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J. Biol. Chem., Vol. 281, Issue 1, 99-106, January 6, 2006

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Estrogen-related Receptor Is a Repressor of Phosphoenolpyruvate Carboxykinase Gene Transcription^*

Birger Herzog, Jessica Cardenas¶, Robert K. Hall, Josep A. Villena¶, Philip J. Budge, Vincent Giguère||, Daryl K. Granner, and Anastasia Kralli¶1

From the Institute of Reproductive and Developmental Biology, Imperial College London, London W12 0NN, United Kingdom, the ^¶Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, the Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine and Veterans Affairs Medical Center, Nashville, Tennessee 37232, and the ^||Molecular Oncology Group, McGill University Health Centre, Montréal, Québec H3A 1A1, Canada

The orphan nuclear receptor estrogen-related receptor (ERR) is a downstream effector of the transcriptional coactivator PGC-1 in the regulation of genes important for mitochondrial oxidative capacity. PGC-1 is also a potent activator of the transcriptional program required for hepatic gluconeogenesis, and in particular of the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK). We report here that the regulatory sequences of the PEPCK gene harbor a functional ERR binding site. However, in contrast to the co-stimulating effects of ERR and PGC-1 on mitochondrial gene expression, ERR acts as a transcriptional repressor of the PEPCK gene. Suppression of ERR expression by small interfering RNA leads to reduced binding of ERR to the endogenous PEPCK gene, and an increase in promoter occupancy by PGC-1, suggesting that part of the ERR function at this gene is to antagonize the action of PGC-1. In agreement with the in vitro studies, animals that lack ERR show increased expression of gluconeogenic genes, including PEPCK and glycerol kinase, but decreased expression of mitochondrial genes, such as ATP synthase subunit and cytochrome c-1. Our findings suggest that ERR has opposing effects on genes important for mitochondrial oxidative capacity and gluconeogenesis. The different functions of ERR in the regulation of these pathways suggest that enhancing ERR activity could have beneficial effects on glucose metabolism in diabetic subjects by two distinct mechanisms: increasing mitochondrial oxidative capacity in peripheral tissues and liver, and suppressing hepatic glucose production.

Received for publication, August 23, 2005 , and in revised form, October 31, 2005.

^* This work was supported by a Mentor-based Research Fellowship award from the American Diabetes Association, the Veterans Affairs Research Service, Grants DK064951 (to A. K.), DK35107 and DK02887 (to D. K. G.) from the National Institutes of Health, a grant from the Canadian Institutes for Health Research (to V. G.), and Vanderbilt Diabetes Research and Training Center Grant DK20593. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 10550 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-7287; Fax: 858-784-9132; E-mail: kralli{at}scripps.edu.

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