Journal
MOLECULAR CELL
Volume 48, Issue 6, Pages 900-913Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2012.09.030
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Funding
- National Institutes of Health
- Ewha Womans University
- DFCI
- American Diabetes Association
- NIH/NIDDK [RO1 069966]
- NIH [DK059635]
- Department of Defense
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Hepatic glucose production (HGP) maintains blood glucose levels during fasting but can also exacerbate diabetic hyperglycemia. HGP is dynamically controlled by a signaling/transcriptional network that regulates the expression/activity of gluconeogenic enzymes. A key mediator of gluconeogenic gene transcription is PGC-1 alpha. PGC-1 alpha's activation of gluconeogenic gene expression is dependent upon its acetylation state, which is controlled by the acetyltransferase GCN5 and the deacetylase Sirt1. Nevertheless, whether other chromatin modifiers-particularly other sirtuins-can modulate PGC-1 alpha acetylation is currently unknown. Herein, we report that Sirt6 strongly controls PGC-1 alpha acetylation. Surprisingly, Sirt6 induces PGC-1 alpha acetylation and suppresses HGP. Sirt6 depletion decreases PGC-1 alpha acetylation and promotes HGP. These acetylation effects are GCN5 dependent: Sirt6 interacts with and modifies GCN5, enhancing GCN5's activity. Lepr(db/db) mice, an obese/diabetic animal model, exhibit reduced Sirt6 levels; ectopic re-expression suppresses gluconeogenic genes and normalizes glycemia. Activation of hepatic Sirt6 may therefore be therapeutically useful for treating insulin-resistant diabetes.
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