Estrogen‐Related Receptor α (ERRα) represses PGC‐1α‐activated PEPCK gene transcription

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The orphan nuclear receptor ERRα acts as a downstream effector of the transcriptional coactivator PGC-1α in the induction of genes important for mitochondrial oxidative metabolism. PGC-1α is also known as a potent activator of the transcriptional program required for hepatic gluconeogenesis, and in particular of the key gluconeogenic enzyme PEPCK. We report here that ERRα binding to the PEPCK gene promoter leads to the repression of PEPCK expression. Gain- and loss-of function studies suggest that ERRα at the PEPCK promoter antagonizes the recruitment and stimulatory action of PGC-1α. Consistent with these findings, animals that lack ERRα show increased expression of gluconeogenic genes, including PEPCK and glycerol kinase, but decreased expression of mitochondrial genes. We conclude that ERRα has opposing effects on genes important for mitochondrial oxidative capacity and for gluconeogenesis. Decreased mitochondrial oxidative function and increased gluconeogenesis are associated with diabetes. The different functions of ERRα in the regulation of these pathways suggest that increased ERRα activity may exert beneficial effects in diabetic subjects by two distinct mechanisms: enhancing mitochondrial oxidative capacity in peripheral tissues and liver, and suppressing hepatic glucose production.