CIRCADIAN CONTROL OF THE NAD+ SALVAGE PATHWAY BY CLOCK-SIRT1

By Yasukazu Nakahata, Saurabh Sahar, G. Astarita, M. Kaluzová, Paolo Sassone-Corsi. Science, 2009

1,205 citations recorded by the source corpus.

Circadian Oscillations The 24-hour day-night cycle plays an important role in mammalian physiology and behavior and, as most travelers are well aware, there is an intimate link between our in-built circadian clocks and metabolic rhythms. This link is in part forged by the protein deacetylase SIRT1, which regulates the clock's molecular circuitry. SIRT1 uses as a cofactor the cellular metabolite NAD+, which is synthesized through a salvage pathway that includes the enzyme nicotinamide phosphoribosyltransferase (NAMPT) (see the Perspective by Wijnen). Ramsey et al. (p. 651; published online 19 March) and Nakahata et al. (p. 654, published online 12 March) now show that NAMPT and NAD+ levels oscillate during the daily 24-hour cycle and that this oscillation is regulated by the circadian clock. Furthermore, the oscillations in NAD+ modulate the activity of SIRT1 feeding back into the circadian clock. A transcriptional-enzymatic feedback loop controls interactions between metabolism and circadian rhythms in mouse cells. 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.

Subfields: Biological Psychiatry, Endocrine and Autonomic Systems, Geriatrics and Gerontology

View Paper: https://www.semanticscholar.org/paper/106d1cb3cef7cd117cbe3e546e445bb342a4e5ab

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In Biological Psychiatry

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In Endocrine and Autonomic Systems

In Geriatrics and Gerontology

Citations in the corpus

CENTRAL AND PERIPHERAL CIRCADIAN CLOCKS IN MAMMALS (2012, background): “HNF4α is responsive to glucocorticoids (Reddy et al. 2007), contains E-boxes, which may allow for transcriptional control by CLOCK:BMAL1 (Reddy et al. 2007), and can interact with PER2 (Schmutz et al. 2010).”
NAD+ metabolism and the control of energy homeostasis - a balancing act between mitochondria and the nucleus (2015, background): “ACMS, a-amino-b-carboxymuconate-ε-semialdehyde; ACMSD, ACMS decarboxylase; AMS, a-amino-b-muconate-ε-semialdehyde; IDO, indoleamine 2,3-dioxygenase; NA, nicotinic acid; NAAD, NA adenine dinucleotide; NADSYN, NAD+ synthetase; NAMN, NAmononucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NAPR”
Melatonin--a pleiotropic, orchestrating regulator molecule. (2011, background): “It modulates chromatin remodeling via the oscillator protein CLK and, moreover, seems to directly influence at least peripheral oscillators by interacting with the CLK/BMAL1 complex (Nakahata et al., 2008, 2009; Grimaldi et al., 2009), actions that should have numerous secondary effects.”
NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential (2020, background): “Besides, the oscillation activation of SIRT1 also regulates the circadian dynamics via deacetylation of the core clock repressor PER2 and mixed-lineage leukemia 1 (MLL1), thereby controlling rhythmic chromatin property and the activity of BMAL1: CLOCK complex.(36,38,238,242,244) Similar to sirtuins,”
Bile Acid Signaling in Metabolic Disease and Drug Therapy (2014, background): “Alcohol also alters the NAD/ NADH ratio, which regulates sirtuin SIRT1 activity and downstream target genes Bmal1/Npas2/Clock (Nakahata et al., 2009).”