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Mol Cell DOI:10.1016/j.molcel.2012.09.030

The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis.

Publication TypeJournal Article
Year of Publication2012
AuthorsDominy, JE, Lee, Y, Jedrychowski, MP, Chim, H, Jurczak, MJ, Camporez, JPaulo, Bin Ruan, H-, Feldman, J, Pierce, K, Mostoslavsky, R, Denu, JM, Clish, CB, Yang, X, Shulman, GI, Gygi, SP, Puigserver, P
JournalMol Cell
Date Published2012 Dec 28
KeywordsAcetylation, Animals, Blood Glucose, Cell Line, Enzyme Activation, Gene Expression, Gluconeogenesis, Hepatocytes, Humans, Liver, Male, Mice, Mice, Inbred BALB C, Mice, Obese, p300-CBP Transcription Factors, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Phosphorylation, Protein Processing, Post-Translational, Sirtuin 1, Sirtuins, Trans-Activators, Transcription Factors

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-1α. PGC-1α'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-1α acetylation is currently unknown. Herein, we report that Sirt6 strongly controls PGC-1α acetylation. Surprisingly, Sirt6 induces PGC-1α acetylation and suppresses HGP. Sirt6 depletion decreases PGC-1α 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.


Alternate JournalMol. Cell
PubMed ID23142079
PubMed Central IDPMC3534905
Grant ListR01 DK089098 / DK / NIDDK NIH HHS / United States
R01 GM093072 / GM / NIGMS NIH HHS / United States
F32 DK083871 / DK / NIDDK NIH HHS / United States
U24 DK059635 / DK / NIDDK NIH HHS / United States
R01 GM065386 / GM / NIGMS NIH HHS / United States
R01 DK040936 / DK / NIDDK NIH HHS / United States
R01 069966 / / PHS HHS / United States
DK059635 / DK / NIDDK NIH HHS / United States
R37 GM059785 / GM / NIGMS NIH HHS / United States
R01 DK069966 / DK / NIDDK NIH HHS / United States
R01 DK088190 / DK / NIDDK NIH HHS / United States