| First Author | Hu S | Year | 2023 |
| Journal | Hepatology | Volume | 77 |
| Issue | 5 | Pages | 1593-1611 |
| PubMed ID | 35862186 | Mgi Jnum | J:359264 |
| Mgi Id | MGI:7785600 | Doi | 10.1002/hep.32680 |
| Citation | Hu S, et al. (2023) Hepatocyte beta-catenin loss is compensated by Insulin-mTORC1 activation to promote liver regeneration. Hepatology 77(5):1593-1611 |
| abstractText | 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-beta-catenin pathway is activated early during LR and conditional hepatocyte loss of beta-catenin delays LR. Here, we study mechanism of LR in the absence of hepatocyte-beta-catenin. APPROACH AND RESULTS: Eight-week-old hepatocyte-specific Ctnnb1 knockout mice (beta-catenin DeltaHC ) 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 beta-catenin DeltaHC mice at 72-96 h after PH. Deletion of hepatocyte regulatory-associated protein of mTOR (Raptor), a critical mTORC1 partner, in the beta-catenin DeltaHC mice led to progressive hepatic injury and mortality by 30 dys. PH on early stage nonmorbid Raptor DeltaHC -beta-catenin DeltaHC mice led to lethality by 12 h. Raptor DeltaHC mice showed progressive hepatic injury and spontaneous LR with beta-catenin activation but died by 40 days. PH on early stage nonmorbid Raptor DeltaHC mice was lethal by 48 h. Temporal inhibition of insulin receptor and mTORC1 in beta-catenin DeltaHC 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 beta-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 beta-catenin activation. Dual inhibition of beta-catenin and mTOR may have notable untoward hepatotoxic side effects. |
