Figure 10: Model for regulation of hepatic gluconeogenesis by the GCN5-CITED2-PKA signalling module through a cAMP-induced substrate switch of GCN5.

(left) In the fed state, the GCN5-CITED2-PKA signalling module is not assembled as a result of the low level of CITED2 expression maintained in the absence of glucagon signalling and the insulin-induced inhibition of GCN5-CITED2 interaction. GCN5 is not phosphorylated at Ser²⁷⁵ and therefore acetylates PGC-1α rather than histone H3, resulting in inactivation of PGC-1α and consequent suppression of gluconeogenic gene transcription. (middle) In the fasted state or diabetes, glucagon-cAMP signalling increases the expression of CITED2 and GCN5 and thereby promotes formation of the GCN5-CITED2-PKA signalling module, within which PKA activated by cAMP phosphorylates GCN5 at Ser²⁷⁵. (right) Phosphorylation of GCN5 induces a substrate switch from PGC-1α to histone H3 and a consequent increase in H3K9 acetylation and the deacetylation-mediated activation of PGC-1α at gluconeogenic gene promoters. The increase in the amount of H3K9ac promotes further epigenetic changes and the recruitment of transcriptional regulators required for initiation of gene transcription, whereas activated PGC-1α functions as a co-activator for gluconeogenic transcription factors such as FoxO1 and HNF-4α. These two effects act cooperatively to activate the gluconeogenic program. AT, acetyltransferase.