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♦ See referenced article, J. Biol. Chem. 2013, 288, 31350–31356
The NAD+-dependent protein deacetylase SIRT6 is crucial for genomic and metabolic stability. In mice, overexpression of SIRT6 lowers LDL and triglyceride levels, improves glucose tolerance, and increases mitochondrial respiration. Despite in vivo evidence that SIRT6 is a potent histone deacetylase, SIRT6 is extremely inefficient in vitro, suggesting that there is an activating mechanism in cells. In this Paper of the Week, a team led by John M. Denu at the University of Wisconsin-Madison demonstrated that SIRT6 is directly activated by free long-chain fatty acids, including ones linked to the health benefits of dietary polyunsaturated fatty acids. These results suggest the SIRT6 is stimulated to down-regulate carbohydrate and lipid metabolism during conditions that increase levels of particular omega-3 and omega-6 fatty acids, such fasting and dietary supplement intake. In addition, the discovery of these endogenous, small-molecule activators of SIRT6 reveals the therapeutic potential of compounds that promote SIRT6 function, particularly for improved metabolism, anti-inflammation, and decreased tumorigenesis.
Mammalian sirtuins (SIRT1 through SIRT7) are members of a highly conserved family of NAD+-dependent protein deacetylases that function in metabolism, genome maintenance, and stress responses. Emerging evidence suggests that some sirtuins display substrate specificity toward other acyl groups attached to the lysine ϵ-amine. SIRT6 was recently reported to preferentially hydrolyze long-chain fatty acyl groups over acetyl groups. Here we investigated the catalytic ability of all sirtuins to hydrolyze 13 different acyl groups from histone H3 peptides, ranging in carbon length, saturation, and chemical diversity.