Activation of TR4 orphan nuclear receptor gene promoter by cAMP/PKA and C/EBP signaling.
In earlier studies, we had suggested that the fasting signal induces TR4 orphan nuclear receptor expression in vivo. The detailed mechanism(s), however, remain unclear. In this study, we found that cAMP/PKA, the mediator of fasting and glucagon signals, could induce TR4 gene expression that in turn modulates gluconeogenesis. Mechanistic dissection by in vitro studies in hepatocytes demonstrated that cAMP/PKA might trigger C/EBP alpha and beta binding to the selective cAMP response element, which is located at the TR4 promoter, thus inducing TR4 transcription. We also demonstrated that the binding activity of C/EBPs to the TR4 promoter is increased in response to cAMP treatment. Together, our data identified a new signaling pathway from the fasting signal --> cAMP/PKA --> C/EBP alpha and beta --> TR4 --> gluconeogenesis in hepatocytes; and suggested that TR4 could be an important regulator to control glucose homeostasis. The identification of activator(s)/inhibitor(s) or ligand(s) of TR4 may provide us an alternative way to control gluconeogenesis.
Liu
Ning-Chun
NC
George Whipple Laboratory for Cancer Research, Department of Pathology and Urology, University of Rochester Medical Center, Rochester, NY, 14642, USA.
Lin
Wen-Jye
WJ
Yu
I-Chen
IC
Lin
Hung-Yun
HY
Liu
Su
S
Lee
Yi-Fen
YF
Chang
Chawnshang
C
D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology* / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D005786:Gene Expression Regulation; D005943:Gluconeogenesis / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011485:Protein Binding / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects
D022762:CCAAT-Enhancer-Binding Proteins; C490515:NR2C2 protein, human; D012333:RNA, Messenger; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D000242:Cyclic AMP; C069767:phosphoenolpyruvate carboxylase kinase; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases