Loss of TR4 orphan nuclear receptor reduces phosphoenolpyruvate carboxykinase-mediated gluconeogenesis.
OBJECTIVE
Regulation of phosphoenolpyruvate carboxykinase (PEPCK), the key gene in gluconeogenesis, is critical for glucose homeostasis in response to quick nutritional depletion and/or hormonal alteration.
Here, we identified the testicular orphan nuclear receptor 4 (TR4) as a key PEPCK regulator modulating PEPCK gene via a transcriptional mechanism. TR4 transactivates the 490-bp PEPCK promoter-containing luciferase reporter gene activity by direct binding to the TR4 responsive element (TR4RE) located at -451 to -439 in the promoter region. Binding to TR4RE was confirmed by electrophoretic mobility shift and chromatin immunoprecipitation assays. Eliminating TR4 via knockout and RNA interference (RNAi) in hepatocytes significantly reduced the PEPCK gene expression and glucose production in response to glucose depletion. In contrast, ectopic expression of TR4 increased PEPCK gene expression and hepatic glucose production in human and mouse hepatoma cells. Mice lacking TR4 also display reduction of PEPCK expression with impaired gluconeogenesis.


CONCLUSIONS
Together, both in vitro and in vivo data demonstrate the identification of a new pathway, TR4 --> PEPCK --> gluconeogenesis --> blood glucose, which may allow us to modulate metabolic programs via the control of a new key player, TR4, a member of the nuclear receptor superfamily.
Liu
Ning-Chun
NC
Department of Pathology, Cancer Center, University of Rochester, Rochester, NY 14642, USA.
Lin
Wen-Jye
WJ
Kim
Eungseok
E
Collins
Loretta L
LL
Lin
Hung-Yun
HY
Yu
I-Chen
IC
Sparks
Janet D
JD
Chen
Lu-Min
LM
Lee
Yi-Fen
YF
Chang
Chawnshang
C
D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D005943:Gluconeogenesis / Q000502:physiology*; D022781:Hepatocytes / Q000502:physiology; D008297:Male; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism*; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D051381:Rats; D011987:Receptors, Steroid / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D014158:Transcription, Genetic; D014162:Transfection