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.
at the CNIC
Tag: liver (Page 1 of 7)
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.
Ana Victoria Lechuga-Vieco, Ana Latorre-Pellicer, Iain G. Johnston, Gennaro Prota, Uzi Gileadi, Raquel Justo-Méndez, Rebeca Acín-Pérez, Raquel Martínez-de-Mena, Jose María Fernández-Toro, Daniel Jimenez-Blasco, Alfonso Mora, Jose A. Nicolás-Ávila, Demetrio J. Santiago, Silvia G. Priori, Juan Pedro Bolaños, Guadalupe Sabio, Luis Miguel Criado, Jesús Ruíz-Cabello, Vincenzo Cerundolo, Nick S. Jones, José Antonio Enríquez.
Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development.
Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specific mtDNA segregation pattern, with few tissues that do not show segregation. The driving force for this dynamic complex pattern has remained unexplained for decades, challenging our understanding of this fundamental biological problem and hindering clinical planning for inherited diseases.
Here, we demonstrate that the nonrandom mtDNA segregation is an intracellular process based on organelle selection. This cell type–specific decision arises jointly from the impact of mtDNA haplotypes on the oxidative phosphorylation (OXPHOS) system and the cell metabolic requirements and is strongly sensitive to the nuclear context and to environmental cues.
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