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...

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Detalles Bibliográficos
Autores: 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
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
Descripción
Sumario:[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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