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

Hsu-Wen Chao, Masao Doi, Jean-Michel Fustin, Huatao Chen, Kimihiko Murase, Yuki Maeda, Hida Hayashi, Rina Tanaka, Maho Sugawa, Naoki Mizukuchi, Yoshiaki Yamaguchi, Jun-ichirou Yasunaga, Masao Matsuoka, Mashito Sakai, Michihiro Matsumoto, Shinshichi Hamada and Hitoshi Okamura ()
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Hsu-Wen Chao: Graduate School of Pharmaceutical Sciences, Kyoto University
Masao Doi: Graduate School of Pharmaceutical Sciences, Kyoto University
Jean-Michel Fustin: Graduate School of Pharmaceutical Sciences, Kyoto University
Huatao Chen: Graduate School of Pharmaceutical Sciences, Kyoto University
Kimihiko Murase: Graduate School of Pharmaceutical Sciences, Kyoto University
Yuki Maeda: Graduate School of Pharmaceutical Sciences, Kyoto University
Hida Hayashi: Graduate School of Pharmaceutical Sciences, Kyoto University
Rina Tanaka: Graduate School of Pharmaceutical Sciences, Kyoto University
Maho Sugawa: Graduate School of Pharmaceutical Sciences, Kyoto University
Naoki Mizukuchi: Graduate School of Pharmaceutical Sciences, Kyoto University
Yoshiaki Yamaguchi: Graduate School of Pharmaceutical Sciences, Kyoto University
Jun-ichirou Yasunaga: Kyoto University
Masao Matsuoka: Kyoto University
Mashito Sakai: Research Institute, National Center for Global Health and Medicine
Michihiro Matsumoto: Research Institute, National Center for Global Health and Medicine
Shinshichi Hamada: Otsu City Hospital
Hitoshi Okamura: Graduate School of Pharmaceutical Sciences, Kyoto University

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-02207-7

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