Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function

• Type: Article in International Scientific Journal
• Date: 2022

Authors

Lima, ND (Author) Other; Fondevila, MF (Author) Other; Novoa, E (Author) Other; Buque, X (Author) Other; Mercado Gomez, M (Author) Other; Gallet, S (Author) Other; Gonzalez Rellan, MJ (Author) Other; Fernandez, U (Author) Other; Loyens, A (Author) Other; Garcia Vence, M (Author) Other; Chantada Vazquez, MD (Author) Other; Bravo, SB (Author) Other; Maranon, P (Author) Other; Senra, A (Author) Other; Escudero, A (Author) Other; Leiva, M (Author) Other; Guallar, D (Author) Other; Fidalgo, M (Author) Other; Pedro Gomes (Author) FMUP; Claret, M (Author) Other; Sabio, G (Author) Other; Varela Rey, M (Author) Other; Delgado, TC (Author) Other; Montero Vallejo, R (Author) Other; Ampuero, J (Author) Other; Lopez, M (Author) Other; Dieguez, C (Author) Other; Herrero, L (Author) Other; Serra, D (Author) Other; Schwaninger, M (Author) Other; Prevot, V (Author) Other; Gallego Duran, R (Author) Other; Romero Gomez, M (Author) Other; Iruzubieta, P (Author) Other; Crespo, J (Author) Other; Martinez Chantar, ML (Author) Other; Garcia Monzon, C (Author) Other; Gonzalez Rodriguez, A (Author) Other; Aspichueta, P (Author) Other; Nogueiras, R (Author) Other

Journal

Title: Journal of Hepatology

Vol. 76

Pages: 11-24

ISSN: 0168-8278

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 0 Citations

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Other information

Authenticus ID: P-00V-MQ9

DOI: 10.1016/j.jhep.2021.09.008

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

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 15