The Deacetylase Sirt6 Activates the Acetyltransferase GCN5 and Suppresses Hepatic Gluconeogenesis

John E. Dominy, Yoonjin Lee, Mark P. Jedrychowski, Helen Chim, Michael J. Jurczak, Joao Paulo Camporez, Hai Bin Ruan, Jessica Feldman, Kerry Pierce, Raul Mostoslavsky, John M. Denu, Clary B. Clish, Xiaoyong Yang, Gerald I. Shulman, Steven P. Gygi, Pere Puigserver

Research output: Contribution to journalArticle

149 Scopus citations

Abstract

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. Leprdb/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.

Original languageEnglish (US)
Pages (from-to)900-913
Number of pages14
JournalMolecular Cell
Volume48
Issue number6
DOIs
StatePublished - Dec 28 2012

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    Dominy, J. E., Lee, Y., Jedrychowski, M. P., Chim, H., Jurczak, M. J., Camporez, J. P., Ruan, H. B., Feldman, J., Pierce, K., Mostoslavsky, R., Denu, J. M., Clish, C. B., Yang, X., Shulman, G. I., Gygi, S. P., & Puigserver, P. (2012). The Deacetylase Sirt6 Activates the Acetyltransferase GCN5 and Suppresses Hepatic Gluconeogenesis. Molecular Cell, 48(6), 900-913. https://doi.org/10.1016/j.molcel.2012.09.030