{"doi":"10.1002/hep.32680","title":"Hepatocyte β‐catenin loss is compensated by Insulin‐mTORC1 activation to promote liver regeneration","abstract":"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-β-catenin pathway is activated early during LR and conditional hepatocyte loss of β-catenin delays LR. Here, we study mechanism of LR in the absence of hepatocyte-β-catenin. APPROACH AND RESULTS: Eight-week-old hepatocyte-specific Ctnnb1 knockout mice (β-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 β-catenin ΔHC mice at 72-96 h after PH. Deletion of hepatocyte regulatory-associated protein of mTOR (Raptor), a critical mTORC1 partner, in the β-catenin ΔHC mice led to progressive hepatic injury and mortality by 30 dys. PH on early stage nonmorbid Raptor ΔHC -β-catenin ΔHC mice led to lethality by 12 h. Raptor ΔHC mice showed progressive hepatic injury and spontaneous LR with β-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 β-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 β-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 β-catenin activation. Dual inhibition of β-catenin and mTOR may have notable untoward hepatotoxic side effects.","journal":"Hepatology","year":2022,"id":280463,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9552,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":712552,"name":"Catherine Cao","orcid":null,"position":1,"is_corresponding":false},{"id":562515,"name":"Minakshi Poddar","orcid":null,"position":2,"is_corresponding":false},{"id":271461,"name":"Evan R. Delgado","orcid":"0000-0003-2706-0946","position":3,"is_corresponding":false},{"id":369006,"name":"Sucha Singh","orcid":"0000-0002-9131-1423","position":4,"is_corresponding":false},{"id":955385,"name":"Anya Singh‐Varma","orcid":null,"position":5,"is_corresponding":false},{"id":260205,"name":"Donna B. Stolz","orcid":"0000-0002-1833-7010","position":6,"is_corresponding":false},{"id":460848,"name":"Aaron Bell","orcid":"0000-0001-6648-0834","position":7,"is_corresponding":false},{"id":277667,"name":"Satdarshan P. Monga","orcid":"0000-0002-8437-3378","position":8,"is_corresponding":false},{"id":561896,"name":"Shikai Hu","orcid":"0000-0002-0817-991X","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T00:29:03.247347Z","pmid":"35862186","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}