2026-06-14T13:00:31Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/132492024-09-27T07:59:28Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud
author
Crespo-Ruiz, Maria
author
Gonzalez-Teran, Barbara
author
Nikolic, Ivana
author
Mora, Alfonso
author
Folgueira, Cintia
author
Rodriguez, Elena
author
Leiva-Vega, Luis
author
Pintor-Chocano, Aranzazu
author
Fernandez-Chacon, Macarena
author
Ruiz-Garrido, Irene
author
Cicuendez, Beatriz
author
Tomas-Loba, Antonia
author
Alonso-Gonzalez, Noelia
author
Caballero-Molano, Ainoa
author
Beiroa, Daniel
author
Hernandez-Cosido, Lourdes
author
Torres, Jorge L
author
Kennedy, Norman J
author
Davis, Roger J
author
Benedito, Rui
author
Marcos, Miguel
author
Nogueiras, Ruben
author
Hidalgo, Andres
author
Matesanz, Nuria
author
Leiva, Magdalena
author
Sabio, Guadalupe
funder
Fundación Lilly
funder
Unión Europea. Comisión Europea. H2020
funder
Howard Hughes Medical Institute
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
funder
Fundación BBVA
funder
Ministerio de Asuntos Económicos y Transformación Digital (España)
funder
Comunidad de Madrid (España)
funder
Asociación Española Contra el Cáncer
funder
National Institutes of Health (Estados Unidos)
funder
Junta de Castilla y León (España)
funder
Ministerio de Ciencia, Innovación y Universidades (España)
funder
Fundación ProCNIC
funder
Instituto de Salud Carlos III
2021-07-19T12:38:40Z
2021-07-19T12:38:40Z
2020-12
Elife. 2020; 9:e59258
10.7554/eLife.59258
2050-084X
eLife
33287957
http://hdl.handle.net/20.500.12105/13249
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.
eng
Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism.
journal article
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NeutrophilInfiltrationRegulatesClock_2020_supp.pdf
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NeutrophilInfiltrationRegulatesClock_2020.pdf.txt
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