1. Academic Validation
  2. Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via the DEPTOR-mTOR axis

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

  • Mol Metab. 2021 Nov;53:101275. doi: 10.1016/j.molmet.2021.101275.
Marina Serrano-Maciá 1 Jorge Simón 2 Maria J González-Rellan 3 Mikel Azkargorta 4 Naroa Goikoetxea-Usandizaga 1 Fernando Lopitz-Otsoa 5 Diego Saenz De Urturi 6 Rubén Rodríguez-Agudo 1 Sofia Lachiondo-Ortega 1 Maria Mercado-Gomez 1 Virginia Gutiérrez de Juan 5 Maider Bizkarguenaga 5 David Fernández-Ramos 7 Xabier Buque 8 Guido A Baselli 9 Luca V C Valenti 9 Paula Iruzubieta 10 Javier Crespo 10 Erica Villa 11 Jesus M Banales 12 Matias A Avila 13 Jose J G Marin 14 Patricia Aspichueta 15 James Sutherland 16 Rosa Barrio 16 Ugo Mayor 17 Félix Elortza 4 Dimitris P Xirodimas 18 Rubén Nogueiras 3 Teresa C Delgado 19 María Luz Martínez-Chantar 20
Affiliations

Affiliations

  • 1 Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain.
  • 2 Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain; 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; Centro de Investigación Biomédica en Red de Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Carlos III National Health Institute, Madrid, Spain.
  • 4 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.
  • 5 Precision Medicine and Metabolism Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain.
  • 6 Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain.
  • 7 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain; Precision Medicine and Metabolism Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain.
  • 8 Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain; Biocruces Bizkaia Health Research Institute, 48903, Barakaldo, Bizkaia, Spain.
  • 9 Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122, Milan, Italy; Department of Transfusion Medicine and Hematology - Translational Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122, Milan, Italy.
  • 10 Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, 39008, Santander, Spain; Clinical and Translational Digestive Research Group, Research Institute Marqués de Valdecilla (IDIVAL), 39011, Santander, Spain.
  • 11 Department of Gastroenterology, Azienda Ospedaliero-Universitaria & University of Modena and Reggion Emilia, 41121, Modena, Italy.
  • 12 Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain; 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.
  • 13 Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain; Hepatology Programme, Center for Applied Medical Research (CIMA), IDISNA, University of Navarra, 31008, Pamplona, Spain.
  • 14 Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain; Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, 37007, Salamanca, Spain.
  • 15 Precision Medicine and Metabolism Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain; Biocruces Bizkaia Health Research Institute, 48903, Barakaldo, Bizkaia, Spain.
  • 16 Ubiquitin-likes And Development Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain.
  • 17 Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48940, Leioa, Spain; Ikerbasque - Basque Foundation for Science, Bilbao, Spain.
  • 18 Centre de Recherche en Biologie cellulaire de Montpellier (CRBM-CNRS), Univ. Montpellier, UMR5237, Montpellier 34090, Cedex 5, France.
  • 19 Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain. Electronic address: [email protected].
  • 20 Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain. Electronic address: [email protected].
Abstract

Objective: Neddylation is a druggable and reversible ubiquitin-like post-translational modification upregulated in many diseases, including liver fibrosis, hepatocellular carcinoma, and more recently, non-alcoholic fatty liver disease (NAFLD). Herein, we propose to address the effects of neddylation inhibition and the underlying mechanisms in pre-clinical models of NAFLD.

Methods: Hepatic neddylation measured by immunohistochemical analysis and NEDD8 serum levels measured by ELISA assay were evaluated in NAFLD clinical and pre-clinical samples. The effects of neddylation inhibition by using a pharmacological small inhibitor, MLN4924, or molecular approaches were assessed in isolated mouse hepatocytes and pre-clinical mouse models of diet-induced NAFLD, male adult C57BL/6 mice, and the AlfpCre transgenic mice infected with AAV-DIO-shNedd8.

Results: Neddylation inhibition reduced lipid accumulation in oleic acid-stimulated mouse primary hepatocytes and ameliorated liver steatosis, preventing lipid peroxidation and inflammation in the mouse models of diet-induced NAFLD. Under these conditions, increased Deptor levels and the concomitant repression of mTOR signaling were associated with augmented fatty acid oxidation and reduced lipid content. Moreover, Deptor silencing in isolated mouse hepatocytes abolished the anti-steatotic effects mediated by neddylation inhibition. Finally, serum NEDD8 levels correlated with hepatic neddylation during the disease progression in the clinical and pre-clinical models CONCLUSIONS: Overall, the upregulation of Deptor, driven by neddylation inhibition, is proposed as a novel effective target and therapeutic approach to tackle NAFLD.

Keywords

Deptor; Fatty acid oxidation; MLN4924; NAFLD; Neddylation; mTOR.

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