The liver metabolisms undergo robust circadian oscillations. This dynamic metabolic regulation is performed by the circadian clock in self-renewing hepatocytes, but the molecular pathway of the clock on their cell proliferation remains elusive. Here we find that hepatocyte polyploidization is markedly accelerated in mice deficient with circadian Period genes (Per-null). The massive accumulation of polyploid cells occurs around the central vein, where permanent self-renewal of cell occurs. We found that absence of Periods impairs the 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 changes the ploidy level of hepatocytes. These data indicate that the circadian clock not only orchestrates diurnal dynamic changes of metabolism, but also regulates homeostatic self-renewal of hepatocytes through Mkp1-Erk1/2 signaling pathway.
JST CREST （http://www.jst.go.jp/kisoken/crest/en/）
Research Area “Creation of Fundamental Technologies for Understanding and Control of Biosystem Dynamics”
Research Theme “Chronometabolism: Molecular analysis of biological timing”
Chao H-W, Doi M, Fustin JM, Chen H, Murase K, Maeda Y, Hayashi H, Tanaka R, Sugawa M, Mizukuchi N, Yamaguchi Y, Yasunaga J, Matsuoka M, Sakai M, Matsumoto M, Hamada S, Okamura H. “Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway”. Nature Communications, published online Dec. 21, 2017, doi: 10.1038/s41467-017-02207-7.
Professor, Graduate School of Pharmaceutical Sciences, Kyoto University
Life Innovation Group, Department of Innovation Research , JST