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Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway

Liver metabolism undergoes robust circadian oscillations in gene expression and enzymatic activity essential for liver homeostasis, but whether the circadian clock controls homeostatic self-renewal of hepatocytes is unknown. Here we show that hepatocyte polyploidization is markedly accelerated aroun...

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Autores principales: Chao, Hsu-Wen, Doi, Masao, Fustin, Jean-Michel, Chen, Huatao, Murase, Kimihiko, Maeda, Yuki, Hayashi, Hida, Tanaka, Rina, Sugawa, Maho, Mizukuchi, Naoki, Yamaguchi, Yoshiaki, Yasunaga, Jun-ichirou, Matsuoka, Masao, Sakai, Mashito, Matsumoto, Michihiro, Hamada, Shinshichi, Okamura, Hitoshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740157/
https://www.ncbi.nlm.nih.gov/pubmed/29269828
http://dx.doi.org/10.1038/s41467-017-02207-7
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author Chao, Hsu-Wen
Doi, Masao
Fustin, Jean-Michel
Chen, Huatao
Murase, Kimihiko
Maeda, Yuki
Hayashi, Hida
Tanaka, Rina
Sugawa, Maho
Mizukuchi, Naoki
Yamaguchi, Yoshiaki
Yasunaga, Jun-ichirou
Matsuoka, Masao
Sakai, Mashito
Matsumoto, Michihiro
Hamada, Shinshichi
Okamura, Hitoshi
author_facet Chao, Hsu-Wen
Doi, Masao
Fustin, Jean-Michel
Chen, Huatao
Murase, Kimihiko
Maeda, Yuki
Hayashi, Hida
Tanaka, Rina
Sugawa, Maho
Mizukuchi, Naoki
Yamaguchi, Yoshiaki
Yasunaga, Jun-ichirou
Matsuoka, Masao
Sakai, Mashito
Matsumoto, Michihiro
Hamada, Shinshichi
Okamura, Hitoshi
author_sort Chao, Hsu-Wen
collection PubMed
description Liver metabolism undergoes robust circadian oscillations in gene expression and enzymatic activity essential for liver homeostasis, but whether the circadian clock controls homeostatic self-renewal of hepatocytes is unknown. Here we show that hepatocyte polyploidization is markedly accelerated around the central vein, the site of permanent cell self-renewal, in mice deficient in circadian Period genes. In these mice, a massive accumulation of hyperpolyploid mononuclear and binuclear hepatocytes occurs due to impaired mitogen-activated protein kinase phosphatase 1 (Mkp1)-mediated circadian modulation of the extracellular signal-regulated kinase (Erk1/2) activity. Time-lapse imaging of hepatocytes suggests that the reduced activity of Erk1/2 in the midbody during cytokinesis results in abscission failure, leading to polyploidization. Manipulation of Mkp1 phosphatase activity is sufficient to change the ploidy level of hepatocytes. These data provide clear evidence that the Period genes not only orchestrate dynamic changes in metabolic activity, but also regulate homeostatic self-renewal of hepatocytes through Mkp1-Erk1/2 signaling pathway.
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spelling pubmed-57401572017-12-26 Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway Chao, Hsu-Wen Doi, Masao Fustin, Jean-Michel Chen, Huatao Murase, Kimihiko Maeda, Yuki Hayashi, Hida Tanaka, Rina Sugawa, Maho Mizukuchi, Naoki Yamaguchi, Yoshiaki Yasunaga, Jun-ichirou Matsuoka, Masao Sakai, Mashito Matsumoto, Michihiro Hamada, Shinshichi Okamura, Hitoshi Nat Commun Article Liver metabolism undergoes robust circadian oscillations in gene expression and enzymatic activity essential for liver homeostasis, but whether the circadian clock controls homeostatic self-renewal of hepatocytes is unknown. Here we show that hepatocyte polyploidization is markedly accelerated around the central vein, the site of permanent cell self-renewal, in mice deficient in circadian Period genes. In these mice, a massive accumulation of hyperpolyploid mononuclear and binuclear hepatocytes occurs due to impaired mitogen-activated protein kinase phosphatase 1 (Mkp1)-mediated circadian modulation of the extracellular signal-regulated kinase (Erk1/2) activity. Time-lapse imaging of hepatocytes suggests that the reduced activity of Erk1/2 in the midbody during cytokinesis results in abscission failure, leading to polyploidization. Manipulation of Mkp1 phosphatase activity is sufficient to change the ploidy level of hepatocytes. These data provide clear evidence that the Period genes not only orchestrate dynamic changes in metabolic activity, but also regulate homeostatic self-renewal of hepatocytes through Mkp1-Erk1/2 signaling pathway. Nature Publishing Group UK 2017-12-21 /pmc/articles/PMC5740157/ /pubmed/29269828 http://dx.doi.org/10.1038/s41467-017-02207-7 Text en © The Author(s) 2017 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
Chao, Hsu-Wen
Doi, Masao
Fustin, Jean-Michel
Chen, Huatao
Murase, Kimihiko
Maeda, Yuki
Hayashi, Hida
Tanaka, Rina
Sugawa, Maho
Mizukuchi, Naoki
Yamaguchi, Yoshiaki
Yasunaga, Jun-ichirou
Matsuoka, Masao
Sakai, Mashito
Matsumoto, Michihiro
Hamada, Shinshichi
Okamura, Hitoshi
Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway
title Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway
title_full Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway
title_fullStr Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway
title_full_unstemmed Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway
title_short Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway
title_sort circadian clock regulates hepatic polyploidy by modulating mkp1-erk1/2 signaling pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740157/
https://www.ncbi.nlm.nih.gov/pubmed/29269828
http://dx.doi.org/10.1038/s41467-017-02207-7
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