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

Authors:
Hai-Bin Ruan
Hai-Bin Ruan
United States
Xuemei Han
Xuemei Han
The Scripps Research Institute
San Diego | United States
Dr. Min-Dian Li, PhD
Dr. Min-Dian Li, PhD
Harvard TH Chan School of Public Health
Postdoctoral Fellow
Cellular and Molecular Physiology
Boston, MA | United States
Jay Prakash Singh
Jay Prakash Singh
Yale University School of Medicine
New Haven | United States
Kevin Qian
Kevin Qian
Yale University School of Medicine
New Haven | United States
Sascha Azarhoush
Sascha Azarhoush
United States
Lin Zhao
Lin Zhao
College of Automation
China
Anton M Bennett
Anton M Bennett
Yale University School of Medicine
New Haven | United States

Cell Metab 2012 Aug;16(2):226-37

Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06519, USA.

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.

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http://dx.doi.org/10.1016/j.cmet.2012.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480732PMC

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August 2012
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