SIRT3 Deficiency and Mitochondrial Protein Hyperacetylation Accelerate the Development of the Metabolic Syndrome

By M. Hirschey, Tadahiro Shimazu, Enxuan Jing, Carrie A. Grueter, Amy M. Collins, B. Aouizerat, A. Stančáková, E. Goetzman, M. Lam, B. Schwer and 11 more. Molecules and Cells, 2011

758 citations recorded by the source corpus.

SUMMARY 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.

Subfields: Geriatrics and Gerontology, Physiology

View Paper: https://www.semanticscholar.org/paper/ec3530b66c36e176900e69e8f3db5fe36bb2038c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Geriatrics and Gerontology

1. Johan Auwerx
2. C. Cantó
3. R. Houtkooper
4. Yana Cen
5. E. Pirinen
6. A. Sauve
7. E. Verdin
8. D. Sinclair

In Physiology

1. Johan Auwerx
2. C. Cantó
3. R. Houtkooper
4. E. Pirinen
5. A. Sauve
6. E. Verdin
7. D. Sinclair
8. Keir J. Menzies

Citations in the corpus

• The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet induced obesity (2012, positive): “During the last decade, an overwhelming body of evidence indicates that the activity of mammalian sirtuins, most notably SIRT1 and SIRT3, have the ability to enhance fat oxidation and prevent against metabolic disease (Hirschey et al., 2011; Lagouge et al., 2006; Pfluger et al., 2008).”
• Sirtuins as regulators of metabolism and healthspan (2012, background): “As a result, deletion of Sirt3 in mice impairs fat breakdown, exacerbating diet-induced obesity and rendering them sensitive to cold upon fastin”