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  • The EMBO Journal (2007) 26, 3607 - 3615
  • doi:10.1038/sj.emboj.7601784

Published online: 12 July 2007

Foxo1 links insulin signaling to C/EBPalpha and regulates gluconeogenesis during liver development

Keisuke Sekine1,2,a, Yen-Rong Chen1, Nobuhiko Kojima1,b, Kazuhiro Ogata3, Akiyoshi Fukamizu2,4 and Atsushi Miyajima1,2

  1. Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan
  2. CREST, Japan Science and Technology Agency, Kawaguchi, Japan
  3. Department of Biochemistry, Yokohama City University School of Medicine, Kanagawa, Japan
  4. Center for Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan

Correspondence to:

Atsushi Miyajima, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Tel.: +81 3 5841 7884; Fax: +81 3 5841 8475; E-mail: miyajima@iam.u-tokyo.ac.jp

aPresent address: Department of Oral Biology and Tissue Engineering, Meikai University School of Dentistry, Saitama, Japan

bPresent address: Medical and Research Services, Greater Los Angeles Veterans Affairs, Healthcare System at Sepulveda, California, USA

Received 29 January 2007; Accepted 11 June 2007

C/EBPalpha is a key transcription factor indispensable for the onset of gluconeogenesis in perinatal liver. However, C/EBPalpha was already expressed in fetal liver, suggesting that the expression of C/EBPalpha alone does not account for the dramatic increase of the expression of metabolic genes, and hence an additional factor(s) is expected to function cooperatively with C/EBPalpha in perinatal liver. We show here that expression of Foxo1 was sharply increased in the perinatal liver and augmented C/EBPalpha-dependent transcription. Foxo1 bound C/EBPalpha via its forkhead domain, and Foxo1 bound to the promoter of a gluconeogenic gene, phosphoenolpyruvate carboxykinase (PEPCK), in a C/EBPalpha-dependent manner in vivo. Insulin inhibited the expression of PEPCK in a culture of fetal liver cells, and also the C/EBPalpha-dependent transcription enhanced by Foxo1. These results indicate that Foxo1 regulates gluconeogenesis cooperatively with C/EBPalpha, and also links insulin signaling to C/EBPalpha during liver development.

  • Keywords:

    • C/EBPalpha,
    • Foxo1,
    • gluconeogenesis,
    • hepatocyte maturation
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