期刊
CELL METABOLISM
卷 16, 期 2, 页码 226-237出版社
CELL PRESS
DOI: 10.1016/j.cmet.2012.07.006
关键词
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资金
- NIH [R01-DK089098, P30-DK34989, P30-DK045735, P30-AG021342, P01-DK057751, P41-RR011823]
- American Diabetes Association Junior Faculty Award
- Ellison Medical Foundation New Scholar Award
- Brown-Coxe fellowship
- China Scholarship Council-Yale World Scholars fellowship
A major cause of hyperglycemia in diabetic patients is inappropriate hepatic gluconeogenesis. PGC-1 alpha 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 beta-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 alpha, and O-GlcNAcylation facilitates the binding of the deubiquitinase BAP1, thus protecting PGC-1 alpha from degradation and promoting gluconeogenesis. Glucose availability modulates gluconeogenesis through the regulation of PGC-1 alpha 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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