title: CITED2 links hormonal signaling to PGC-1α acetylation in the regulation of gluconeogenesis.
abstract: During fasting, induction of hepatic gluconeogenesis is crucial to ensure proper energy homeostasis. Such induction is dysregulated in type 2 diabetes, resulting in the development of fasting hyperglycemia. Hormonal and nutrient regulation of metabolic adaptation during fasting is mediated predominantly by the transcriptional coactivator peroxisome proliferative activated receptor γ coactivator 1α (PGC-1α) in concert with various other transcriptional regulators. Although CITED2 (CBP- and p300-interacting transactivator with glutamic acid- and aspartic acid-rich COOH-terminal domain 2) interacts with many of these molecules, the role of this protein in the regulation of hepatic gluconeogenesis was previously unknown. Here we show that CITED2 is required for the regulation of hepatic gluconeogenesis through PGC-1α. The abundance of CITED2 was increased in the livers of mice by fasting and in cultured hepatocytes by glucagon-cAMP-protein kinase A (PKA) signaling, and the amount of CITED2 in liver was higher in mice with type 2 diabetes than in non-diabetic mice. CITED2 inhibited the acetylation of PGC-1α by blocking its interaction with the acetyltransferase general control of amino acid synthesis 5-like 2 (GCN5). The consequent downregulation of PGC-1α acetylation resulted in an increase in its transcriptional coactivation activity and an increased expression of gluconeogenic genes. The interaction of CITED2 with GCN5 was disrupted by insulin in a manner that was dependent on phosphoinositide 3-kinase (PI3K)-thymoma viral proto-oncogene (Akt) signaling. Our results show that CITED2 functions as a transducer of glucagon and insulin signaling in the regulation of PGC-1α activity that is associated with the transcriptional control of gluconeogenesis and that this function is mediated through the modulation of GCN5-dependent PGC-1α acetylation. We also found that loss of hepatic CITED2 function suppresses gluconeogenesis in diabetic mice, suggesting it as a therapeutic target for hyperglycemia.
authors.affiliation: Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Mashito
authors.initials: M
authors.lastname: Sakai
authors.forename: Michihiro
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tujimura
authors.forename: Cao
authors.initials: C
authors.lastname: Yongheng
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Noguchi
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Inagaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hosooka
authors.forename: Kazuo
authors.initials: K
authors.lastname: Takazawa
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kido
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yasuda
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hiramatsu
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuki
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000123:Acetyltransferases / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005943:Gluconeogenesis / Q000235:genetics / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D054411:Receptors, Leptin / Q000172:deficiency; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D000123:Acetyltransferases; D002867:Chromones; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004791:Enzyme Inhibitors; D005947:Glucose; D009025:Morpholines; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054411:Receptors, Leptin; D012097:Repressor Proteins; D037761:Sirtuins; D015534:Trans-Activators; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C110087:Cited2 protein, mouse; C485290:Ppargc1a protein, mouse; C542554:SIRT5 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one