title: Activation of TR4 orphan nuclear receptor gene promoter by cAMP/PKA and C/EBP signaling.
abstract: 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.
authors.affiliation: George Whipple Laboratory for Cancer Research, Department of Pathology and Urology, University of Rochester Medical Center, Rochester, NY, 14642, USA.
authors.forename: Ning-Chun
authors.initials: NC
authors.lastname: Liu
authors.forename: Wen-Jye
authors.initials: WJ
authors.lastname: Lin
authors.forename: I-Chen
authors.initials: IC
authors.lastname: Yu
authors.forename: Hung-Yun
authors.initials: HY
authors.lastname: Lin
authors.forename: Su
authors.initials: S
authors.lastname: Liu
authors.forename: Yi-Fen
authors.initials: YF
authors.lastname: Lee
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: 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
chemical_list: 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