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Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via the DEPTOR-mTOR axis

Authors
  • Serrano-Maciá, Marina1
  • Simón, Jorge1, 2
  • González-Rellan, Maria J.3, 4
  • Azkargorta, Mikel5
  • Goikoetxea-Usandizaga, Naroa1
  • Lopitz-Otsoa, Fernando6
  • De Urturi, Diego Saenz7
  • Rodríguez-Agudo, Rubén1
  • Lachiondo-Ortega, Sofia1
  • Mercado-Gomez, Maria1
  • Gutiérrez de Juan, Virginia6
  • Bizkarguenaga, Maider6
  • Fernández-Ramos, David2, 6
  • Buque, Xabier7, 8
  • Baselli, Guido A.9, 10
  • Valenti, Luca V.C.9, 10
  • Iruzubieta, Paula11, 12
  • Crespo, Javier11, 12
  • Villa, Erica13
  • Banales, Jesus M.7, 14
  • And 11 more
  • 1 Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain
  • 2 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain
  • 3 Department of Physiology, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela-Instituto de Investigación Sanitaria, Galician Agency of Innovation (GAIN), Xunta de Galicia, 15782, Santiago de Compostela, Spain
  • 4 Centro de Investigación Biomédica en Red de Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Carlos III National Health Institute, Madrid, Spain
  • 5 Proteomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Carlos III Networked Proteomics Platform (ProteoRed-ISCIII), 48160, Derio, Bizkaia, Spain
  • 6 Precision Medicine and Metabolism Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain
  • 7 Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain
  • 8 Biocruces Bizkaia Health Research Institute, 48903, Barakaldo, Bizkaia, Spain
  • 9 Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122, Milan, Italy
  • 10 Department of Transfusion Medicine and Hematology – Translational Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122, Milan, Italy
  • 11 Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, 39008, Santander, Spain
  • 12 Clinical and Translational Digestive Research Group, Research Institute Marqués de Valdecilla (IDIVAL), 39011, Santander, Spain
  • 13 & University of Modena and Reggion Emilia, 41121, Modena, Italy
  • 14 Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, 20014, San Sebastian, Spain
  • 15 Hepatology Programme, Center for Applied Medical Research (CIMA), IDISNA, University of Navarra, 31008, Pamplona, Spain
  • 16 Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, 37007, Salamanca, Spain
  • 17 Ubiquitin-likes And Development Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain
  • 18 Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48940, Leioa, Spain
  • 19 Ikerbasque - Basque Foundation for Science, Bilbao, Spain
  • 20 Centre de Recherche en Biologie cellulaire de Montpellier (CRBM-CNRS), Univ. Montpellier, UMR5237, Montpellier 34090, Cedex 5, France
Type
Published Article
Journal
Molecular Metabolism
Publisher
Elsevier BV
Publication Date
Jun 18, 2021
Volume
53
Identifiers
DOI: 10.1016/j.molmet.2021.101275
PMID: 34153521
PMCID: PMC8280515
Source
PubMed Central
Keywords
Disciplines
  • Original Article
License
Unknown

Abstract

• Hepatic neddylation is induced in clinical and pre-clinical NAFLD. • Neddylation inhibition reduces hepatic steatosis in pre-clinical models of NAFLD. • Neddylation inhibition boosts fatty acid oxidation through a DEPTOR/mTOR axis. • Neddylation inhibition reduces hepatic inflammation and lipid peroxidation in NAFLD. • Serum NEDD8 levels correlate positively with liver disease in patients and pre-clinical models of NAFLD.

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