Inhibition of the FOXO1 transcription factor has beneficial effects on diabetic hyperglycaemia through the suppression of glucose-6-phosphatase (G6PC) activation, but it also suppresses glucokinase (GCK) inhibition, which promotes lipogenesis. Here, Langlet et al. identify SIN3A as the corepressor required for FOXO1-mediated inhibition of GCK. SIN3A ablation in mice impaired nutrient regulation of GCK without affecting other FOXO1 target genes. In primary hepatocytes from these mice, insulin-mediated FOXO1 inhibition lowered glucose production but did not induce lipogenesis. A FOXO1 inhibitor was identified which did not clear SIN3A from the GCK promoter, inhibiting glucose production without activating lipogenesis.
References
Langlet, F. et al. Selective inhibition of FOXO1 activator/repressor balance modulates hepatic glucose handling. Cell 171, 824–835 (2017)10.1016/j.cell.2017.09.045
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Crunkhorn, S. Selective FOXO1 modulation. Nat Rev Drug Discov 16, 828 (2017). https://doi.org/10.1038/nrd.2017.235
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DOI: https://doi.org/10.1038/nrd.2017.235