SIRT3 Deficiency and Mitochondrial Protein Hyperacetylation Accelerate the Development of the Metabolic Syndrome
MD Hirschey, T Shimazu, E Jing, CA Grueter, AM Collins, B Aouizerat, A Stančáková, E Goetzman, MM Lam, B Schwer, RD Stevens, MJ Muehlbauer, S Kakar, NM Bass, J Kuusisto, M Laakso, FW Alt, CB Newgard, RV Farese Jr., CR Kahn and E Verdin (2011) SIRT3 Deficiency and Mitochondrial Protein Hyperacetylation Accelerate the Development of the Metabolic Syndrome. Molecular Cell, In press
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Acetylation is increasingly recognized as an important metabolic regulatory post- translational 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 loss of SIRT3 and dysregulation of mitochondrial protein acetylation contribute to the metabolic syndrome.