Nakahata Y, Sahar S, Astarita G et al.Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science 324:654-657

Department of Pharmacology, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
Science (Impact Factor: 33.61). 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, Sep 28, 2015
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    • "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 · 17.57 Impact Factor
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    • "An increasing number of studies suggest the existence of an important crosstalk between the molecular clock and the redoxsystem . The cellular redox state is critically important for the regulation of the master clock Bmal1, Clock, Npas2 and Per2 genes transcriptional activity (Rutter et al., 2001; Nakahata et al., 2009). "
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    ABSTRACT: Circadian clock is regulated by a transcriptional/translational feedback loop (TTFL) lasting ∼24h. Circadian oscillation of peroxiredoxins (PRDX1-6) redox status has been shown in mature erythrocytes. We have recently reported that nuclear levels of PRDX2 are circadian regulated in the HaCaT keratinocytes. In this study, we addressed whether PRDX2 translocation could influence the TTFL. A reporter HaCaT cell line stably expressing the luciferase gene under control of Bmal1 promoter was lentivirally transduced either with an empty vector (EV), a vector carrying a myc-tagged wild type PRDX2 (PRDX2-Myc) or the same gene with a nuclear localization sequence (PRDX2-MycNuc). PRDX2 overexpressing cells were protected from H2O2-induced oxidative stress. The amplitude of the Bmal1 promoter activity was significantly dampened in PRDX2-MycNuc versus EV cells when synchronized either by dexamethasone treatment or temperature cycles. Clock synchronization was not affected in PRDX2 silenced cells. N-acetyl cysteine or melatonin treatments, significantly dampened the Bmal1 promoter activity suggesting that sustained scavenging of ROS impairs clock synchronization. Noteworthy, H2O2 treatment rescued proper oscillation of the clock in synchronized PRDX2-MycNuc HaCaT cells. Since the histone deacetylase Sirtuin 1 (Sirt1) modulates clock gene expression amplitude, the effect of Sirt1 activator resveratrol or Sirt1 inhibitor nicotinamide were also investigated. Interestingly, NAM enhanced the molecular clock synchronization in PRDX2-MycNuc cells. Our findings demonstrate that PRDX2 regulates the TTFL oscillation by finely tuning the cellular redox status of the nucleus likely influencing the deacetilase activity of SIRT1 enzyme. Copyright © 2015. Published by Elsevier Ltd.
    The international journal of biochemistry & cell biology 05/2015; 65. DOI:10.1016/j.biocel.2015.05.018 · 4.05 Impact Factor
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    • "Increased SIRT1 activity enhances mitochondrial biogenesis, suppresses inflammation, prevents apoptosis following DNA damage, and generally promotes cell survival in degenerative conditions (Banks et al., 2008; Chen et al., 2005; Jiang et al., 2012; Kang et al., 2009; Kim et al., 2007a; Pfluger et al., 2008; Yuan et al., 2011). The deacetylase activity of SIRT1 is limited by cellular levels of NAD + , which fluctuate in response to changing rates of NAD + biosynthesis and consumption (Houtkooper et al., 2010; Nakahata et al., 2009; Ramsey et al., 2009; Revollo et al., 2004). Several protein regulators of SIRT1 also have been identified, including the positive regulators AROS (active regulator of SIRT1) and Necdin (Hasegawa and Yoshikawa, 2008; Kim et al., 2008) and an inhibitory protein DBC1 (deleted in breast cancer 1) (Kim et al., 2008; Zhao et al., 2008). "
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    ABSTRACT: The NAD(+)-dependent protein deacetylase SIRT1 regulates energy metabolism, responses to stress, and aging by deacetylating many different proteins, including histones and transcription factors. The mechanisms controlling SIRT1 enzymatic activity are complex and incompletely characterized, yet essential for understanding how to develop therapeutics that target SIRT1. Here, we demonstrate that the N-terminal domain of SIRT1 (NTERM) can trans-activate deacetylation activity by physically interacting with endogenous SIRT1 and promoting its association with the deacetylation substrate NF-κB p65. Two motifs within the NTERM domain contribute to activation of SIRT1-dependent activities, and expression of one of these motifs in mice is sufficient to lower fasting glucose levels and improve glucose tolerance in a manner similar to overexpression of SIRT1. Our results provide insights into the regulation of SIRT1 activity and a rationale for pharmacological control of SIRT1-dependent activities. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; 10(10). DOI:10.1016/j.celrep.2015.02.036 · 8.36 Impact Factor
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