Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science

Department of Pharmacology, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
Science (Impact Factor: 31.48). 04/2009; 324(5927):654-7. DOI: 10.1126/science.1170803
Source: PubMed

ABSTRACT Many metabolic and physiological processes display circadian oscillations. We have shown that the core circadian regulator,
CLOCK, is a histone acetyltransferase whose activity is counterbalanced by the nicotinamide adenine dinucleotide (NAD+)–dependent histone deacetylase SIRT1. Here we show that intracellular NAD+ levels cycle with a 24-hour rhythm, an oscillation driven by the circadian clock. CLOCK:BMAL1 regulates the circadian expression
of NAMPT (nicotinamide phosphoribosyltransferase), an enzyme that provides a rate-limiting step in the NAD+ salvage pathway. SIRT1 is recruited to the Nampt promoter and contributes to the circadian synthesis of its own coenzyme. Using the specific inhibitor FK866, we demonstrated
that NAMPT is required to modulate circadian gene expression. Our findings in mouse embryo fibroblasts reveal an interlocked
transcriptional-enzymatic feedback loop that governs the molecular interplay between cellular metabolism and circadian rhythms.

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Available from: Yasukazu Nakahata, Aug 20, 2015
    • "However, NAD + levels can change up to $2-fold in response to diverse physiological stimuli. For example, NAD + levels increase in response to energy stresses, such as glucose deprivation (Fulco et al., 2008), fasting (Cantó et al., 2010; Rodgers et al., 2005), CR (Chen et al., 2008), and exercise (Cantó et al., 2010; Costford et al., 2010), and fluctuate in a circadian fashion (Nakahata et al., 2009; Ramsey et al., 2009). So, where and how do these changes take place in the cell? "
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    ABSTRACT: NAD(+) has emerged as a vital cofactor that can rewire metabolism, activate sirtuins, and maintain mitochondrial fitness through mechanisms such as the mitochondrial unfolded protein response. This improved understanding of NAD(+) metabolism revived interest in NAD(+)-boosting strategies to manage a wide spectrum of diseases, ranging from diabetes to cancer. In this review, we summarize how NAD(+) metabolism links energy status with adaptive cellular and organismal responses and how this knowledge can be therapeutically exploited. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell metabolism 06/2015; DOI:10.1016/j.cmet.2015.05.023 · 16.75 Impact Factor
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    • "Recent studies have shown that SIRT1 and NAMPT work cooperatively in the regulation of metabolism including glucose-regulated insulin secretion at pancreatic b-cells and circadian regulation of NAD + biosynthesis (Imai & Kiess, 2009; Nakahata et al., 2009; Ramsey et al., 2009). Our findings suggest that NAMPT and SIRT1 constitute a positive regulatory loop under nutrient-deprived conditions (Fig. 6K). "
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    ABSTRACT: SIRT1 is an NAD(+) -dependent deacetylase that is implicated in prevention of many age-related diseases including metabolic disorders. Since SIRT1 deacetylase activity is dependent on NAD(+) levels and the development of compounds that directly activate SIRT1 has been controversial, indirectly activating SIRT1 through enhancing NAD(+) bioavailability has received increasing attention. NAD(+) levels are reduced in obesity and the aged, but the underlying mechanisms remain unclear. We recently showed that hepatic microRNA-34a (miR-34a), which is elevated in obesity, directly targets and decreases SIRT1 expression. Here we further show that miR-34a reduces NAD(+) levels and SIRT1 activity by targeting NAMPT, the rate-limiting enzyme for NAD(+) biosynthesis. A functional binding site for miR-34a is present in the 3' UTR of NAMPT mRNA. Hepatic overexpression of miR-34a reduced NAMPT/NAD(+) levels, increased acetylation of the SIRT1 target transcriptional regulators, PGC-1α, SREBP-1c, FXR, and NF-κB, and resulted in obesity-mimetic outcomes. The decreased NAMPT/NAD(+) levels were independent of miR-34a effects on SIRT1 levels since they were also observed in SIRT1 liver-specific knockout mice. Further, the miR-34a-mediated decreases were reversed by treatment with the NAD(+) intermediate, nicotinamide mononucleotide. Conversely, antagonism of miR-34a in diet-induced obese mice restored NAMPT/NAD(+) levels and alleviated steatosis, inflammation, and glucose intolerance. Anti-miR-34a-mediated increases in NAD(+) levels were attenuated when NAMPT was downregulated. Our findings reveal a novel function of miR-34a in reducing both SIRT1 expression and activity in obesity. The miR-34a/NAMPT axis presents a potential target for treating obesity- and aging-related diseases involving SIRT1 dysfunction like steatosis and type 2 diabetes. This article is protected by copyright. All rights reserved.
    Aging cell 07/2013; 12(6). DOI:10.1111/acel.12135 · 5.94 Impact Factor
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    • "Recently, however, several compelling studies regarding the regulation of circadian rhythm have provided a hint for this mechanism. NAMPT-mediated NAD + biosynthesis and intracellular NAD + levels display circadian oscillations that are regulated by a negative feedback loop involving NAMPT/NAD + and CLOCK/SIRT1 [60] [61]. SIRT1 regulates the circadian clock oscillatory mechanisms via deacetylation of circadian clock components [62] [63]. "
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    ABSTRACT: Sirtuin1 (SIRT1) regulates inflammation, aging (lifespan and healthspan), calorie restriction/energetics, mitochondrial biogenesis, stress resistance, cellular senescence, endothelial functions, apoptosis/autophagy, and circadian rhythms through deacetylation of transcription factors and histones. SIRT1 level and activity are decreased in chronic inflammatory conditions and aging where oxidative stress occurs. SIRT1 is regulated by a NAD(+)-dependent DNA repair enzyme poly(ADP-ribose)-polymerase-1 (PARP-1), and subsequent NAD(+) depletion by oxidative stresses may have consequent effects on inflammatory and stress responses as well as cellular senescence. SIRT1 has been shown to undergo covalent oxidative modifications by cigarette smoke-derived oxidants/aldehydes, leading to post-translational modifications, inactivation, and protein degradation. Furthermore, oxidant/carbonyl stress-mediated reduction of SIRT1 leads to the loss of its control on acetylation of target proteins including p53, RelA/p65 and FOXO3, thereby enhancing the inflammatory, pro-senescent and apoptotic responses, as well as endothelial dysfunction. In this review, the mechanisms of cigarette smoke/oxidant-mediated redox post-translational modifications of SIRT1 and its role in PARP1, NF-κB activation, FOXO3 and eNOS regulation, as well as chromatin remodeling/histone modifications during inflammaging are discussed. Furthermore, we also discussed various novel ways to activate SIRT1 either directly or indirectly, which may have therapeutic potential in attenuating inflammation and premature senescence involved in chronic lung diseases.
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