Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function
[EN]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...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universidad del País Vasco |
| Repositorio: | Addi. Archivo Digital para la Docencia y la Investigación |
| OAI Identifier: | oai:addi.ehu.eus:10810/54853 |
| Acceso en línea: | http://hdl.handle.net/10810/54853 |
| Access Level: | acceso abierto |
| Palabra clave: | ATG3 sirtuin 1 lipid metabolism NAFLD NASH mitochondria |
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Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function |
| title |
Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function |
| spellingShingle |
Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function Da Silva Lima, Natalia ATG3 sirtuin 1 lipid metabolism NAFLD NASH mitochondria |
| title_short |
Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function |
| title_full |
Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function |
| title_fullStr |
Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function |
| title_full_unstemmed |
Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function |
| title_sort |
Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function |
| dc.creator.none.fl_str_mv |
Da Silva Lima, Natalia Fondevila, Marcos F. Novoa, Eva Buqué García, Xabier Mercado Gómez, María Gallet, Sarah González Rellán, María Jesús Fernández, Uxia Loyens, Anne García Vence, María Chantada Vázquez, María del Pilar Bravo López, Susana Belén Marañón, Patricia Senra, Ana Escudero González, Adriana Leiva, Magdalena Guallar, Diana Fidalgo, Miguel Gomes, Pedro Claret, Marc Sabio, Guadalupe Varela Rey, Marta Cardoso Delgado, Teresa de Jesús Montero Vallejo, Rocío Ampuero Herrojo, Javier López, Miguel Diéguez González, Carlos Herrero, Laura Serra, Dolors Schwaninger, Markus Prevot, Vincent Gallego Durán, Rocío Romero Gómez, Manuel Iruzubieta, Paula Crespo, Javier Martínez Chantar, María Luz García Monzón, Carmelo González Rodríguez, Águeda Aspichueta Celaá, Patricia Nogueiras Pozo, Rubén |
| author |
Da Silva Lima, Natalia |
| author_facet |
Da Silva Lima, Natalia Fondevila, Marcos F. Novoa, Eva Buqué García, Xabier Mercado Gómez, María Gallet, Sarah González Rellán, María Jesús Fernández, Uxia Loyens, Anne García Vence, María Chantada Vázquez, María del Pilar Bravo López, Susana Belén Marañón, Patricia Senra, Ana Escudero González, Adriana Leiva, Magdalena Guallar, Diana Fidalgo, Miguel Gomes, Pedro Claret, Marc Sabio, Guadalupe Varela Rey, Marta Cardoso Delgado, Teresa de Jesús Montero Vallejo, Rocío Ampuero Herrojo, Javier López, Miguel Diéguez González, Carlos Herrero, Laura Serra, Dolors Schwaninger, Markus Prevot, Vincent Gallego Durán, Rocío Romero Gómez, Manuel Iruzubieta, Paula Crespo, Javier Martínez Chantar, María Luz García Monzón, Carmelo González Rodríguez, Águeda Aspichueta Celaá, Patricia Nogueiras Pozo, Rubén |
| author_role |
author |
| author2 |
Fondevila, Marcos F. Novoa, Eva Buqué García, Xabier Mercado Gómez, María Gallet, Sarah González Rellán, María Jesús Fernández, Uxia Loyens, Anne García Vence, María Chantada Vázquez, María del Pilar Bravo López, Susana Belén Marañón, Patricia Senra, Ana Escudero González, Adriana Leiva, Magdalena Guallar, Diana Fidalgo, Miguel Gomes, Pedro Claret, Marc Sabio, Guadalupe Varela Rey, Marta Cardoso Delgado, Teresa de Jesús Montero Vallejo, Rocío Ampuero Herrojo, Javier López, Miguel Diéguez González, Carlos Herrero, Laura Serra, Dolors Schwaninger, Markus Prevot, Vincent Gallego Durán, Rocío Romero Gómez, Manuel Iruzubieta, Paula Crespo, Javier Martínez Chantar, María Luz García Monzón, Carmelo González Rodríguez, Águeda Aspichueta Celaá, Patricia Nogueiras Pozo, Rubén |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
ATG3 sirtuin 1 lipid metabolism NAFLD NASH mitochondria |
| topic |
ATG3 sirtuin 1 lipid metabolism NAFLD NASH mitochondria |
| description |
[EN]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 nonalcoholic 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. Lay summary: We show that autophagy-related gene 3 (ATG3) contributes to the progression of non-alcoholic fatty liver disease |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 2022 2022 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10810/54853 |
| url |
http://hdl.handle.net/10810/54853 |
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Inglés |
| language_invalid_str_mv |
Inglés |
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info:eu-repo/grantAgreement/MINECO/SAF2017-83813-C3-1-R/ info:eu-repo/grantAgreement/MINECO/BFU2017-87721/ info:eu-repo/grantAgreement/MINECO/SAF2017-87301-R/ info:eu-repo/grantAgreement/MICIU/RTI2018-095134-B-100/ info:eu-repo/grantAgreement/MICIU/RTI2018-101840-B-I0 0/ info:eu-repo/grantAgreement/MICIU/RTI2018-099413-B-I0 0/ info:eu-repo/grantAgreement/MICIU/RED2018-102379-T/ info:eu-repo/grantAgreement/MICIU/RTI2018-096759-A-10 0/ info:eu-repo/grantAgreement/MICINN/RTC2019-007125-1/ info:eu-repo/grantAgreement/MICINN/PID2019-104399RB-I0 0/ https://www.sciencedirect.com/science/article/pii/S0168827821020389?via%3Dihub |
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info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/3.0/es/ Atribución-NoComercial-SinDerivadas 3.0 España |
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openAccess |
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http://creativecommons.org/licenses/by-nc-nd/3.0/es/ Atribución-NoComercial-SinDerivadas 3.0 España |
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application/pdf |
| dc.publisher.none.fl_str_mv |
Elsevier |
| publisher.none.fl_str_mv |
Elsevier |
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reponame:Addi. Archivo Digital para la Docencia y la Investigación instname:Universidad del País Vasco |
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Universidad del País Vasco |
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Addi. Archivo Digital para la Docencia y la Investigación |
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Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial functionDa Silva Lima, NataliaFondevila, Marcos F.Novoa, EvaBuqué García, XabierMercado Gómez, MaríaGallet, SarahGonzález Rellán, María JesúsFernández, UxiaLoyens, AnneGarcía Vence, MaríaChantada Vázquez, María del PilarBravo López, Susana BelénMarañón, PatriciaSenra, AnaEscudero González, AdrianaLeiva, MagdalenaGuallar, DianaFidalgo, MiguelGomes, PedroClaret, MarcSabio, GuadalupeVarela Rey, MartaCardoso Delgado, Teresa de JesúsMontero Vallejo, RocíoAmpuero Herrojo, JavierLópez, MiguelDiéguez González, CarlosHerrero, LauraSerra, DolorsSchwaninger, MarkusPrevot, VincentGallego Durán, RocíoRomero Gómez, ManuelIruzubieta, PaulaCrespo, JavierMartínez Chantar, María LuzGarcía Monzón, CarmeloGonzález Rodríguez, ÁguedaAspichueta Celaá, PatriciaNogueiras Pozo, RubénATG3sirtuin 1lipid metabolismNAFLDNASHmitochondria[EN]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 nonalcoholic 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. Lay summary: We show that autophagy-related gene 3 (ATG3) contributes to the progression of non-alcoholic fatty liver diseaseThis work has been supported by grants from FEDER/Ministerio de Ciencia, Innovacion y Universidades-Agencia Estatal de Investigacion (PA: RTI2018-095134-B-100; DS and LH: SAF2017-83813-C3-1-R; MLMC: RTC2019-007125-1; CD: BFU2017-87721; ML: RTI2018-101840-B-I0 0; GS; PID2019-104399RB-I0 0; RN: RTI2018-099413-B-I0 0 and RED2018-102379-T; MLMC: SAF2017-87301-R; TCD: RTI2018-096759-A-10 0) , FEDER/Instituto de Salud Carlos III (AGR: PI19/00123) , Xunta de Galicia (ML: 2016-PG068; RN: 2015-CP080 and 2016-PG057) , Fundacion BBVA (RN, GS and MLM) , Proyectos Investigacion en Salud (MLMC: DTS20/00138) , Sistema Universitario Vasco (PA: IT971-16) ; Fun-dacion Atresmedia (ML and RN) , Fundacion La Caixa (M.L., R.N. and M.C.) , Gilead Sciences International Research Scholars Pro-gram in Liver Disease (MVR) , Marato TV3 Foundation (DS: 201627) , Government of Catalonia (DS: 2017SGR278) and Euro-pean 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 Investigacion Biomedica en Red (CIBER) de Fisiopatologia de la Obesidad y Nutricion (CIBERobn) , Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Hepaticas y Digestivas (CIBERehd) and CIBER de Diabetes y Enfermedades Metabolicas 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-2016-064 4) .Elsevier202220222022info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/54853reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoInglésinfo:eu-repo/grantAgreement/MINECO/SAF2017-83813-C3-1-R/info:eu-repo/grantAgreement/MINECO/BFU2017-87721/info:eu-repo/grantAgreement/MINECO/SAF2017-87301-R/info:eu-repo/grantAgreement/MICIU/RTI2018-095134-B-100/info:eu-repo/grantAgreement/MICIU/RTI2018-101840-B-I0 0/info:eu-repo/grantAgreement/MICIU/RTI2018-099413-B-I0 0/info:eu-repo/grantAgreement/MICIU/RED2018-102379-T/info:eu-repo/grantAgreement/MICIU/RTI2018-096759-A-10 0/info:eu-repo/grantAgreement/MICINN/RTC2019-007125-1/info:eu-repo/grantAgreement/MICINN/PID2019-104399RB-I0 0/https://www.sciencedirect.com/science/article/pii/S0168827821020389?via%3Dihubinfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-nd/3.0/es/© 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY-NC-ND licenseAtribución-NoComercial-SinDerivadas 3.0 Españaoai:addi.ehu.eus:10810/548532026-06-18T09:23:17Z |
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15,300719 |