Estrogen-related receptor α is a repressor of phosphoenolpyruvate carboxykinase gene transcription

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