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.
Bibliographical noteFunding Information:
We thank Marc Montminy for providing G6pc-luc plasmids; Winship Herr for HA-tagged FL-, N-, and C- HCF-1 plasmids and HCF-1 (H12) antibody; Thomas Kristie for HCF-1/V5 and pU6-Si-HCF-1 plasmids; Yuichi Machida for 3 ∗ Flag/His8-BAP1 plasmid; Fredric Wondisford for pFA-CREB, pFA-CRTC2 plasmids; Terry Unterman for pEGFP-FOXO1 and pEGFP-FOXO1 (3A) plasmids; Pere Puigserver for Flag/HA-PGC-1α and PGC-1α shRNA adenovirus; and Sohail Malik for A ∗ 2.luc plasmid. We thank Peter Van Ness and Mark Trentalange for assistance in statistic analysis and Colleen Feriod for critical reading of the manuscript. This work was supported by NIH R01-DK089098, P30-DK34989, P30-DK045735, P30-AG021342, American Diabetes Association Junior Faculty Award, and Ellison Medical Foundation New Scholar Award to X.Y.; NIH P01-DK057751 to A.M.B. and X.Y.; the Brown-Coxe fellowship to H.-B.R.; the China Scholarship Council-Yale World Scholars fellowship to M.-D.L.; and NIH P41-RR011823 to J.R.Y.