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: 27.32). 07/2012; 92(3):1479-514. DOI: 10.1152/physrev.00022.2011
Source: PubMed


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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Available from: Kirk Habegger, Oct 04, 2015
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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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    ABSTRACT: Sirtuins are a conserved family of NAD(+)-dependent class III lysine deacetylases, known to regulate longevity. In mammals, the sirtuin family has seven members (SIRT1-7), which vary in enzymatic activity, subcellular distribution and targets. Pharmacological and genetic modulation of SIRTs has been widely spread as a promising approach to slow aging and neurodegenerative processes. Huntington's disease (HD) is a neurodegenerative disorder linked to expression of polyglutamine-expanded huntingtin (HTT) protein for which there is still no disease-reversing treatment. Studies in different animal models provide convincing evidence that SIRT1 protects both cellular and animal models from mutant HTT toxicity, however controversial results were recently reported. Indeed, as a consequence of a variety of SIRT-activation pathways, either activation or inhibition of a specific SIRT appears to be neuroprotective. Therefore, this review summarizes the recent progress and knowledge in sirtuins (particularly SIRT1-3) and their implications for HD treatment. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 07/2015; DOI:10.1016/j.bbadis.2015.07.003 · 4.66 Impact Factor
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    • "Sirtuin 1 (SIRT1) is a member of the sirtuin family of NAD+ dependent deacetylases which is implicated as a metabolic sensor of the cell [11-13]. SIRT1 is neuroprotective in numerous models of neurodegenerative diseases including ischemia/reperfusion [14-16]. "
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    ABSTRACT: Ischemic preconditioning is a neuroprotective mechanism whereby a sublethal ischemic exposure is protective against a subsequent lethal ischemic attack. We previously demonstrated that SIRT1, a nuclear localized stress-activated deacetylase, is vital for ischemic preconditioning neuroprotection. However, a recent study demonstrated that SIRT1 can also localize to the mitochondria. Mitochondrial localized SIRT1 may allow for a direct protection of mitochondria following ischemic preconditioning. The objective of this study was to determine whether ischemic preconditioning increases brain mitochondrial SIRT1 protein levels and to determine the role of PKCɛ and HSP90 in targeting SIRT1 to the mitochondria. Here we report that preconditioning rats, with 2 min of global cerebral ischemia, induces a delayed increase in non-synaptic mitochondrial SIRT1 protein levels which was not observed in synaptic mitochondria. This increase in mitochondrial SIRT1 protein was found to occur only in neuronal cells and was mediated by PKCε activation. Inhibition of HSP90, a protein chaperone involved in mitochondrial protein import, prevented preconditioning induced increases in mitochondrial SIRT1 and PKCε protein. Our work provides new insights into a possible direct role of SIRT1 in modulating mitochondrial function under both normal and stress conditions, and to a possible role of mitochondrial SIRT1 in activating preconditioning induced ischemic tolerance.
    PLoS ONE 09/2013; 8(9):e75753. DOI:10.1371/journal.pone.0075753 · 3.23 Impact Factor
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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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    ABSTRACT: In this review, we discuss the dual control of mitochondrial biogenesis and energy metabolism by silent information regulator-1 and -3 (SIRT1 and SIRT3). SIRT1 activates the peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α) mediated transcription of nuclear and mitochondrial genes encoding for proteins promoting mitochondria proliferation, oxidative phosphorylation and energy production, whereas SIRT3 directly acts as an activator of proteins important for oxidative phosphorylation, tricarboxylic acid (TCA) cycle and fatty-acid oxidation and indirectly of PGC-1α and AMP-activated protein kinase (AMPK). The complex network involves different cellular compartments, transcriptional activation, post-translational modification and a plethora of secondary effectors. Overall, the mode of interaction between both sirtuin family members may be considered as a prominent case of molecular job-sharing.
    Mitochondrion 04/2013; 13(6). DOI:10.1016/j.mito.2013.04.002 · 3.25 Impact Factor
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