{"doi":"10.1016/j.jcmgh.2024.01.016","title":"A Structure-function Analysis of Hepatocyte Arginase 2 Reveals Mitochondrial Ureahydrolysis as a Determinant of Glucose Oxidation","abstract":"BACKGROUND & AIMS: Restoring hepatic and peripheral insulin sensitivity is critical to prevent or reverse metabolic syndrome and type 2 diabetes. Glucose homeostasis comprises in part the complex regulation of hepatic glucose production and insulin-mediated glucose uptake and oxidation in peripheral tissues. We previously identified hepatocyte arginase 2 (Arg2) as an inducible ureahydrolase that improves glucose homeostasis and enhances glucose oxidation in multiple obese, insulin-resistant models. We therefore examined structure-function determinants through which hepatocyte Arg2 governs systemic insulin action and glucose oxidation. METHODS: ) mice. RESULTS: failed to suppress glucose appearance during hyperinsulinemic-euglycemic clamping. Quantification of heavy-isotope-labeled glucose oxidation further revealed that mistargeting or ablating Arg2 enzymatic function abrogates Arg2-induced peripheral glucose oxidation. CONCLUSION: We conclude that the metabolic effects of Arg2 extend beyond its enzymatic activity, yet hepatocyte mitochondrial ureahydrolysis drives hepatic and peripheral oxidative metabolism. The data define a structure-based mechanism mediating hepatocyte Arg2 function and nominate hepatocyte mitochondrial ureahydrolysis as a key determinant of glucose oxidative capacity in mammals.","journal":"Cellular and Molecular Gastroenterology and Hepatology","year":2024,"id":452671,"datarank":0.3596842909197557,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.0,"self_endowment_contribution":0.3596842909197557,"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":0.9628,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":898869,"name":"Jiameng Sun","orcid":"0000-0002-1176-8010","position":1,"is_corresponding":false},{"id":1275329,"name":"Henry D. Wasserman","orcid":null,"position":2,"is_corresponding":false},{"id":911666,"name":"Joshua A. Adams","orcid":"0009-0006-4589-859X","position":3,"is_corresponding":false},{"id":883278,"name":"Cassandra B. Higgins","orcid":"0000-0003-4751-9611","position":4,"is_corresponding":false},{"id":801898,"name":"Shannon C. Kelly","orcid":"0000-0002-9942-9602","position":5,"is_corresponding":false},{"id":238138,"name":"Louise Lantier","orcid":"0000-0002-6620-4976","position":6,"is_corresponding":false},{"id":258410,"name":"Brian J. DeBosch","orcid":"0000-0002-9924-7921","position":7,"is_corresponding":false},{"id":883280,"name":"Yiming Zhang","orcid":"0000-0002-6020-0237","position":0,"is_corresponding":true}],"reference_count":32,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:02:54.415477Z","pmid":"38280549","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":[]}