Regulatory Actions of Glucocorticoid Hormones: From Organisms to Mechanisms.

The history of glucocorticoid hormone research is an excellent example of "bedside to bench" investigation. It started with two very insightful clinical observations. Thomas Addison described the syndrome of what came to be known as adrenal hormone insufficiency and Harvey Cushing the syndrome of glucocorticoid hormone excess.

Insulin represses phosphoenolpyruvate carboxykinase gene transcription by causing the rapid disruption of an active transcription complex: a potential epigenetic effect.

Insulin represses gluconeogenesis, in part, by inhibiting the transcription of genes that encode rate-determining enzymes, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase). Glucocorticoids stimulate expression of the PEPCK gene but the repressive action of insulin is dominant. Here, we show that treatment of H4IIE hepatoma cells with the synthetic glucocorticoid, dexamethasone (dex), induces the accumulation of glucocorticoid receptor, as well as many transcription factors, coregulators, and RNA polymerase II, on the PEPCK gene promoter.

Estrogen-related receptor alpha 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-1alpha in the regulation of genes important for mitochondrial oxidative capacity. PGC-1alpha 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 ERRalpha binding site.