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, Hitoshi Okamura

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Article number2238
JournalNature Communications
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Chao, H. W., Doi, M., Fustin, J. M., Chen, H., Murase, K., Maeda, Y., Hayashi, H., Tanaka, R., Sugawa, M., Mizukuchi, N., Yamaguchi, Y., Yasunaga, J. I., Matsuoka, M., Sakai, M., Matsumoto, M., Hamada, S., & Okamura, H. (2017). Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway. Nature Communications, 8(1), [2238]. https://doi.org/10.1038/s41467-017-02207-7