RT Journal Article
T1 Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via the DEPTOR-mTOR axis
A1 Serrano Maciá, Marina
A1 Simón, Jorge
A1 González Rellán, María Jesús
A1 Azkargorta, Mikel
A1 Goikoetxea-Usandizaga, Naroa
A1 Lopitz Otsoa, Fernando
A1 Sáenz de Urturi, Diego
A1 Rodríguez Agudo, Rubén
A1 Lachiondo-Ortega, Sofia
A1 Mercado Gómez, María
A1 Gutiérrez de Juan, Virginia
A1 Bizkarguenaga-Uribiarte, Maider
A1 Fernández-Ramos, David
A1 Buqué, Xabier
A1 Baselli, Guido Alessandro
A1 Valenti, Luca
A1 Iruzubieta, Paula
A1 Crespo, Javier
A1 Villa, Erica
A1 Banales, Jesus
A1 Avila, Matias A.
A1 Marin, Jose
A1 Aspichueta, Patricia
A1 Sutherland, James D.
A1 Barrio, Rosa
A1 Mayor, Ugo
A1 Elortza, Felix
A1 Xirodimas, Dimitris
A1 Nogueiras Pozo, Rubén
A1 Delgado, Teresa
A1 Martínez Chantar, María Luz
K1 Neddylation
K1 NAFLD
K1 Deptor
K1 mTOR
K1 Fatty acid oxidation
K1 MLN4924
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
PB Elsevier
SN 2212-8778
YR 2021
FD 2021
LK http://hdl.handle.net/10347/26654
UL http://hdl.handle.net/10347/26654
LA eng
NO Molecular Metabolism, 53 (2021), 101275. https://doi.org/10.1016/j.molmet.2021.101275
NO This work was supported by grants from Gobierno Vasco-Departamento de Salud 2013111114 (to M.L.M.-C), ELKARTEK 2016, Departamento de Industria del Gobierno Vasco (to M.L.M−C), Ministerio de Ciencia, Innovación y Universidades MICINN: SAF2017-87301-R, and RTI2018-096759-A-100 integrado en el Plan Estatal de Investigación Científica y Técnica y Innovación, cofinanciado con Fondos FEDER (to M.L.M− T.C.D respectively); MCIU/AEI/FEDER, UE (RTI2018-095134-B-100) (to P.A.), AECC Bizkaia (M.S-M); Asociación Española contra el Cáncer (T.C.D), Fundación Científica de la Asociación Española Contra el Cáncer (AECC Scientific Foundation) Rare Tumor Calls 2017 (to M.L.M, J.M.B., M.A.A., J.J.G.M.), La Caixa Foundation Program (to M.L.M and J.M.B.), 2018 BBVA Foundation Grants for Scientific Research Teams (to M.L.M.-C.), Ayudas para apoyar grupos de investigación del sistema Universitario Vasco IT971-16 (P.A.). MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02364358, Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico (to LV), the European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- “Liver Investigation: Testing Marker Utility in Steatohepatitis” (to LV), Fondazione IRCCS Ca’ Granda “Liver BIBLE” PR-0391, Fondazione IRCCS Ca’ Granda core COVID-19 Biobank (RC100017A) (to LV). This research was funded by the CIBERehd (EHD15PI05/2016) and “Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III”, Spain (PI16/00598 and PI19/00819, co-funded by European Regional Development Fund/European Social Fund, “Investing in your future”); Spanish Ministry of Economy, Industry and Competitiveness (SAF2016-75197-R); “Junta de Castilla y Leon” (SA063P17); AECC Scientific Foundation (2017/2020), Spain; “Centro Internacional sobre el Envejecimiento” (OLD-HEPAMARKER, 0348_CIE_6_E), Spain; University of Salamanca Foundation, Spain (PC-TCUE18-20_051), and Fundació Marato TV3 (Ref. 201916–31), Spain. RB acknowledges BFU2017-84653-P (MINECO/FEDER, EU), SEV-2016-0644 (Severo Ochoa Excellence Program), 765445-EU (UbiCODE Program), SAF2017-90900-REDT (UBIRed Program), and IT1165-19 (Basque Country Government). Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III. We thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644)
DS Minerva
RD 28 abr 2026