HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: db07-0359v1 56/12/2901    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, N.-C. Articles by Chang, C. Search for Related Content PubMed PubMed Citation Articles by Liu, N.-C. Articles by Chang, C. Social Bookmarking                What's this?

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.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				N. Grarup, G. Andersen, N. T. Krarup, A. Albrechtsen, O. Schmitz, T. Jorgensen, K. Borch-Johnsen, T. Hansen, and O. Pedersen Association Testing of Novel Type 2 Diabetes Risk Alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 Loci With Insulin Release, Insulin Sensitivity, and Obesity in a Population-Based Sample of 4,516 Glucose-Tolerant Middle-Aged Danes Diabetes, September 1, 2008; 57(9): 2534 - 2540. [Abstract] [Full Text] [PDF]