Article

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

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, Jul 27, 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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    • "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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    • "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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