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

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.