1. ITCH E3 ubiquitin ligase downregulation compromises hepatic degradation of branched-chain amino acids
- Author
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Rossella Menghini, Lesley Hoyles, Marina Cardellini, Viviana Casagrande, Arianna Marino, Paolo Gentileschi, Francesca Davato, Maria Mavilio, Ivan Arisi, Alessandro Mauriello, Manuela Montanaro, Manuel Scimeca, Richard H. Barton, Francesca Rappa, Francesco Cappello, Manlio Vinciguerra, José Maria Moreno-Navarrete, Wifredo Ricart, Ottavia Porzio, José-Manuel Fernández-Real, Rémy Burcelin, Marc-Emmanuel Dumas, Massimo Federici, Menghini R., Hoyles L., Cardellini M., Casagrande V., Marino A., Gentileschi P., Davato F., Mavilio M., Arisi I., Mauriello A., Montanaro M., Scimeca M., Barton R.H., Rappa F., Cappello F., Vinciguerra M., Moreno-Navarrete J.M., Ricart W., Porzio O., Fernandez-Real J.-M., Burcelin R., Dumas M.-E., Federici M., Nottingham Trent University, Università degli Studi di Roma Tor Vergata [Roma], University of Rome TorVergata, European Brain Research Institute [Rome, Italy] (EBRI), Cardiff Business School, Cardiff University, Euro-Mediterranean Institute of Science and Technology (IEMEST), Università degli studi di Palermo - University of Palermo, Section of Diabetes, Endocrinology and Nutrition, University Hospital of Girona-Biomedical Research Institute 'Dr Josep Trueta'-CIBERobn Fisiopatología de la Obesidad y Nutrición, Hospital Dr Josep Trueta de Girona, Universitat de Girona (UdG), Instituto de Salud Carlos III [Madrid] (ISC), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Imperial College London, ANR-16-IDEX-0004,ULNE,ULNE(2016), and ANR-18-IBHU-0001,PreciDIAB,PreciDIAB Institute, the holistic approach of personal diabets care(2018)
- Subjects
Mice, Knockout ,BCAAm Metabolomic, NAFLD, Transcriptomics ,Ubiquitin-Protein Ligases ,[SDV]Life Sciences [q-bio] ,Liver Neoplasms ,Down-Regulation ,BCAA ,Metabolomics ,NAFLD ,Transcriptomics ,Settore MED/09 ,Cell Biology ,Mice ,Non-alcoholic Fatty Liver Disease ,otorhinolaryngologic diseases ,Animals ,Humans ,Female ,Obesity ,skin and connective tissue diseases ,Molecular Biology ,Amino Acids, Branched-Chain - Abstract
Objective: Metabolic syndrome, obesity, and steatosis are characterized by a range of dysregulations including defects in ubiquitin ligase tagging proteins for degradation. The identification of novel hepatic genes associated with fatty liver disease and metabolic dysregulation may be relevant to unravelling new mechanisms involved in liver disease progression Methods: Through integrative analysis of liver transcriptomic and metabolomic obtained from obese subjects with steatosis, we identified itchy E ubiquitin protein ligase (ITCH) as a gene downregulated in human hepatic tissue in relation to steatosis grade. Wild-type or ITCH knockout mouse models of non-alcoholic fatty liver disease (NAFLD) and obesity-related hepatocellular carcinoma were analyzed to dissect the causal role of ITCH in steatosis Results: We show that ITCH regulation of branched-chain amino acids (BCAAs) degradation enzymes is impaired in obese women with grade 3 compared with grade 0 steatosis, and that ITCH acts as a gatekeeper whose loss results in elevation of circulating BCAAs associated with hepatic steatosis. When ITCH expression was specifically restored in the liver of ITCH knockout mice, ACADSB mRNA and protein are restored, and BCAA levels are normalized both in liver and plasma Conclusions: Our data support a novel functional role for ITCH in the hepatic regulation of BCAA metabolism and suggest that targeting ITCH in a liver-specific manner might help delay the progression of metabolic hepatic diseases and insulin resistance.
- Published
- 2022