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O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1α stability.
Hai-Bin Ruan1, Xuemei Han, Min-Dian Li
1Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06519, USA.
Cell Metabolism
|August 14, 2012
Summary
The O-GlcNAc transferase (OGT)/host cell factor C1 (HCF-1) complex regulates hepatic gluconeogenesis by modifying PGC-1α. Inhibiting OGT and HCF-1 improves glucose homeostasis in diabetic mice, offering new diabetes treatment strategies.
Area of Science:
- Biochemistry
- Molecular Biology
- Metabolic Diseases
Background:
- Inappropriate hepatic gluconeogenesis is a primary driver of hyperglycemia in diabetes.
- PGC-1α, a key regulator of gluconeogenesis, is controlled by posttranslational modifications.
- The hexosamine biosynthetic pathway generates O-linked β-N-acetylglucosamine (O-GlcNAc) modifications.
Purpose of the Study:
- To investigate the role of O-GlcNAc transferase (OGT) and its associated proteins in regulating hepatic gluconeogenesis.
- To elucidate the mechanism by which glucose metabolism influences gluconeogenesis.
- To identify potential therapeutic targets for diabetes treatment.
Main Methods:
- Proteomic analysis to identify O-GlcNAc transferase (OGT)-associated proteins.
- Investigating the interaction between OGT, host cell factor C1 (HCF-1), and PGC-1α.
- Assessing the impact of OGT and HCF-1 knockdown on glucose homeostasis in diabetic mouse models.
Main Results:
- Host cell factor C1 (HCF-1) was identified as a highly abundant OGT-associated protein.
- HCF-1 recruits OGT to O-GlcNAcylate PGC-1α, enhancing its stability and promoting gluconeogenesis.
- Hepatic knockdown of OGT and HCF-1 significantly improved glucose homeostasis in diabetic mice.
Conclusions:
- The OGT/HCF-1 complex acts as a glucose sensor, regulating PGC-1α stability and hepatic gluconeogenesis.
- Targeting the OGT/HCF-1 complex offers a promising therapeutic strategy for managing diabetes.
- This study reveals a novel regulatory pathway controlling glucose metabolism.
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