Foxo1 links insulin signaling to C/EBPalpha and regulates gluconeogenesis during liver development.
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.
Sekine
Keisuke
K
Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
Chen
Yen-Rong
YR
Kojima
Nobuhiko
N
Ogata
Kazuhiro
K
Fukamizu
Akiyoshi
A
Miyajima
Atsushi
A
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism / Q000502:physiology*; D005943:Gluconeogenesis / Q000502:physiology*; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction
D022763:CCAAT-Enhancer-Binding Protein-alpha; D017931:DNA Primers; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D012333:RNA, Messenger