1. Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via the DEPTOR-mTOR axis
- Author
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Xabier Buqué, Javier Crespo, David Fernández-Ramos, Ugo Mayor, Maria J. Gonzalez-Rellan, Virginia Gutiérrez-de Juan, Fernando Lopitz-Otsoa, Sofia Lachiondo-Ortega, Erica Villa, Maider Bizkarguenaga, Diego Saenz de Urturi, Mikel Azkargorta, Patricia Aspichueta, Jorge Simón, María L. Martínez-Chantar, Guido Baselli, Naroa Goikoetxea-Usandizaga, Matías Ávila, James D. Sutherland, Luca Valenti, Teresa C. Delgado, Rosa Barrio, Marina Serrano-Macia, Rubén Rodríguez-Agudo, Maria Mercado-Gómez, Rubén Nogueiras, Paula Iruzubieta, Dimitris P. Xirodimas, Felix Elortza, Jesus M. Banales, Jose J.G. Marin, Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Fisioloxía, European Commission, CIC BioGUNE, CIC Spain, Basque Research and Technology Alliance (BRTA), Centre de recherche en Biologie Cellulaire (CRBM), and Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)
- Subjects
Adult ,Male ,Coronavirus disease 2019 (COVID-19) ,Adolescent ,MLN4924 ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Diet, High-Fat ,03 medical and health sciences ,Mice ,Young Adult ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Political science ,NAFLD ,media_common.cataloged_instance ,Animals ,Humans ,European union ,Neddylation ,Molecular Biology ,Internal medicine ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,media_common ,Aged ,0303 health sciences ,TOR Serine-Threonine Kinases ,Fatty Acids ,Intracellular Signaling Peptides and Proteins ,Cell Biology ,Middle Aged ,RC31-1245 ,3. Good health ,Mice, Inbred C57BL ,Rare tumor ,Disease Models, Animal ,Deptor ,Fatty acid oxidation ,mTOR ,Hepatocytes ,030211 gastroenterology & hepatology ,Christian ministry ,Original Article ,Humanities ,Signal Transduction - 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., Graphical abstract Image 1, Highlights • 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.
- Published
- 2021