The GCN5-CITED2-PKA signalling module controls hepatic glucose metabolism through a cAMP-induced substrate switch

Mashito Sakai, Tomoko Tujimura-Hayakawa, Takashi Yagi, Hiroyuki Yano, Masaru Mitsushima, Hiroyuki Unoki-Kubota, Yasushi Kaburagi, Hiroshi Inoue, Yoshiaki Kido, Masato Kasuga and Michihiro Matsumoto ()
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Mashito Sakai: Diabetes Research Center, Research Institute, National Center for Global Health and Medicine
Tomoko Tujimura-Hayakawa: Diabetes Research Center, Research Institute, National Center for Global Health and Medicine
Takashi Yagi: Diabetes Research Center, Research Institute, National Center for Global Health and Medicine
Hiroyuki Yano: Diabetes Research Center, Research Institute, National Center for Global Health and Medicine
Masaru Mitsushima: Diabetes Research Center, Research Institute, National Center for Global Health and Medicine
Hiroyuki Unoki-Kubota: Diabetes Research Center, Research Institute, National Center for Global Health and Medicine
Yasushi Kaburagi: Diabetes Research Center, Research Institute, National Center for Global Health and Medicine
Hiroshi Inoue: Metabolism and Nutrition Research Unit, Innovative Integrated Bio-research Core, Institute for Frontier Science Initiative, Kanazawa University
Yoshiaki Kido: Kobe University Graduate School of Health Sciences
Masato Kasuga: National Center for Global Health and Medicine
Michihiro Matsumoto: Diabetes Research Center, Research Institute, National Center for Global Health and Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: Abstract 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-1α 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-1α. This substrate switch concomitantly promotes both epigenetic changes associated with transcriptional activation and PGC-1α–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.

Date: 2016
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DOI: 10.1038/ncomms13147

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