2026-04-30T10:43:39Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/189142025-03-26T11:54:24Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc da Silva Lima, Natália author Fondevila, Marcos F author Nóvoa, Eva author Buqué, Xabier author Mercado-Gómez, Maria author Gallet, Sarah author González-Rellan, Maria J author Fernandez, Uxia author Loyens, Anne author Garcia-Vence, Maria author Chantada-Vazquez, Maria Del Pilar author Bravo, Susana-Belén author Marañon, Patricia author Senra, Ana author Escudero, Adriana author Leiva, Magdalena author Guallar, Diana author Fidalgo, Miguel author Gomes, Pedro author Claret, Marc author Sabio, Guadalupe author Varela-Rey, Marta author Delgado, Teresa C author Montero-Vallejo, Rocio author Ampuero, Javier author López, Miguel author Diéguez, Carlos author Herrero, Laura author Serra, Dolors author Schwaninger, Markus author Prevot, Vincent author Gallego-Duran, Rocio author Romero-Gomez, Manuel author Iruzubieta, Paula author Crespo, Javier author Martinez-Chantar, Maria L author Garcia-Monzon, Carmelo author Gonzalez-Rodriguez, Agueda author Aspichueta, Patricia author Nogueiras, Ruben author 2022-01 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. J Hepatol. 2022 Jan;76(1):11-24. 10.1016/j.jhep.2021.09.008 1600-0641 Journal of hepatology 34555423 http://hdl.handle.net/20.500.12105/18914 Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function.