravec,
Carl Jorns,
Ewa Ellis,
Jan Mulder,
Mathias Uhlén,
Christina Bark,
Tomas Hökfelt
Publication year - 2021
Publication title -
science advances
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.928
H-Index - 146
ISSN - 2375-2548
DOI - 10.1126/sciadv.abg5733
Subject(s) - nonalcoholic fatty liver disease , degeneration (medical) , fatty liver , pathology , medicine , liver disease , disease
Hepatic nerves have a complex role in synchronizing liver metabolism. Here, we used three-dimensional (3D) immunoimaging to explore the integrity of the hepatic nervous system in experimental and human nonalcoholic fatty liver disease (NAFLD). We demonstrate parallel signs of mild degeneration and axonal sprouting of sympathetic innervations in early stages of experimental NAFLD and a collapse of sympathetic arborization in steatohepatitis. Human fatty livers display a similar pattern of sympathetic nerve degeneration, correlating with the severity of NAFLD pathology. We show that chronic sympathetic hyperexcitation is a key factor in the axonal degeneration, here genetically phenocopied in mice deficient of the Rac-1 activator Vav3. In experimental steatohepatitis, 3D imaging reveals a severe portal vein contraction, spatially correlated with the extension of the remaining nerves around the portal vein, enlightening a potential intrahepatic neuronal mechanism of portal hypertension. These fundamental alterations in liver innervation and vasculature uncover previously unidentified neuronal components in NAFLD pathomechanisms.