Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via the DEPTOR-mTOR axis
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.
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BibTeX
@article{serranomacia2026neddylation,
title = {{Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via the DEPTOR-mTOR axis}},
author = {Marina Serrano-Maciá and Jorge Simón and Maria González-Rellan and Mikel Azkargorta and Naroa Goikoetxea-Usandizaga and Fernando Lopitz-Otsoa and Diego Saenz de Urturi and Rubén Rodríguez-Agudo and Sofia Lachiondo-Ortega and Maria Mercado-Gomez and Virginia Gutiérrez de Juan and Maider Bizkarguenaga and David Fernández-Ramos and Xabier Buque and Guido Baselli and Luca V.C. Valenti and Paula Iruzubieta and Javier Crespo and Erica Villa and Jesus Banales and Matias Avila and Jose J.G. Marin and Patricia Aspichueta and James Sutherland and Rosa Barrio and Ugo Mayor and Félix Elortza and Dimitris Xirodimas and Rubén Nogueiras and Teresa Delgado and María Luz Martínez-Chantar},
journal = {Molecular metabolism},
year = {2026},
month = sep,
doi = {10.1016/j.molmet.2021.101275},
url = {https://hal.science/hal-05751976v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via the DEPTOR-mTOR axis
AU - Marina Serrano-Maciá
AU - Jorge Simón
AU - Maria González-Rellan
AU - Mikel Azkargorta
AU - Naroa Goikoetxea-Usandizaga
AU - Fernando Lopitz-Otsoa
AU - Diego Saenz de Urturi
AU - Rubén Rodríguez-Agudo
AU - Sofia Lachiondo-Ortega
AU - Maria Mercado-Gomez
AU - Virginia Gutiérrez de Juan
AU - Maider Bizkarguenaga
AU - David Fernández-Ramos
AU - Xabier Buque
AU - Guido Baselli
AU - Luca V.C. Valenti
AU - Paula Iruzubieta
AU - Javier Crespo
AU - Erica Villa
AU - Jesus Banales
AU - Matias Avila
AU - Jose J.G. Marin
AU - Patricia Aspichueta
AU - James Sutherland
AU - Rosa Barrio
AU - Ugo Mayor
AU - Félix Elortza
AU - Dimitris Xirodimas
AU - Rubén Nogueiras
AU - Teresa Delgado
AU - María Luz Martínez-Chantar
PY - 2026
DA - 2026/09/16
JO - Molecular metabolism
DO - 10.1016/j.molmet.2021.101275
UR - https://hal.science/hal-05751976v1
AB - 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.
SN - 2212-8778
ER -