at the CNIC

Tag: JNK1

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.

Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism

María Crespo, Barbara Gonzalez-Teran, Ivana Nikolic, Alfonso Mora, Cintia Folgueira, Elena Rodríguez, Luis Leiva-Vega, Aránzazu Pintor-Chocano, Macarena Fernández-Chacón, Irene Ruiz-Garrido, Beatriz Cicuéndez, Antonia Tomás-Loba, Noelia A-Gonzalez, Ainoa Caballero-Molano, Daniel Beiroa, Lourdes Hernández-Cosido, Jorge L Torres, Norman J Kennedy, Roger J Davis, Rui Benedito, Miguel Marcos, Ruben Nogueiras, Andrés Hidalgo, Nuria Matesanz, Magdalena Leiva & Guadalupe Sabio.

Liver metabolism follows diurnal fluctuations through the modulation of molecular clock genes. Disruption of this molecular clock can result in metabolic disease but its potential regulation by immune cells remains unexplored.

3-D image of liver section showing the distribution on infiltrated neutrophils in red (Image: Magdalena Leiva).

Here, we demonstrated that in steady state, neutrophils infiltrated the mouse liver following a circadian pattern and regulated hepatocyte clock-genes by neutrophil elastase (NE) secretion. NE signals through c-Jun NH2-terminal kinase (JNK) inhibiting fibroblast growth factor 21 (FGF21) and activating Bmal1 expression in the hepatocyte. Interestingly, mice with neutropenia, defective neutrophil infiltration or lacking elastase were protected against steatosis correlating with lower JNK activation, reduced Bmal1 and increased FGF21 expression, together with decreased lipogenesis in the liver. Lastly, using a cohort of human samples we found a direct correlation between JNK activation, NE levels and Bmal1 expression in the liver.

This study demonstrates that neutrophils contribute to the maintenance of daily hepatic homeostasis through the regulation of the NE/JNK/Bmal1 axis.

Brain JNK and metabolic disease

Rubén Nogueiras & Guadalupe Sabio.

Obesity, which has long since reached epidemic proportions worldwide, is associated with long-term stress to a variety of organs and results in diseases including type 2 diabetes. In the brain, overnutrition induces hypothalamic stress associated with the activation of several signalling pathways, together with central insulin and leptin resistance. This central action of nutrient overload appears very rapidly, suggesting that nutrition-induced hypothalamic stress is a major upstream initiator of obesity and associated diseases. The cellular response to nutrient overload includes the activation of the stress-activated c-Jun N-terminal kinases (JNKs) JNK1, JNK2 and JNK3, which are widely expressed in the brain.

Opposing roles of JNK1 and JNK3 in the hypothalamus.

Here, we review recent findings on the regulation and effects of these kinases, with particular focus on the hypothalamus, a key brain region in the control of energy and glucose homeostasis. JNK1 blocks the hypothalamic–pituitary–thyroid axis, reducing energy expenditure and promoting obesity. Recently, opposing roles have been identified for JNK1 and JNK3 in hypothalamic agouti gene-related protein (AgRP) neurons: while JNK1 activation in AgRP neurons induces feeding and weight gain and impairs insulin and leptin signalling, JNK3 (also known as MAPK10) deletion in the same neuronal population produces very similar effects. The opposing roles of these kinases, and the unknown role of hypothalamic JNK2, reflect the complexity of JNK biology.

Future studies should address the specific function of each kinase, not only in different neuronal subsets, but also in non-neuronal cells in the central nervous system. Decoding the puzzle of brain stress kinases will help to define the central stimuli and mechanisms implicated in the control of energy balance.

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