O‐glycosylation of FoxO1 increases its transcriptional activity towards the glucose 6‐phosphatase gene

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Abstract
Mono‐O‐glycosylations post‐translationally regulate the activity of nucleocytoplasmic proteins. We showed that glucosamine and an inhibitor of deglycosylation (PUGNAc) induced O‐glycosylation of FoxO1, resulting in increased expression of a glucose‐6‐phosphatase reporter gene. This effect was independent of FoxO1 re‐localisation, since it was also observed with constitutively nuclear FoxO1‐AAA mutant. Moreover, in HepG2 cells, glucosamine and PUGNAc have a synergistic effect on the glucose‐6‐phosphatase reporter gene, and this effect was inhibited by FoxO1 siRNAs. Since glucose‐6‐phosphatase plays a key role in hepatic glucose production, our observation may be of importance with regard to glucotoxicity associated with chronic hyperglycaemia in diabetes.