Transcription factors and coactivators controlling nutrient and hormonal regulation of hepatic gluconeogenesis

Abstract

Hepatic gluconeogenesis is a major pathway that maintains normal plasma glucose levels during prolonged starvation. The aim of this review is to provide insights into the integration of transcriptional regulation of gluconeogenic enzyme genes in response to nutritional and hormonal changes. The roles of transcription factors/co-regulators in response to those factors will be discussed. Overall, glucagon and glucocorticoids are positive regulators of gluconeogenesis. Glucagon, via cAMP, promotes the interaction of cAMP-responsive binding protein with CREB-regulated transcription coactivator 2 which facilitates its binding to cAMP-responsive elements (CREs). The response to glucocorticoids is mediated by the glucocorticoid receptor that binds to glucocorticoid responsive elements (GREs) in the promoters of gluconeogenic genes. These CREs and GREs may be arranged as distinct elements or combined to form a "unit" to ensure the maximal transcriptional response to these hormones. The hepatocyte nuclear factors, forkhead O box, and the peroxisome proliferator-activated receptor-γ coactivator 1α can also synergistically increase transcription of gluconeogenic genes. Surtuin 1, an energy sensor can also modify the transcriptional activity of some of these transcription factors. In contrast, insulin secreted during fed conditions acts to repress transcription of gluconeogenic enzymes. This is achieved via activation of Akt/PKB and the consequent disruption of interactions between certain transcription factors/coactivators and their positive response elements in the promoters of those genes. Hypothalamic signaling via the insulin/leptin axis also regulates hepatic gluconeogenesis. Mice lacking the above transcription factors/coactivators show impaired gluconeogenesis, indicating their essential roles in the control of this vital metabolic process.