Investigadoras del CNIC dirigidas por la extremeña Guadalupe Sabio descubren un mecanismo a través del cual se desarrolla la esteatosis. Esta patología es uno de los principales factores de riesgo del cáncer de hígado.
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.
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.
Our lab mate María Crespo has been awarded the second prize in the Archimedes Competition. She will receive a prize of € 2,000.
The competition, organized by the Spanish Ministry of Education, favours the incorporation of young students into the research field by awarding them for their original Master projects of scientific or technological research. On this occasion, more than 350 students throughout Spain participated, of which only 25 went to the final.
Under the supervision of Guadalupe Sabio and Magdalena Leiva, Crespo has studied the circadian rhythm of neutrophil infiltration in the liver and the possible role that these cells play in the regulation of hepatic activity. Through the use of neutropenic mice, she has analyzed the contribution of neutrophils in the progress of non-alcoholic fatty liver disease (NAFLD).