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Loss of TR4 Orphan Nuclear Receptor Reduces Phosphoenolpyruvate Carboxykinase–Mediated Gluconeogenesis

¹ George Whipple Laboratory for Cancer Research, Department of Pathology, Urology, and Radiation Oncology and the Cancer Center, University of Rochester, Rochester, New York
² Department of Biological Sciences, Chonnam National University, Gwangju, Korea
³ Department of Obstetrics and Gynecology, China Medical University/Hospital, Taichung, Taiwan, Republic of China

Address correspondence and reprint requests to Chawnshang Chang, PhD, Department of Pathology, University of Rochester, Rochester, NY 14642. E-mail: chang{at}urmc.rochester.edu; and Yi-Fen Lee, PhD, Department of Urology, University of Rochester, Rochester, NY 14642. E-mail: yifen_lee{at}urmc.rochester.edu

Abbreviations: AUC, area under the curve; ChIP, chromatin immunoprecipitation; DMEM, Dulbecco’s modified Eagle’s medium; DR, direct repeat; EMSA, electrophoretic mobility shift assay; HGP, hepatic glucose production; HOMA, homeostasis model assessment; HRE, hormone response element; PEPCK, phosphoenolpyruvate carboxykinase; PKA, cAMP-dependent protein kinase; QUICKI, quantitative insulin-sensitivity check index; TR4, testicular orphan nuclear receptor 4; TR4RE, TR4 responsive element

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.

RESEARCH DESIGN/METHODS AND RESULTS— 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.

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