| First Author | Sakai M | Year | 2016 |
| Journal | Nat Commun | Volume | 7 |
| Pages | 13147 | PubMed ID | 27874008 |
| Mgi Jnum | J:243073 | Mgi Id | MGI:5907565 |
| Doi | 10.1038/ncomms13147 | Citation | Sakai M, et al. (2016) The GCN5-CITED2-PKA signalling module controls hepatic glucose metabolism through a cAMP-induced substrate switch. Nat Commun 7:13147 |
| abstractText | Hepatic gluconeogenesis during fasting results from gluconeogenic gene activation via the glucagon-cAMP-protein kinase A (PKA) pathway, a process whose dysregulation underlies fasting hyperglycemia in diabetes. Such transcriptional activation requires epigenetic changes at promoters by mechanisms that have remained unclear. Here we show that GCN5 functions both as a histone acetyltransferase (HAT) to activate fasting gluconeogenesis and as an acetyltransferase for the transcriptional co-activator PGC-1alpha to inhibit gluconeogenesis in the fed state. During fasting, PKA phosphorylates GCN5 in a manner dependent on the transcriptional coregulator CITED2, thereby increasing its acetyltransferase activity for histone and attenuating that for PGC-1alpha. This substrate switch concomitantly promotes both epigenetic changes associated with transcriptional activation and PGC-1alpha-mediated coactivation, thereby triggering gluconeogenesis. The GCN5-CITED2-PKA signalling module and associated GCN5 substrate switch thus serve as a key driver of gluconeogenesis. Disruption of this module ameliorates hyperglycemia in obese diabetic animals, offering a potential therapeutic strategy for such conditions. |
