Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases. Trends Pharmacol Sci

Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Trends in Pharmacological Sciences (Impact Factor: 11.54). 03/2010; 31(5):212-20. DOI: 10.1016/
Source: PubMed


Since the discovery of NAD-dependent deacetylase activity of the silent information regulator-2 (SIR2) family ('sirtuins'), many exciting connections between protein deacetylation and energy metabolism have been revealed. The importance of sirtuins in the regulation of many fundamental biological responses to various nutritional and environmental stimuli has been firmly established. Sirtuins have also emerged as critical regulators for aging and longevity in model organisms. Their absolute requirement of NAD has revived an enthusiasm in the study of mammalian biosynthesis of NAD. Sirtuin-targeted pharmaceutical and nutriceutical interventions against age-associated diseases are also on the horizon. This review summarizes the recent progress in sirtuin research (particularly in mammalian sirtuin biology) and re-evaluates the connection between sirtuins, metabolism, and age-associated diseases (e.g., type-2 diabetes) to set a basis for the next ten years of sirtuin research.

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    • "some proliferator-activated receptor γ coactivator 1α (PPARGC1A) and the forkhead box O1 transcription factor (FoxO1; Imai and Guarente, 2010), promoting the expression of the gluconeogenic genes phosphoenolpyruvate carboxykinase (PCK) and glucose-6-phosphatase (G6PC; Erion et al., 2009). In muscle, Sirt1 deacetylates PPARGC1A to switch from glucose to free fatty acid oxidation under nutrient deprivation (Nasrin et al., 2010). "
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    ABSTRACT: Sirtuins (Sirt) are NAD-dependent deacetylases that are activated by the antioxidants resveratrol (RSV) and lipoic acid (LA). The objective of this study was to determine in bovine liver and muscle slice cultures the effect of RSV and LA treatment on the expresssion of Sirt1, Sirt3, peroxisome proliferator-activated receptor γ coactivator 1α (PPARGC1A), and the forkhead box O transcription factors FoxO1 and FoxO3 as well as other factors involved in glucose and lipid metabolism and related to Sirt activity. Tissue slices from crossbred bulls were treated during 60 min with 40 or 80 μ RSV and 30, 100, 300, or 1,000 μ LA under restricted conditions (Krebs-Ringer buffer without nutrients) and fed conditions (2.5 m propionate in combination with 1 n glucagon) for liver slices or with 0.01 μ epinephrine for muscle slices. Quantitative real-time PCR was used to analyze the expression of the mRNA for the genes studied and western blot analysis for the expression of the protein for Sirt1. Our results show that the expression of the mRNA for Sirt1 was enhanced by RSV in liver under restriction ( ≤ 0.0112) and by LA in muscle, more under restriction ( ≤ 0.0121) than after epinephrine administration ( < 0.0001). Sirt3 is affected in a dose-dependent manner by both compounds in both tissues and under both metabolic conditions ( ≤ 0.0452). The expression of the protein for Sirt1 was increased by LA in both tissues under restricted conditions ( = 0.0026 and = 0.0201, respectively) but in liver also in fed conditions ( = 0.0016). Genes involved in the antioxidant response were upregulated in both tissues. These results indicate that bovine Sirt respond differently to RSV and LA stimulation than monogastric Sirt do and that gluconeogenesis in ruminants is not related to Sirt to the same degree as in monogastric species. However, these results provide information about the possible role of Sirt in ruminant metabolism.
    Full-text · Article · Oct 2015 · Journal of Animal Science
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    • "Among them, SIRT6 is localized to the nucleus and is involved in transcriptional silencing, genome stability, and longevity [7]. Sirt6 is implicated in the regulation of life span and ageing through the regulation of NFkB function [7]. We previously disclosed that Sirt6 is expressed in chondrocytes and controls proliferation and differentiation of chondrocytes through the regulation of Indian hedgehog (Ihh) expression [8]. "
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    ABSTRACT: Osteoarthritis (OA) is a chronic degenerative joint disorder commonly associated with metabolic syndrome. As ageing and obesity has a great impact on the initiation/severity of OA, herein we sought to investigate the involvement of Sirt6 in the crosstalk between ageing and metabolic syndrome/OA. Sirt6 haploinsufficiency in mice promoted the expression of inflammatory cytokines in the IPFP. Enhanced inflammation of the IPFP in the aged Sirt6+/- HFD group was paralleled with accelerated OA change, including osteophyte growth and chondrocyte hypertrophy. Conversely, mesenchyme-specific Sirt6-deficient mice revealed both attenuated chondrocyte hypertrophy and proteoglycan synthesis, although chondrocyte senescence was enhanced as shown in the aged WT mice. Thus Sirt6 has key roles in the relationship among ageing, metabolic syndrome, and OA.
    Full-text · Article · Sep 2015 · Biochemical and Biophysical Research Communications
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    • "Our western blotting showed a decreased expression of acetylated p53 and no increase of acetyl-FOXO1 in uveitic tissues that occurred after the stimulation of intravitreal RvD1 and blockade of the SIRT1 activity with EX527. p53 and FOXO are some of the numerous no-histone proteins targeted by SIRT1 together with such NF-í µí¼…B and mKu70 that are involved in DNA repair and factors involved in the nitric oxide synthase [2] [3] [30] [36]. Together with SIRT1 they orchestrate the mechanisms of the "
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    ABSTRACT: Rat endotoxin-induced uveitis (EIU) is a well-established model of human uveitis. In this model, intravitreal injection of resolvin D1 (RvD1, 10-100-1000 ng/kg) 1 hour after subcutaneous treatment of Sprague-Dawley rats with lipopolysaccharide (LPS, 200 μg/rat) significantly prevented the development of uveitis into the eye. RvD1 dose-dependently increased the expression of sirtuin-1 (SIRT1) within the eye, while it decreased the expression of acetyl-p53 and acetyl-FOXO1. These effects were accompanied by local downregulation of some microRNAs related to the expression and activity of SIRT1. These were miR-195-5p, miR-200a-3p, miR-34a-5p, and miR-145-5p. An increase of manganese superoxide dismutase and decrease of caspase 3 were evident after RvD1 treatment. In another set of experiments, the protective effects of RvD1 (1000 ng/kg) were partly abolished by the pretreatment of the rats with EX527 (10 mg/kg/day, i.p.), a specific inhibitor of SIRT1 activity, for 7 days prior to the induction of EIU in rats. Similarly, the effects of RvD1 (1000 ng/kg) on the SIRT1 protein expression were abolished by Boc2, N-t-butoxycarbonyl-PLPLP, a specific formyl-peptide receptor type 2/lipoxin A receptor antagonist. Therefore, an interplay of the SIRT1 activity on the RvD1 mediated resolution of EIU is argued.
    Full-text · Article · Jul 2015 · Mediators of Inflammation
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