Referencia

Elife. 2020 Dec 8;9:e59258. doi: 10.7554/eLife.59258.5Foto portada eLife150x130

Autores

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

Resumen

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. 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.

Descripción

Nuestra investigación desvela por primera vez que los neutrófilos actúan como mensajeros circadianos en el hígado, donde se infiltran de forma circadiana para mantener la correcta oscilación del metabolismo hepático durante el ciclo de 24 horas. Hemos descubierto que los neutrófilos activan en el hepatocito la quinasa activada por el estrés, JNK, y el gen circadiano Bmal1 para modular la expresión de las proteínas implicadas en el metabolismo lipídico. En modelos animales donde se altera el ritmo circadiano hepático, es posible proteger de los cambios metabólicos que sufre el hígado modificando la respuesta de los neutrófilos. Estos descubrimientos abren una nueva ventana terapéutica para el tratamiento de las enfermedades hepáticas.

Foto de grupo SabioLab

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo dirigido por la Dra. Guadalupe Sabio tiene como principal objetivo descubrir el papel de las proteínas quinasas activadas por el estrés en el desarrollo de las patologías asociadas a la obesidad, incluyendo enfermedades cardiovasculares y hepáticas y el cáncer. El estudio de la obesidad desde los diferentes puntos de vista de la biología, el uso de modelos animales modificados genéticamente y el potencial traslacional de las quinasas activadas por el estrés para su uso terapéutico en humanos, hacen de nuestra investigación un aporte incondicional para el avance en el tratamiento y diagnóstico de todas estas enfermedades.

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