title: SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome.
abstract: Acetylation is increasingly recognized as an important metabolic regulatory posttranslational protein modification, yet the metabolic consequence of mitochondrial protein hyperacetylation is unknown. We find that high-fat diet (HFD) feeding induces hepatic mitochondrial protein hyperacetylation in mice and downregulation of the major mitochondrial protein deacetylase SIRT3. Mice lacking SIRT3 (SIRT3KO) placed on a HFD show accelerated obesity, insulin resistance, hyperlipidemia, and steatohepatitis compared to wild-type (WT) mice. The lipogenic enzyme stearoyl-CoA desaturase 1 is highly induced in SIRT3KO mice, and its deletion rescues both WT and SIRT3KO mice from HFD-induced hepatic steatosis and insulin resistance. We further identify a single nucleotide polymorphism in the human SIRT3 gene that is suggestive of a genetic association with the metabolic syndrome. This polymorphism encodes a point mutation in the SIRT3 protein, which reduces its overall enzymatic efficiency. Our findings show that loss of SIRT3 and dysregulation of mitochondrial protein acetylation contribute to the metabolic syndrome.
authors.affiliation: Gladstone Institute of Virology and Immunology, San Francisco, CA 94158, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hirschey
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Shimazu
authors.forename: Enxuan
authors.initials: E
authors.lastname: Jing
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Grueter
authors.forename: Amy M
authors.initials: AM
authors.lastname: Collins
authors.forename: Bradley
authors.initials: B
authors.lastname: Aouizerat
authors.forename: Alena
authors.initials: A
authors.lastname: Stančáková
authors.forename: Eric
authors.initials: E
authors.lastname: Goetzman
authors.forename: Maggie M
authors.initials: MM
authors.lastname: Lam
authors.forename: Bjoern
authors.initials: B
authors.lastname: Schwer
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Muehlbauer
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kakar
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Bass
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
mesh_terms: D000107:Acetylation; D000818:Animals; D059305:Diet, High-Fat; D006801:Humans; D024821:Metabolic Syndrome / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008954:Models, Biological; D056566:Sirtuin 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D056566:Sirtuin 3