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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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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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. |
format | Online Article Text |
id | pubmed-5740157 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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