Article

Sirtuin 1 and sirtuin 3: Physiological modulators of metabolism

Department of Physiology, School of Medicine-Instituto de Investigaciones Sanitarias, University of Santiago de Compostela, Santiago de Compostela, Spain.
Physiological Reviews (Impact Factor: 29.04). 07/2012; 92(3):1479-514. DOI: 10.1152/physrev.00022.2011
Source: PubMed

ABSTRACT The sirtuins are a family of highly conserved NAD(+)-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes. Two sirtuins that are central to the control of metabolic processes are mammalian sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), which are localized to the nucleus and mitochondria, respectively. Both are activated by high NAD(+) levels, a condition caused by low cellular energy status. By deacetylating a variety of proteins that induce catabolic processes while inhibiting anabolic processes, SIRT1 and SIRT3 coordinately increase cellular energy stores and ultimately maintain cellular energy homeostasis. Defects in the pathways controlled by SIRT1 and SIRT3 are known to result in various metabolic disorders. Consequently, activation of sirtuins by genetic or pharmacological means can elicit multiple metabolic benefits that protect mice from diet-induced obesity, type 2 diabetes, and nonalcoholic fatty liver disease.

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    • "In light of this knowledge, both SIRT1 activators and inhibitors are being actively explored. Resveratrol (RESV), a naturally occurring polyphenolic SIRT-activating compound (STAC) isolated from the skin of red grapes, was reported to be a potent, but unselective, activator of SIRT1 in vitro, protecting against detrimental effects of high-fat diet exposure such as glucose intolerance, insulin resistance or lifespan reduction [71]. A screen for molecule activators for SIRT1 identified 21 different SIRT1-activating molecules, and the most potent of which was RESV [72]. "
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    • "Furthermore, a recent study has identified increased acetylation of more than 1000 non-mitochondrial sites in mouse embryonic fibroblasts from Sirt3 knockout mice (Sol et al., 2012), also implying roles of SIRT3 outside the mitochondrion. Importantly, functional interaction of SIRT1 and SIRT3 is not novel and has been discussed before e.g. on the level of acetyl-CoA synthases for metabolic control (Hirschey et al., 2011; Nogueiras et al., 2012). "
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