Estrogen-related receptor α 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, Anastasia Kralli

Research output: Contribution to journalArticle

Abstract

The orphan nuclear receptor estrogen-related receptor (ERR) α is a downstream effector of the transcriptional coactivator PGC-1α in the regulation of genes important for mitochondrial oxidative capacity. PGC-1α 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 ERRα binding site. However, in contrast to the co-stimulating effects of ERRα and PGC-1α on mitochondrial gene expression, ERRα acts as a transcriptional repressor of the PEPCK gene. Suppression of ERRα expression by small interfering RNA leads to reduced binding of ERRα to the endogenous PEPCK gene, and an increase in promoter occupancy by PGC-1α, suggesting that part of the ERRα function at this gene is to antagonize the action of PGC-1α. In agreement with the in vitro studies, animals that lack ERRα show increased expression of gluconeogenic genes, including PEPCK and glycerol kinase, but decreased expression of mitochondrial genes, such as ATP synthase subunit β and cytochrome c-1. Our findings suggest that ERRα has opposing effects on genes important for mitochondrial oxidative capacity and gluconeogenesis. The different functions of ERRα in the regulation of these pathways suggest that enhancing ERRα 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.

Original languageEnglish (US)
Pages (from-to)99-106
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number1
DOIs
StatePublished - Jan 6 2006
Externally publishedYes

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Phosphoenolpyruvate
Transcription
Estrogen Receptors
Estrogens
Genes
Mitochondrial Genes
Gluconeogenesis
Liver
Glycerol Kinase
Orphan Nuclear Receptors
Cytochromes c1
Gene Expression
Glucose
Ports and harbors
Small Interfering RNA
Metabolism
Gene expression
Adenosine Triphosphate
Binding Sites
Animals

ASJC Scopus subject areas

  • Biochemistry

Cite this

Estrogen-related receptor α is a repressor of phosphoenolpyruvate carboxykinase gene transcription. / Herzog, Birger; Cardenas, Jessica; Hall, Robert K.; Villena, Josep A.; Budge, Philip J.; Giguère, Vincent; Granner, Daryl K.; Kralli, Anastasia.

In: Journal of Biological Chemistry, Vol. 281, No. 1, 06.01.2006, p. 99-106.

Research output: Contribution to journalArticle

Herzog, B, Cardenas, J, Hall, RK, Villena, JA, Budge, PJ, Giguère, V, Granner, DK & Kralli, A 2006, 'Estrogen-related receptor α is a repressor of phosphoenolpyruvate carboxykinase gene transcription', Journal of Biological Chemistry, vol. 281, no. 1, pp. 99-106. https://doi.org/10.1074/jbc.M509276200
Herzog, Birger ; Cardenas, Jessica ; Hall, Robert K. ; Villena, Josep A. ; Budge, Philip J. ; Giguère, Vincent ; Granner, Daryl K. ; Kralli, Anastasia. / Estrogen-related receptor α is a repressor of phosphoenolpyruvate carboxykinase gene transcription. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 1. pp. 99-106.
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