O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1? stability.

ABSTRACT: A major cause of hyperglycemia in diabetic patients is inappropriate hepatic gluconeogenesis. PGC-1? 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 ?-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-1?, and O-GlcNAcylation facilitates the binding of the deubiquitinase BAP1, thus protecting PGC-1? from degradation and promoting gluconeogenesis. Glucose availability modulates gluconeogenesis through the regulation of PGC-1? 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.

SUBMITTER: Ruan HB 

PROVIDER: S-EPMC3480732 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature