SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome |
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Authors: | Hirschey Matthew D Shimazu Tadahiro Jing Enxuan Grueter Carrie A Collins Amy M Aouizerat Bradley Stančáková Alena Goetzman Eric Lam Maggie M Schwer Bjoern Stevens Robert D Muehlbauer Michael J Kakar Sanjay Bass Nathan M Kuusisto Johanna Laakso Markku Alt Frederick W Newgard Christopher B Farese Robert V Kahn C Ronald Verdin Eric |
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Institution: | Gladstone Institute of Virology and Immunology, San Francisco, CA 94158, USA. |
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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. |
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