| First Author | Dominy JE Jr | Year | 2012 |
| Journal | Mol Cell | Volume | 48 |
| Issue | 6 | Pages | 900-13 |
| PubMed ID | 23142079 | Mgi Jnum | J:193985 |
| Mgi Id | MGI:5470010 | Doi | 10.1016/j.molcel.2012.09.030 |
| Citation | Dominy JE Jr, et al. (2012) The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis. Mol Cell 48(6):900-13 |
| abstractText | 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-1alpha. PGC-1alpha'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-1alpha acetylation is currently unknown. Herein, we report that Sirt6 strongly controls PGC-1alpha acetylation. Surprisingly, Sirt6 induces PGC-1alpha acetylation and suppresses HGP. Sirt6 depletion decreases PGC-1alpha 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. |
