Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function
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2022-01Author
Da Silva Lima, Natalia
Fondevila, Marcos F.
Novoa, Eva
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
García Monzón, Carmelo
González Rodríguez, Águeda
Aspichueta Celaá, Patricia
Nogueiras Pozo, Rubén
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Journal of hepatology 76(1) : 11-24 (2022)
Abstract
[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
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Except where otherwise noted, this item's license is described as © 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 license
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