Minireview: NAD+, a circadian metabolite with an epigenetic twist

Abstract

A wide variety of endocrine, physiological, and metabolic functions follow daily oscillations. Most of these regulations are controlled at the level of gene expression by the circadian clock and, a remarkably coordinated transcription-translation machinery that exerts its function in virtually all mammalian cells. A large fraction of the genome is under control of the circadian clock, a regulation that is achieved through dynamic changes in chromatin states. Recent findings have demonstrated intimate connections between the circadian clock and epigenetic control. The case of nicotinamide adenine dinucleotide, which modulates the circadian activity of the deacetylase sirtuin 1, constitutes a paradigmatic example of the link between cyclic cellular metabolism and chromatin remodeling. Indeed, the clock transcriptional feedback loop is interlocked with the enzymatic loop of the nicotinamide adenine dinucleotide salvage pathway.

Fig. 1.

By activating SIRT1, NAD⁺ conjoins two feedback loops necessary for cross talk between the circadian clock and metabolite production. The levels of the metabolite NAD⁺ were shown to oscillate in a circadian manner in various cell types, suggesting that it could determine the cyclic function of NAD⁺-dependent enzymes, such as SIRT1. It has been shown that the salvage pathway is critical to regulate intracellular NAD⁺ levels. After the conversion of NAM into NAM mononucleotide (NMN) by NAMPT, NMN is further modified into NAD⁺ by the NAM mononucleotide adenylyl transferases (Nmnat-1, -2, and -3). Although NAM inhibits SIRT1 activity, NAD⁺-activated SIRT1 feeds back into the NAD⁺ salvage pathway by directly regulating Nampt gene expression in a CLOCK:BMAL1-dependent manner (28). By this mechanism, NAD⁺ conjoins the two feedback loops, contributing to the fine tuning necessary for achieving energy balance.