title: The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis.
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. 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.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Dominy
authors.forename: Yoonjin
authors.initials: Y
authors.lastname: Lee
authors.forename: Mark P
authors.initials: MP
authors.lastname: Jedrychowski
authors.forename: Helen
authors.initials: H
authors.lastname: Chim
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.forename: Joao Paulo
authors.initials: JP
authors.lastname: Camporez
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Ruan
authors.forename: Jessica
authors.initials: J
authors.lastname: Feldman
authors.forename: Kerry
authors.initials: K
authors.lastname: Pierce
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
authors.forename: John M
authors.initials: JM
authors.lastname: Denu
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Yang
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: Pere
authors.initials: P
authors.lastname: Puigserver
mesh_terms: D000107:Acetylation; D000818:Animals; D001786:Blood Glucose; D002460:Cell Line; D004789:Enzyme Activation; D015870:Gene Expression; D005943:Gluconeogenesis / Q000235:genetics; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008820:Mice, Obese; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D056564:Sirtuin 1 / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D001786:Blood Glucose; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D056564:Sirtuin 1; D037761:Sirtuins; D015534:Trans-Activators; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C485290:Ppargc1a protein, mouse; C501860:Sirt6 protein, mouse; C470545:Sirt1 protein, mouse