Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function

Autor: Marta Varela-Rey, Susana B. Bravo, Guadalupe Sabio, Teresa C. Delgado, Ana Senra, Vincent Prevot, Xabier Buqué, Manuel Romero-Gómez, Sarah Gallet, Magdalena Leiva, Pedro Gomes, Carlos Dieguez, Laura Herrero, Miguel Fidalgo, Anne Loyens, Eva Novoa, Carmelo García-Monzón, Dolors Serra, Patricia Aspichueta, María Del Pilar Chantada-Vázquez, Diana Guallar, Maria Mercado-Gómez, María García-Vence, Maria J. Gonzalez-Rellan, Patricia Marañón, Javier Crespo, Águeda González-Rodríguez, María L. Martínez-Chantar, Adriana Escudero, Miguel López, Rocío Montero-Vallejo, Marc Claret, Javier Ampuero, Marcos F. Fondevila, Markus Schwaninger, Rubén Nogueiras, Natália da Silva Lima, Paula Iruzubieta, Rocío Gallego-Durán, Uxia Fernandez
Přispěvatelé: European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Xunta de Galicia, Fundación BBVA, Eusko Jaurlaritza, Atresmedia, Fundación 'la Caixa', Gilead Sciences, Fundació La Marató de TV3, Generalitat de Catalunya, European Foundation for the Study of Diabetes, Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (España), Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (España), Ministerio de Economía y Competitividad (España), Lima, Natália da Silva, Fondevila, Marcos F., Nóvoa, Eva, Buqué, Xabier, Gallet, Sarah, Fernández, Uxía, Bravo, Susana Belén, Leiva, Magdalena, Guallar, Diana, Fidalgo, Miguel, Gomes, Pedro, Varela-Rey, Marta, Delgado, Teresa C., Montero-Vallejo, Rocío, López, Miguel, Diéguez, Carlos, Herrero, Laura, Iruzubieta, Paula, Crespo, Javier, García-Monzón, Carmelo, González-Rodríguez, Águeda, Aspichueta, Patricia, Nogueiras, Rubén, Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Bioquímica e Bioloxía Molecular, Universidade de Santiago de Compostela. Departamento de Fisioloxía
Rok vydání: 2022
Předmět:
Zdroj: Addi. Archivo Digital para la Docencia y la Investigación
instname
JOURNAL OF HEPATOLOGY
r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
Dipòsit Digital de la UB
Universidad de Barcelona
Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
ISSN: 0168-8278
Popis: [Background & Aims] Autophagy-related gene 3 (ATG3) is an enzyme mainly known for its actions in the LC3 lipidation process, which is essential for autophagy. Whether ATG3 plays a role in lipid metabolism or contributes to non-alcoholic fatty liver disease (NAFLD) remains unknown.
[Methods] By performing proteomic analysis on livers from mice with genetic manipulation of hepatic p63, a regulator of fatty acid metabolism, we identified ATG3 as a new target downstream of p63. ATG3 was evaluated in liver samples from patients with NAFLD. Further, genetic manipulation of ATG3 was performed in human hepatocyte cell lines, primary hepatocytes and in the livers of mice.
[Results] ATG3 expression is induced in the liver of animal models and patients with NAFLD (both steatosis and non-alcoholic steatohepatitis) compared with those without liver disease. Moreover, genetic knockdown of ATG3 in mice and human hepatocytes ameliorates p63- and diet-induced steatosis, while its overexpression increases the lipid load in hepatocytes. The inhibition of hepatic ATG3 improves fatty acid metabolism by reducing c-Jun N-terminal protein kinase 1 (JNK1), which increases sirtuin 1 (SIRT1), carnitine palmitoyltransferase 1a (CPT1a), and mitochondrial function. Hepatic knockdown of SIRT1 and CPT1a blunts the effects of ATG3 on mitochondrial activity. Unexpectedly, these effects are independent of an autophagic action.
[Conclusions] Collectively, these findings indicate that ATG3 is a novel protein implicated in the development of steatosis.
This work has been supported by grants from FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (PA: RTI2018-095134-B-100; DS and LH: SAF2017-83813-C3-1-R; MLMC: RTC2019-007125-1; CD: BFU2017-87721; ML: RTI2018–101840-B-I00; GS; PID2019-104399RB-I00; RN: RTI2018-099413-B-I00 and RED2018-102379-T; MLMC: SAF2017-87301-R; TCD: RTI2018-096759-A-100), FEDER/Instituto de Salud Carlos III (AGR: PI19/00123), Xunta de Galicia (ML: 2016-PG068; RN: 2015-CP080 and 2016-PG057), Fundación BBVA (RN, GS and MLM), Proyectos Investigación en Salud (MLMC: DTS20/00138), Sistema Universitario Vasco (PA: IT971-16); Fundación Atresmedia (ML and RN), Fundación La Caixa (M.L., R.N. and M.C.), Gilead Sciences International Research Scholars Program in Liver Disease (MVR), Marató TV3 Foundation (DS: 201627), Government of Catalonia (DS: 2017SGR278) and European Foundation for the Study of Diabetes (RN and GS). This research also received funding from the European Community’s H2020 Framework Programme (ERC Synergy Grant-2019-WATCH- 810331, to RN, VP and MS). Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Hepáticas y Digestivas (CIBERehd) and CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem). CIBERobn, CIBERehd and CIBERdem are initiatives of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds. We thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644).
Databáze: OpenAIRE
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