The Deacetylase Sirt6 Activates the Acetyltransferase GCN5 and Suppresses Hepatic Gluconeogenesis

Abstract

Summary 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/Leprdb 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.

Calorie restriction and sirtuins revisited

“…Thus, SIRT4 deletion would prevent the accumulation of malonyl CoA, the key precursor for fat synthesis, as would the reduction in SIRT4 levels in CR. Finally, hepatic SIRT6, like SIRT1, appears to be protective, since two studies show that its deletion sensitizes animals to steatosis Dominy et al 2012).…”

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

“…Additionally, SIRT1 binds the PGC-1α promoter and takes part in its positive regulation loop [6]. An interesting interaction takes place between PGC-1α and SIRT6: the sirtuin deacetylates and activates the acetyltransferase GCN5 (general control non-repressed protein 5), which leads to increased acetylation of PGC-1α and inhibition of its transcriptional co-activator function [46]. PGC-1 has been proposed to mediate the protective SIRT1/PPAR-dependent action of Aβ-challenged astrocytes towards neurons (the increase of neuronal biogenesis of mitochondria and survival in the co-culture with astroglia) [4].…”

The Methionine Transamination Pathway Controls Hepatic Glucose Metabolism through Regulation of the GCN5 Acetyltransferase and the PGC-1α Transcriptional Coactivator

“…The molecular mechanisms underlying the methioninemediated increase of GCN5 activity are currently unknown, and future studies will hopefully shed more light on this matter. It is possible that alteration in the post-translational modifications on GCN5, such as phosphorylation (28,36) or acetylation (28), could be responsible for the increased activity observed. GCN5 is part of the SAGA (Spt-Ada-Gcn5 acetyltransferase) and ATAC (Ada2a-containing) coactivator complexes (37).…”

“…The acetylation status of PGC-1␣ is primarily determined by opposing activities of the general control nonrepressed protein 5 (GCN5) acetyltransferase and the NAD ϩ -dependent silent mating type information regulation 2 homolog 1 (SIRT1) deacetylase (25,26). Various signaling cascades converge on GCN5 and SIRT1 to regulate their activities, including those stimulated by insulin and glucagon (28,29). These peptide hormones play a major role in defining the necessity for glucose production by the liver during fasting and fed states (30) and operate, at least in part, through regulating PGC-1␣.…”