Foxa2 integrates the transcriptional response of the hepatocyte to fasting.
Survival during prolonged food deprivation depends on the activation of hepatic gluconeogenesis. Inappropriate regulation of this process is a hallmark of diabetes and other metabolic diseases. Activation of the genes encoding gluconeogenic enzymes is mediated by hormone-responsive transcription factors such as the cyclic AMP response element binding protein (CREB) and the glucocorticoid receptor (GR). Here we show using cell-type-specific gene ablation that the winged helix transcription factor Foxa2 is required for activation of the hepatic gluconeogenic program during fasting. Specifically, Foxa2 promotes gene activation both by cyclic AMP, the second messenger for glucagon, and glucocorticoids. Foxa2 mediates these effects by enabling recruitment of CREB and GR to their respective target sites in chromatin. We conclude that Foxa2 is required for execution of the hepatic gluconeogenic program by integrating the transcriptional response of the hepatocyte to hormonal stimulation.
Zhang
Liping
L
Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Rubins
Nir E
NE
Ahima
Rexford S
RS
Greenbaum
Linda E
LE
Kaestner
Klaus H
KH
D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005215:Fasting; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015290:Second Messenger Systems / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C496503:Foxa2 protein, mouse; D005938:Glucocorticoids; D009687:Nuclear Proteins; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta; D000242:Cyclic AMP