COUP-TFII revisited: Its role in metabolic gene regulation

Abstract

Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) is an orphan member of the nuclear receptor family of transcriptional regulators. Although hormonal activation of COUP-TFII has not yet been identified, rodent genetic models have uncovered vital and diverse roles for COUP-TFII in biological processes. These include control of cardiac function and angiogenesis, reproduction, neuronal development, cell fate and organogenesis. Recently, an emerging body of evidence has demonstrated COUP-TFII involvement in various metabolic systems such as adipogenesis, lipid metabolism, hepatic gluconeogenesis, insulin secretion, and regulation of blood pressure. The potential relevance of these observations to human pathology has been corroborated by the identification of single nucleotide polymorphism in the human COUP-TFII promoter controlling insulin sensitivity. Of particular interest to metabolism is the ability of COUP-TFII to interact with the Glucocorticoid Receptor (GR). This interaction is known to control gluconeogenesis, principally through direct binding of COUP-TFII/GR complexes to the promoters of gluconeogenic enzyme genes. However, it is likely that this interaction is critical to other metabolic processes, since GR, like COUP-TFII, is an essential regulator of adipogenesis, insulin sensitivity, and blood pressure. This review will highlight these unique roles of COUP-TFII in metabolic gene regulation.

Keywords: COUP-TFII; GR; Glucose homeostasis; PEPCK; PPARα.

Figure 1:. The COUP-TFII roles in metabolism.

The COUP-TFII transcription factor controls metabolism at several organs. In the liver, it regulates glucose, lipid and cholesterol metabolism, in part, by upregulating the expression of gluconeogenic enzymes (e.g., Pepck), fatty acid oxidation genes (e.g., Hmg-CoA), and the rate-limiting enzyme in conversion of cholesterol to bile acids (Cyp7a1). In the pancreas, COUP-TFII modulates insulin secretion in response to glucose, although the genes involved are currently unknown. In heart muscle, COUP-TFII is involved in cardiac remodeling, possibly by upregulating the expression of Pgc-1α and Ucp1. Interestingly, in adipose tissue COUP-TFII suppresses Pgc-1α and Ucp1 expression to blunt energy expenditure. In the brain, COUP-TFII expression in the ventromedial nucleus (VMN) of the hypothalamus (not shown) has been shown to regulate systemic glucose homeostasis.

Figure 2:. The glucose/insulin pathway regulates COUP-TFII expression in pancreatic β-cells.

Under low glucose conditions, COUP-TFII expression is promoted by the FOXO1 transcription factor. Elevated COUP-TFII levels will then modulate insulin secretion by a still undefined mechanism (not shown). In response to high glucose, insulin is secreted from β-cells. By autocrine signaling, insulin targets its own receptor on β-cells to activate the phosphoinositide 3-kinase (PI3K) pathway, leading to activation of AKT and phosphorylation of FOXO1, driving down COUP-TFII expression.

Figure 3:. The GR/COUP-TFII interaction drives expression of phosphoenolpyruvate carboxykinase (PEPCK).

Hepatic PEPCK expression is controlled by a set of promoter elements collectively known as the Glucocorticoid Response Unit (GRU) at which a variety of transcription factors can bind, including GR and COUP-TFII. Within the GRU, GR binds at two glucocorticoid response elements (GRE1 and GRE2), while COUP-TFII binds at accessory factor-binding elements (AF sites). Although each receptor can independently bind the GRU, a full response to glucocorticoid hormones (GCs) requires expression of COUP-TFII and GR capable of directly binding COUP-TFII. Thus, GR/ COUP-TFII interaction at the GRU is required for robust induction of hepatic gluconeogenesis in response to glucocorticoid hormones.