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

ABSTRACT 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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    • "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.
    Biochemical and Biophysical Research Communications 09/2015; DOI:10.1016/j.bbrc.2015.09.019 · 2.30 Impact Factor
    • "Mammals have seven sirtuins (SIRT1–SIRT7) with distinct subcellular localization and biological actions (Houtkooper et al., 2012). The enzymatic activity of sirtuins is critically dependent on the obligatory cosubstrate NAD + , making them intracellular sensors of the metabolic environment (Houtkooper et al., 2010; Imai and Guarente, 2010). The function of SIRT7, which, along with SIRT1 and SIRT6, is present in the nucleus, is only partially understood. "
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    ABSTRACT: Mitochondrial activity is controlled by proteins encoded by both nuclear and mitochondrial DNA. Here, we identify Sirt7 as a crucial regulator of mitochondrial homeostasis. Sirt7 deficiency in mice induces multisystemic mitochondrial dysfunction, which is reflected by increased blood lactate levels, reduced exercise performance, cardiac dysfunction, hepatic microvesicular steatosis, and age-related hearing loss. This link between SIRT7 and mitochondrial function is translatable in humans, where SIRT7 overexpression rescues the mitochondrial functional defect in fibroblasts with a mutation in NDUFSI. These wide-ranging effects of SIRT7 on mitochondrial homeostasis are the consequence of the deacetylation of distinct lysine residues located in the hetero- and homodimerization domains of GABPβ1, a master regulator of nuclear-encoded mitochondrial genes. SIRT7-mediated deacetylation of GABPβ1 facilitates complex formation with GABPα and the transcriptional activation of the GABPα/GABPβ heterotetramer. Altogether, these data suggest that SIRT7 is a dynamic nuclear regulator of mitochondrial function through its impact on GABPβ1 function.
    Cell Metabolism 09/2014; 20(5). DOI:10.1016/j.cmet.2014.08.001 · 17.57 Impact Factor
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    • "Various longevity factors (which affect either RLS, CLS or both) have been identified in S. cerevisiae, and some of these factors are associated with Sir2 function. These factors include mitochondrial function [65] [66] [67] [68] [69] [70], stress response/hormesis/mitohormesis [64,66,68,71–74], the NAD + -dependent deacetylase Sir2 family [31] [75], partitioning of damaged proteins [76] [77], genome stability [78] [79] [80], homeostasis of NAD + and other metabolic factors [1] [6] [31] [81] [82], vacuolar function [83] [84], ribosome biogenesis [85], cell hypertrophy [86] [87] [88], proteostasis [89] [90] [91] and metabolitesinduced toxicity [92] [93] [94] [95] [96]. Although whether and how these factors contribute to Sir2 mediated life span extension remain debatable, it is clear that Sir2 promotes RLS under normal conditions. "
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    ABSTRACT: Pyridine nucleotides are essential coenzymes in many cellular redox reactions in all living systems. In addition to functioning as a redox carrier, NAD(+) is also a required co-substrate for the conserved sirtuin deacetylases. Sirtuins regulate transcription, genome maintenance and metabolism and function as molecular links between cells and their environment. Maintaining NAD(+) homeostasis is essential for proper cellular function and aberrant NAD(+) metabolism has been implicated in a number of metabolic- and age-associated diseases. Recently, NAD(+) metabolism has been linked to the phosphate-responsive signaling pathway (PHO pathway) in the budding yeast Saccharomyces cerevisiae. Activation of the PHO pathway is associated with the production and mobilization of the NAD(+) metabolite nicotinamide riboside (NR), which is mediated in part by PHO-regulated nucleotidases. Cross-regulation between NAD(+) metabolism and the PHO pathway has also been reported; however, detailed mechanisms remain to be elucidated. The PHO pathway also appears to modulate the activities of common downstream effectors of multiple nutrient-sensing pathways (Ras-PKA, TOR, Sch9/AKT). These signaling pathways were suggested to play a role in calorie restriction-mediated beneficial effects, which have also been linked to Sir2 function and NAD(+) metabolism. Here, we discuss the interactions of these pathways and their potential roles in regulating NAD(+) metabolism. In eukaryotic cells, intracellular compartmentalization facilitates the regulation of enzymatic functions and also concentrates or sequesters specific metabolites. Various NAD(+)-mediated cellular functions such as mitochondrial oxidative phosphorylation are compartmentalized. Therefore, we also discuss several key players functioning in mitochondrial, cytosolic and vacuolar compartmentalization of NAD(+) intermediates, and their potential roles in NAD(+) homeostasis. To date, it remains unclear how NAD(+) and NAD(+) intermediates shuttle between different cellular compartments. Together, these studies provide a molecular basis for how NAD(+) homeostasis factors and the interacting signaling pathways confer metabolic flexibility and contribute to maintaining cell fitness and genome stability.
    DNA Repair 08/2014; 23. DOI:10.1016/j.dnarep.2014.07.009 · 3.11 Impact Factor
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