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Category: Publications (Page 1 of 9)

Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function

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.

JNK1 inhibitor SP600125 blunted increased lipid content (Image: Magdalena Leiva).

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.

Mitochondrial bioenergetics boost macrophages activation promoting liver regeneration in metabolically compromised animals

Naroa Goikoetxea-Usandizaga, Marina Serrano-Maciá, Teresa C. Delgado, Jorge Simón, David Fernández Ramos, Diego Barriales, Maria E. Cornide, Mónica Jiménez, Marina Pérez-Redondo, Sofia Lachiondo-Ortega, Rubén Rodríguez-Agudo, Maider Bizkarguenaga, Juan Diego Zalamea, Samuel T. Pasco, Daniel Caballero-Díaz, Benedetta Alfano, Miren Bravo, Irene González-Recio, Maria Mercado-Gómez, Clàudia Gil-Pitarch, Jon Mabe, Jordi Gracia-Sancho, Leticia Abecia, Óscar Lorenzo, Paloma Martín-Sanz, Nicola G. A. Abrescia, Guadalupe Sabio, Mercedes Rincón, Juan Anguita, Eduardo Miñambres, César Martín, Marina Berenguer, Isabel Fabregat, Marta Casado, Carmen Peralta, Marta Varela-Rey & María Luz Martínez-Chantar.

BACKGROUND & AIMS: Hepatic ischemia-reperfusion injury (IRI) is the leading cause of early post-transplantation organ failure, as mitochondrial respiration and ATP production are affected. Shortage of donors has extended liver donor criteria, including aged or steatotic livers, which are more susceptible to IRI. Given the lack of an effective treatment and the extensive transplantation waitlist, we aimed at characterizing the effects of an accelerated mitochondrial activity by silencing Methylation-controlled J protein (MCJ) in three pre-clinical models of IRI and liver regeneration, focusing on metabolically compromised animal models.

Hepatic uptake of 18F-fluorodeoxyglucose (Image: Alfonso Mora).

APPROACH & RESULTS: Wt, MCJ KO and Mcj silenced Wt mice were subjected to 70% Partial hepatectomy (Phx), prolonged IRI and 70% Phx with IRI. Old and mice with metabolic syndrome were also subjected to these procedures. Expression of MCJ, an endogenous negative regulator of mitochondrial respiration, increases in pre-clinical models of Phx with or without vascular occlusion, and in donors’ livers. Mice lacking MCJ initiate liver regeneration 12h faster than WT, show reduced ischemic injury and increased survival. MCJ knockdown enables a mitochondrial adaptation that restores the bioenergetic supply for enhanced regeneration and prevents cell death after IRI. Mechanistically, increased ATP secretion facilitates the early activation of kupffer cells and production of TNF, IL-6 and HB-EGF accelerating the priming phase and the progression through G1/S transition during liver regeneration. Therapeutic silencing of MCJ in 15-month-old mice and in mice fed with a high fat-high fructose diet for 12 weeks improves mitochondrial respiration, reduces steatosis and overcomes regenerative limitations.

CONCLUSIONS: Boosting mitochondrial activity by silencing MCJ could pave the way for a novel protective approach after major liver resection or IRI, specially in metabolically compromised, IRI susceptible organs.

O-GlcNAcylated p53 in the liver modulates hepatic glucose production

Maria J. Gonzalez-Rellan, Marcos F. Fondevila, Uxia Fernandez, Amaia Rodríguez, Marta Varela-Rey, Christelle Veyrat-Durebex, Samuel Seoane, Ganeko Bernardo, Fernando Lopitz-Otsoa, David Fernández-Ramos, Jon Bilbao, Cristina Iglesias, Eva Novoa, Cristina Ameneiro, Ana Senra, Daniel Beiroa, Juan Cuñarro, Maria DP Chantada-Vazquez, Maria Garcia-Vence, Susana B. Bravo, Natalia Da Silva Lima, Begoña Porteiro, Carmen Carneiro, Anxo Vidal, Sulay Tovar, Timo D. Müller, Johan Ferno, Diana Guallar, Miguel Fidalgo, Guadalupe Sabio, Stephan Herzig, Won Ho Yang, Jin Won Cho, Maria Luz Martinez-Chantar, Roman Perez-Fernandez, Miguel López, Carlos Dieguez, Jose M. Mato, Oscar Millet, Roberto Coppari, Ashwin Woodhoo, Gema Fruhbeck & Ruben Nogueiras.

p53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic stress, and we hypothesized that p53 could be linked to glucose maintenance.

Pyruvate tolerance test.

We show here that upon starvation hepatic p53 is stabilized by O-GlcNAcylation and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels.

Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible of O-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR.

Overall these results indicate that the O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis.

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