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Genetic overexpression of Sirt1 has been shown to increase insulin sensitivity and improve macrophage cholesterol metabolism in mice. Given these findings and that metabolic syndrome is marked by insulin resistance, dyslipidemia and an increased risk for atherosclerosis, Li Qiang et al. (Cell Metab. 14, 758–767) hypothesized that a transgenic mouse strain mildly overexpressing Sirt1 would be protected from the development of atherosclerosis when placed on a high-fat and high-cholesterol diet.

However, the team found this was not the case. Although they did see improved glycemic control, they also found evidence that atherosclerosis was worse in these mice compared with wild-type mice fed the same diet. Mechanistically, the authors found that Sirt1 deacetylates, and thus represses, the transcriptional factor Creb, which is known to activate hepatic glucose production but inhibit lipid synthesis.

So, whereas the pharmaceutical industry has been looking for specific and potent activators of Sirt1 to improve metabolism, these new results suggest that such clinical approaches should be approached with care, as these compounds may aggravate the risk for atherosclerosis.