Correlation between FOXO1a (FKHR) and FOXO3a (FKHRL1) binding and the inhibition of basal glucose-6-phosphatase catalytic subunit gene transcription by insulin.

Insulin inhibits transcription of the genes encoding the glucose-6-phosphatase catalytic subunit (G6Pase), phosphoenolpyruvate carboxykinase, and IGF binding protein-1 through insulin response sequences (IRSs) that share the same core sequence, T(G/A)TTTT(G/T). The transcription factors FOXO1a and FOXO3a have been shown to bind these elements, but there are conflicting reports as to whether this binding correlates with the action of insulin on gene transcription. Some researchers concluded, from overexpression experiments using FOXO1a, that binding correlated with the insulin response, whereas others concluded, mainly from gel retardation competition experiments using FOXO3a, that it did not.

The glucose-6-phosphatase catalytic subunit gene promoter contains both positive and negative glucocorticoid response elements.

Glucose-6-phosphatase catalyzes the final step in the gluconeogenic and glycogenolytic pathways. Glucocorticoids stimulate glucose-6-phosphatase catalytic subunit (G6Pase) gene transcription and studies performed in H4IIE hepatoma cells demonstrate the presence of a glucocorticoid response unit (GRU) in the proximal G6Pase promoter. In vitro deoxyribonuclease I footprinting analyses show that the glucocorticoid receptor binds to three glucocorticoid response elements (GREs) in the -231 to -129 promoter region and transfection results indicate all three contribute to glucocorticoid induction of G6Pase gene transcription.

The three insulin response sequences in the glucose-6-phosphatase catalytic subunit gene promoter are functionally distinct.

Glucose-6-phosphatase catalyzes the terminal step in the gluconeogenic and glycogenolytic pathways. In HepG2 cells, the maximum repression of basal glucose-6-phosphatase catalytic subunit (G6Pase) gene transcription by insulin requires two distinct promoter regions, designated A (located between -231 and -199) and B (located between -198 and -159), that together form an insulin response unit. Region A binds hepatocyte nuclear factor-1, which acts as an accessory factor to enhance the effect of insulin, mediated through region B, on G6Pase gene transcription.