title: Activation of basal gluconeogenesis by coactivator p300 maintains hepatic glycogen storage.
abstract: Because hepatic glycogenolysis maintains euglycemia during early fasting, proper hepatic glycogen synthesis in the fed/postprandial states is critical. It has been known for decades that gluconeogenesis is essential for hepatic glycogen synthesis; however, the molecular mechanism remains unknown. In this report, we show that depletion of hepatic p300 reduces glycogen synthesis, decreases hepatic glycogen storage, and leads to relative hypoglycemia. We previously reported that insulin suppressed gluconeogenesis by phosphorylating cAMP response element binding protein-binding protein (CBP) at S436 and disassembling the cAMP response element-binding protein-CBP complex. However, p300, which is closely related to CBP, lacks the corresponding S436 phosphorylation site found on CBP. In a phosphorylation-competent p300G422S knock-in mouse model, we found that mutant mice exhibited reduced hepatic glycogen content and produced significantly less glycogen in a tracer incorporation assay in the postprandial state. Our study demonstrates the important and unique role of p300 in glycogen synthesis through maintaining basal gluconeogenesis.
authors.affiliation: Division of Metabolism, Departments of Pediatrics, Physiology and Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. heling@jhmi.edu.
authors.forename: Ling
authors.initials: L
authors.lastname: He
authors.forename: Jia
authors.initials: J
authors.lastname: Cao
authors.forename: Shumei
authors.initials: S
authors.lastname: Meng
authors.forename: Anlin
authors.initials: A
authors.lastname: Ma
authors.forename: Sally
authors.initials: S
authors.lastname: Radovick
authors.forename: Fredric E
authors.initials: FE
authors.lastname: Wondisford
mesh_terms: D000818:Animals; D001786:Blood Glucose; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005943:Gluconeogenesis / Q000235:genetics / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D007003:Hypoglycemia / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008112:Liver Glycogen / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D019518:Postprandial Period / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering; D050880:p300-CBP Transcription Factors / Q000172:deficiency / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D017362:Cyclic AMP Response Element-Binding Protein; D008112:Liver Glycogen; D034741:RNA, Small Interfering; D050880:p300-CBP Transcription Factors; D005947:Glucose