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MCD diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in Klf10 deficient mice

A large number of hepatic functions are regulated by the circadian clock and recent evidence suggests that clock disruption could be a risk factor for liver complications. The circadian transcription factor Krüppel like factor 10 (KLF10) has been involved in liver metabolism as well as cellular infl...

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Autores principales: Leclère, Pierre S., Rousseau, Déborah, Patouraux, Stéphanie, Guérin, Sophie, Bonnafous, Stéphanie, Gréchez-Cassiau, Aline, Ruberto, Anthony A., Luci, Carmelo, Subramaniam, Malayannan, Tran, Albert, Delaunay, Franck, Gual, Philippe, Teboul, Michèle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376252/
https://www.ncbi.nlm.nih.gov/pubmed/32699233
http://dx.doi.org/10.1038/s41598-020-69085-w
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author Leclère, Pierre S.
Rousseau, Déborah
Patouraux, Stéphanie
Guérin, Sophie
Bonnafous, Stéphanie
Gréchez-Cassiau, Aline
Ruberto, Anthony A.
Luci, Carmelo
Subramaniam, Malayannan
Tran, Albert
Delaunay, Franck
Gual, Philippe
Teboul, Michèle
author_facet Leclère, Pierre S.
Rousseau, Déborah
Patouraux, Stéphanie
Guérin, Sophie
Bonnafous, Stéphanie
Gréchez-Cassiau, Aline
Ruberto, Anthony A.
Luci, Carmelo
Subramaniam, Malayannan
Tran, Albert
Delaunay, Franck
Gual, Philippe
Teboul, Michèle
author_sort Leclère, Pierre S.
collection PubMed
description A large number of hepatic functions are regulated by the circadian clock and recent evidence suggests that clock disruption could be a risk factor for liver complications. The circadian transcription factor Krüppel like factor 10 (KLF10) has been involved in liver metabolism as well as cellular inflammatory and death pathways. Here, we show that hepatic steatosis and inflammation display diurnal rhythmicity in mice developing steatohepatitis upon feeding with a methionine and choline deficient diet (MCDD). Core clock gene mRNA oscillations remained mostly unaffected but rhythmic Klf10 expression was abolished in this model. We further show that Klf10 deficient mice display enhanced liver injury and fibrosis priming upon MCDD challenge. Silencing Klf10 also sensitized primary hepatocytes to apoptosis along with increased caspase 3 activation in response to TNFα. This data suggests that MCDD induced steatohepatitis barely affects the core clock mechanism but leads to a reprogramming of circadian gene expression in the liver in analogy to what is observed in other experimental disease paradigms. We further identify KLF10 as a component of this transcriptional reprogramming and a novel hepato-protective factor.
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spelling pubmed-73762522020-07-24 MCD diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in Klf10 deficient mice Leclère, Pierre S. Rousseau, Déborah Patouraux, Stéphanie Guérin, Sophie Bonnafous, Stéphanie Gréchez-Cassiau, Aline Ruberto, Anthony A. Luci, Carmelo Subramaniam, Malayannan Tran, Albert Delaunay, Franck Gual, Philippe Teboul, Michèle Sci Rep Article A large number of hepatic functions are regulated by the circadian clock and recent evidence suggests that clock disruption could be a risk factor for liver complications. The circadian transcription factor Krüppel like factor 10 (KLF10) has been involved in liver metabolism as well as cellular inflammatory and death pathways. Here, we show that hepatic steatosis and inflammation display diurnal rhythmicity in mice developing steatohepatitis upon feeding with a methionine and choline deficient diet (MCDD). Core clock gene mRNA oscillations remained mostly unaffected but rhythmic Klf10 expression was abolished in this model. We further show that Klf10 deficient mice display enhanced liver injury and fibrosis priming upon MCDD challenge. Silencing Klf10 also sensitized primary hepatocytes to apoptosis along with increased caspase 3 activation in response to TNFα. This data suggests that MCDD induced steatohepatitis barely affects the core clock mechanism but leads to a reprogramming of circadian gene expression in the liver in analogy to what is observed in other experimental disease paradigms. We further identify KLF10 as a component of this transcriptional reprogramming and a novel hepato-protective factor. Nature Publishing Group UK 2020-07-22 /pmc/articles/PMC7376252/ /pubmed/32699233 http://dx.doi.org/10.1038/s41598-020-69085-w Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Leclère, Pierre S.
Rousseau, Déborah
Patouraux, Stéphanie
Guérin, Sophie
Bonnafous, Stéphanie
Gréchez-Cassiau, Aline
Ruberto, Anthony A.
Luci, Carmelo
Subramaniam, Malayannan
Tran, Albert
Delaunay, Franck
Gual, Philippe
Teboul, Michèle
MCD diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in Klf10 deficient mice
title MCD diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in Klf10 deficient mice
title_full MCD diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in Klf10 deficient mice
title_fullStr MCD diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in Klf10 deficient mice
title_full_unstemmed MCD diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in Klf10 deficient mice
title_short MCD diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in Klf10 deficient mice
title_sort mcd diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in klf10 deficient mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376252/
https://www.ncbi.nlm.nih.gov/pubmed/32699233
http://dx.doi.org/10.1038/s41598-020-69085-w
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