title: O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1α stability.
abstract: A major cause of hyperglycemia in diabetic patients is inappropriate hepatic gluconeogenesis. PGC-1α is a master regulator of gluconeogenesis, and its activity is controlled by various posttranslational modifications. A small portion of glucose metabolizes through the hexosamine biosynthetic pathway, which leads to O-linked β-N-acetylglucosamine (O-GlcNAc) modification of cytoplasmic and nuclear proteins. Using a proteomic approach, we identified a broad variety of proteins associated with O-GlcNAc transferase (OGT), among which host cell factor C1 (HCF-1) is highly abundant. HCF-1 recruits OGT to O-GlcNAcylate PGC-1α, and O-GlcNAcylation facilitates the binding of the deubiquitinase BAP1, thus protecting PGC-1α from degradation and promoting gluconeogenesis. Glucose availability modulates gluconeogenesis through the regulation of PGC-1α O-GlcNAcylation and stability by the OGT/HCF-1 complex. Hepatic knockdown of OGT and HCF-1 improves glucose homeostasis in diabetic mice. These findings define the OGT/HCF-1 complex as a glucose sensor and key regulator of gluconeogenesis, shedding light on new strategies for treating diabetes.
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06519, USA.
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Ruan
authors.forename: Xuemei
authors.initials: X
authors.lastname: Han
authors.forename: Min-Dian
authors.initials: MD
authors.lastname: Li
authors.forename: Jay Prakash
authors.initials: JP
authors.lastname: Singh
authors.forename: Kevin
authors.initials: K
authors.lastname: Qian
authors.forename: Sascha
authors.initials: S
authors.lastname: Azarhoush
authors.forename: Lin
authors.initials: L
authors.lastname: Zhao
authors.forename: Anton M
authors.initials: AM
authors.lastname: Bennett
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Yang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D002851:Chromatography, High Pressure Liquid; D005943:Gluconeogenesis / Q000502:physiology*; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000378:metabolism*; D056945:Hep G2 Cells; D051863:Host Cell Factor C1 / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology*; D047468:Immunoprecipitation; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism* / Q000502:physiology; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D040901:Proteomics; D060888:Real-Time Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C497692:HCFC1 protein, human; D006360:Heat-Shock Proteins; D051863:Host Cell Factor C1; D046912:Multiprotein Complexes; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase