Title :
O-GlcNAc regulates FoxO activation in response to
glucose.
Abstract :
- FoxO proteins are key transcriptional regulators of nutrient homeostasis and stress response
- The transcription factor FoxO1 activates expression of gluconeogenic, including phosphoenolpyruvate carboxykinase and glucose-6-phosphatase , and also activates the expression of the oxidative stress response enzymes catalase and manganese superoxide dismutase
- Hormonal and stress-dependent regulation of FoxO1 via acetylation, ubiquitination, and phosphorylation, are well established, but FoxOs have not been studied in the context of the glucose-derived O-linked beta-N-acetylglucosamine (O-GlcNAc) modification
- Here we show that O-GlcNAc on hepatic FoxO1 is increased in diabetes
- Furthermore, O-GlcNAc regulates FoxO1 activation in response to glucose, resulting in the paradoxically increased expression of gluconeogenic genes while concomitantly inducing expression of genes encoding enzymes that detoxify reactive oxygen species
- GlcNAcylation of FoxO provides a new mechanism for direct nutrient control of transcription to regulate metabolism and stress response through control of FoxO1 activity