title: The GCN5-CITED2-PKA signalling module controls hepatic glucose metabolism through a cAMP-induced substrate switch.
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.
authors.affiliation: Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
authors.forename: Mashito
authors.initials: M
authors.lastname: Sakai
authors.affiliation: Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tujimura-Hayakawa
authors.affiliation: Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.|Department of Bioregulation, Nippon Medical School, 1-396 Kosugi-machi, Nakahara-ku, Kawasaki 211-8533, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yagi
authors.affiliation: Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.|Department of Bioregulation, Nippon Medical School, 1-396 Kosugi-machi, Nakahara-ku, Kawasaki 211-8533, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yano
authors.affiliation: Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Mitsushima
authors.affiliation: Department of Diabetic Complications, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Unoki-Kubota
authors.affiliation: Department of Diabetic Complications, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kaburagi
authors.affiliation: Metabolism and Nutrition Research Unit, Innovative Integrated Bio-research Core, Institute for Frontier Science Initiative, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Division of Medical Chemistry, Department of Metabolism and Disease, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe 654-0142, Japan.|Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kido
authors.affiliation: National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
authors.affiliation: Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced; D059305:Diet, High-Fat / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose; D012097:Repressor Proteins; D015534:Trans-Activators; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C110087:Cited2 protein, mouse