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Nat Commun. 2017 Dec 21;8(1):2238. doi: 10.1038/s41467-017-02207-7.

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

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Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan.
Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
The Department of Respiratory Care and Sleep Control Medicine, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, 606-8507, Japan.
Department of Hematology, Rheumatology, and Infectious Diseases, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556, Japan.
Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan.
Department of Pathology, Otsu City Hospital, Otsu, 520-0804, Japan.
Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan.


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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