Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function
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 per...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión aceptada para publicación |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/184087 |
| Acceso en línea: | https://hdl.handle.net/2445/184087 |
| Access Level: | acceso abierto |
| Palabra clave: | Metabolisme dels lípids Mitocondris Lipid metabolism Mitochondria |
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Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial functionda Silva Lima, NatáliaFondevila, Marcos F.Novoa Pardo, Eva MariaBuqué, XabierMercado-Gómez, MariaGallet, SarahGonzález-Rellan, Maria J.Fernandez, UxiaLoyens, AnneGarcía-Vence, MariaChantada-Vázquez, Maria Del PilarBravo, SusanaMarañon, PatriciaSenra, AnaEscudero, AdrianaLeiva, MagdalenaGuallar, DianaFidalgo, MiguelGomes, PedroClaret i Carles, MarcSabio, GuadalupeVarela Rey, MartaDelgado, Teresa C.Montero-Vallejo, RocioAmpuero, JavierLópez, MiguelDiéguez, CarlosHerrero Rodríguez, LauraSerra i Cucurull, DolorsSchwaninger, MarkusPrevot, VincentGallego Durán, RocíoRomero Gómez, Manuel 1967-Iruzubieta, PaulaCrespo, JavierMartínez Chantar, Maria LuzGarcía Monzón, CarmeloGonzález Rodríguez, ÁguedaAspichueta, PatriciaNogueiras, RubénMetabolisme dels lípidsMitocondrisLipid metabolismMitochondriaBackground & 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. Lay summary: We show that autophagy-related gene 3 (ATG3) contributes to the progression of non-alcoholic fatty liver disease in humans and mice. Hepatic knockdown of ATG3 ameliorates the development of NAFLD by stimulating mitochondrial function. Thus, ATG3 is an important factor implicated in steatosis. Keywords: ATG3; NAFLD; NASH; lipid metabolism; mitochondria; sirtuin 1.Elsevier2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/184087Articles publicats en revistes (Bioquímica i Fisiologia)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprint del document publicat a: https://doi.org/10.1016/j.jhep.2021.09.008Journal of Hepatology, 2021, vol. 76, p. 11-14https://doi.org/10.1016/j.jhep.2021.09.008cc-by-nc-nd (c) Elsevier, 2021https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1840872026-05-27T06:46:51Z |
| dc.title.none.fl_str_mv |
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, Natália Metabolisme dels lípids Mitocondris Lipid metabolism 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, Natália Fondevila, Marcos F. Novoa Pardo, Eva Maria Buqué, Xabier Mercado-Gómez, Maria Gallet, Sarah González-Rellan, Maria J. Fernandez, Uxia Loyens, Anne García-Vence, Maria Chantada-Vázquez, Maria Del Pilar Bravo, Susana Marañon, Patricia Senra, Ana Escudero, Adriana Leiva, Magdalena Guallar, Diana Fidalgo, Miguel Gomes, Pedro Claret i Carles, Marc Sabio, Guadalupe Varela Rey, Marta Delgado, Teresa C. Montero-Vallejo, Rocio Ampuero, Javier López, Miguel Diéguez, Carlos Herrero Rodríguez, Laura Serra i Cucurull, Dolors Schwaninger, Markus Prevot, Vincent Gallego Durán, Rocío Romero Gómez, Manuel 1967- Iruzubieta, Paula Crespo, Javier Martínez Chantar, Maria Luz García Monzón, Carmelo González Rodríguez, Águeda Aspichueta, Patricia Nogueiras, Rubén |
| author |
da Silva Lima, Natália |
| author_facet |
da Silva Lima, Natália Fondevila, Marcos F. Novoa Pardo, Eva Maria Buqué, Xabier Mercado-Gómez, Maria Gallet, Sarah González-Rellan, Maria J. Fernandez, Uxia Loyens, Anne García-Vence, Maria Chantada-Vázquez, Maria Del Pilar Bravo, Susana Marañon, Patricia Senra, Ana Escudero, Adriana Leiva, Magdalena Guallar, Diana Fidalgo, Miguel Gomes, Pedro Claret i Carles, Marc Sabio, Guadalupe Varela Rey, Marta Delgado, Teresa C. Montero-Vallejo, Rocio Ampuero, Javier López, Miguel Diéguez, Carlos Herrero Rodríguez, Laura Serra i Cucurull, Dolors Schwaninger, Markus Prevot, Vincent Gallego Durán, Rocío Romero Gómez, Manuel 1967- Iruzubieta, Paula Crespo, Javier Martínez Chantar, Maria Luz García Monzón, Carmelo González Rodríguez, Águeda Aspichueta, Patricia Nogueiras, Rubén |
| author_role |
author |
| author2 |
Fondevila, Marcos F. Novoa Pardo, Eva Maria Buqué, Xabier Mercado-Gómez, Maria Gallet, Sarah González-Rellan, Maria J. Fernandez, Uxia Loyens, Anne García-Vence, Maria Chantada-Vázquez, Maria Del Pilar Bravo, Susana Marañon, Patricia Senra, Ana Escudero, Adriana Leiva, Magdalena Guallar, Diana Fidalgo, Miguel Gomes, Pedro Claret i Carles, Marc Sabio, Guadalupe Varela Rey, Marta Delgado, Teresa C. Montero-Vallejo, Rocio Ampuero, Javier López, Miguel Diéguez, Carlos Herrero Rodríguez, Laura Serra i Cucurull, Dolors Schwaninger, Markus Prevot, Vincent Gallego Durán, Rocío Romero Gómez, Manuel 1967- Iruzubieta, Paula Crespo, Javier Martínez Chantar, Maria Luz García Monzón, Carmelo González Rodríguez, Águeda Aspichueta, Patricia Nogueiras, 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 |
Metabolisme dels lípids Mitocondris Lipid metabolism Mitochondria |
| topic |
Metabolisme dels lípids Mitocondris Lipid metabolism Mitochondria |
| description |
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. Lay summary: We show that autophagy-related gene 3 (ATG3) contributes to the progression of non-alcoholic fatty liver disease in humans and mice. Hepatic knockdown of ATG3 ameliorates the development of NAFLD by stimulating mitochondrial function. Thus, ATG3 is an important factor implicated in steatosis. Keywords: ATG3; NAFLD; NASH; lipid metabolism; mitochondria; sirtuin 1. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion |
| format |
article |
| status_str |
acceptedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/184087 |
| url |
https://hdl.handle.net/2445/184087 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Versió postprint del document publicat a: https://doi.org/10.1016/j.jhep.2021.09.008 Journal of Hepatology, 2021, vol. 76, p. 11-14 https://doi.org/10.1016/j.jhep.2021.09.008 |
| dc.rights.none.fl_str_mv |
cc-by-nc-nd (c) Elsevier, 2021 https://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
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cc-by-nc-nd (c) Elsevier, 2021 https://creativecommons.org/licenses/by-nc-nd/4.0/ |
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openAccess |
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application/pdf |
| dc.publisher.none.fl_str_mv |
Elsevier |
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Elsevier |
| dc.source.none.fl_str_mv |
Articles publicats en revistes (Bioquímica i Fisiologia) reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona |
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Universidad de Barcelona |
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Dipòsit Digital de la UB |
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Dipòsit Digital de la UB |
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1869417412235886592 |
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15,301603 |