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Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function

Abstract: 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.

 Fuente: Journal of Hepatology Volume 76, Issue 1, January 2022, Pages 11-24

 Editorial: Elsevier

 Fecha de publicación: 01/01/2022

 Nº de páginas: 15

 Tipo de publicación: Artículo de Revista

 DOI: 10.1016/j.jhep.2021.09.008

 ISSN: 0168-8278,1600-0641

 Proyecto español: SAF2017- 83813-C3-1-R

 Url de la publicación: https://doi.org/10.1016/j.jhep.2021.09.008

Autoría

DA SILVA LIMA, NATÁLIA

FONDEVILA, MARCOS F.

NÓVOA, EVA

BUQUÉ, XABIER

MERCADO-GÓMEZ, MARIA

GALLET, SARAH

GONZÁLEZ-RELLAN, MARIA J.

FERNANDEZ, UXIA

LOYENS, ANNE

GARCIA-VENCE, MARIA

CHANTADA-VAZQUEZ, MARIA DEL PILAR

BRAVO, SUSANA B.

MARAÑON, PATRICIA

SENRA, ANA

ESCUDERO, ADRIANA

LEIVA, MAGDALENA

GUALLAR, DIANA

FIDALGO, MIGUEL

PAULA IRUZUBIETA COZ