Dominy JE Jr, Lee Y, Jedrychowski MP, Chim H, Jurczak MJ, Camporez JP, Ruan HB, Feldman J, Pierce K, Mostoslavsky R, Denu JM, Clish CB, Yang X,Shulman GI, Gygi SP, Puigserver P.
Mol Cell. 2012 Dec 28;48(6):900-13. doi: 10.1016/j.molcel.2012.09.030. Epub 2012 Nov 8.
Identification of factors that control peroxisome peroliferator-activated receptor gamma
coactivator 1-a (PGC1a) promoting gluconeogenesis could support the invention of new
regulatory components for gluconeogenesis.
Acetylation of PGC1a associated with a repression of PGC1a
General control nonrepressed protein 5 (GCN5) catalyzes PGC1a acetylation, while Silent
mating type information regulator 2 homolog 1(Sirt1) leads to PGC1a deacetylation and
activation of its target genes.
Since there has been no systematic examination of the participation of the other nuclear
sirtuins in regulating PGC1a, this study examined the effects of Sirt2, Sirt6 and Sirt7 on
PGC1a acetylation.
This study report that Sirt6 strongly controls PGC-1α acetylation.
Sirt6 induces PGC-1α acetylation and suppresses HGP, while 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.
