Hepatocyte ß-catenin loss is compensated by Insulin-mTORC1 activation to promote liver regeneration.
Hepatology
; 77(5): 1593-1611, 2023 05 01.
Article
em En
| MEDLINE
| ID: mdl-35862186
BACKGROUND AND AIMS: Liver regeneration (LR) following partial hepatectomy (PH) occurs via activation of various signaling pathways. Disruption of a single pathway can be compensated by activation of another pathway to continue LR. The Wnt-ß-catenin pathway is activated early during LR and conditional hepatocyte loss of ß-catenin delays LR. Here, we study mechanism of LR in the absence of hepatocyte-ß-catenin. APPROACH AND RESULTS: Eight-week-old hepatocyte-specific Ctnnb1 knockout mice (ß-catenin ΔHC ) were subjected to PH. These animals exhibited decreased hepatocyte proliferation at 40-120 h and decreased cumulative 14-day BrdU labeling of <40%, but all mice survived, suggesting compensation. Insulin-mediated mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) activation was uniquely identified in the ß-catenin ΔHC mice at 72-96 h after PH. Deletion of hepatocyte regulatory-associated protein of mTOR (Raptor), a critical mTORC1 partner, in the ß-catenin ΔHC mice led to progressive hepatic injury and mortality by 30 dys. PH on early stage nonmorbid Raptor ΔHC -ß-catenin ΔHC mice led to lethality by 12 h. Raptor ΔHC mice showed progressive hepatic injury and spontaneous LR with ß-catenin activation but died by 40 days. PH on early stage nonmorbid Raptor ΔHC mice was lethal by 48 h. Temporal inhibition of insulin receptor and mTORC1 in ß-catenin ΔHC or controls after PH was achieved by administration of linsitinib at 48 h or rapamycin at 60 h post-PH and completely prevented LR leading to lethality by 12-14 days. CONCLUSIONS: Insulin-mTORC1 activation compensates for ß-catenin loss to enable LR after PH. mTORC1 signaling in hepatocytes itself is critical to both homeostasis and LR and is only partially compensated by ß-catenin activation. Dual inhibition of ß-catenin and mTOR may have notable untoward hepatotoxic side effects.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Beta Catenina
/
Regeneração Hepática
Limite:
Animals
Idioma:
En
Revista:
Hepatology
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China