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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    • "In addition to JNK signaling, ROS activates AMP-activated protein kinase (AMPK) to enhance SIRT1 activity by increasing cellular NAD þ levels [37]. SIRT1 regulates several biological events including autophagy, cell metabolism, longevity, apoptosis, and DNA repair (reviewed in [31]). However, the mechanism of SIRT1/autophagy regulation in dental fluorosis is unclear. "
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    ABSTRACT: Fluoride is an effective caries prophylactic, but at high doses can also be an environmental health hazard. Acute or chronic exposure to high fluoride doses can result in dental enamel and skeletal and soft tissue fluorosis. Dental fluorosis is manifested as mottled, discolored, porous enamel that is susceptible to dental caries. Fluoride induces cell stress, including endoplasmic reticulum stress and oxidative stress, which leads to impairment of ameloblasts responsible for dental enamel formation. Recently we reported that fluoride activates SIRT1 and autophagy as an adaptive response to protect cells from stress. However, it still remains unclear how SIRT1/autophagy is regulated in dental fluorosis. In this study, we demonstrate that fluoride exposure generates reactive oxygen species (ROS) and the resulting oxidative damage is counteracted by SIRT1/autophagy induction through JUN-terminal kinase (JNK) signaling in ameloblasts. In the mouse-ameloblast-derived cell line LS8, fluoride induced ROS, mitochondrial damage including cytochrome-c release, up-regulation of UCP2, attenuation of ATP synthesis, and H2AX phosphorylation (γH2AX), which is a marker of DNA damage. We evaluated the effects of the ROS inhibitor N-acetylcysteine (NAC) and the JNK inhibitor SP600125 on fluoride-induced SIRT1/autophagy activation. NAC decreased fluoride-induced ROS generation and attenuated JNK and c-Jun phosphorylation. NAC decreased SIRT1 phosphorylation and formation of the autophagy marker LC3II, which resulted in an increase in the apoptosis mediators γH2AX and cleaved/activated caspase-3. SP600125 attenuated fluoride-induced SIRT1 phosphorylation, indicating that fluoride activates SIRT1/autophagy via the ROS-mediated JNK pathway. In enamel organs from rats or mice treated with 50, 100, or 125ppm fluoride for 6 weeks, cytochrome-c release and the DNA damage markers 8-oxoguanine, p-ATM, and γH2AX were increased compared to those in controls (0ppm fluoride). These results suggest that fluoride-induced ROS generation causes mitochondrial damage and DNA damage, which may lead to impairment of ameloblast function. To counteract this impairment, SIRT1/autophagy is induced via JNK signaling to protect cells/ameloblasts from fluoride-induced oxidative damage that may cause dental fluorosis.
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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.
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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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