Natáliada Silva Lima, Marcos F. Fondevila, Eva Nóvoa, Xabier Buqué, Maria Mercado-Gómez, Sarah Gallet, Maria J. González-Rellan, Uxia Fernandez, Anne Loyens, Maria Garcia-Vence, Maria del Pilar Chantada-Vazquez, Susana B. Bravo, Patricia Marañon, Ana Senra, Adriana Escudero, Magdalena Leiva, Diana Guallar, Miguel Fidalgo, Pedro Gomes, Marc Claret, Guadalupe Sabio, Marta Varela-Rey, Teresa C. Delgado, Rocio Montero-Vallejo, Javier Ampuero, Miguel López, Carlos Diéguez, Laura Herrero, Dolors Serra, Markus Schwaninger, Vincent Prevo, Rocio Gallego-Duran, Manuel Romero-Gomez, Paula Iruzubieta, Javier Crespo, Maria L. Martinez-Chantar, Carmelo Garcia-Monzon, Agueda Gonzalez-Rodriguez, Patricia Aspichueta & Ruben Nogueiras.
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 nonalcoholic fatty liver disease (NAFLD) remains unknown.
METHODS: By performing a liver proteomic analysis 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 of patients with NAFLD. Further, genetic manipulation of ATG3 was performed in human hepatocyte cell lines, primary hepatocytes and in the liver of mice.
RESULTS: ATG3 expression is induced in the liver of animal models and patients with NAFLD (both steatosis and NASH) 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 palmitoiltransferase I (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.