Targeting sirtuin 1 to improve metabolism: all you need is NAD(+)?

Abstract

Sirtuin 1 (SIRT1) is an evolutionarily conserved NAD(+)-dependent deacetylase that is at the pinnacle of metabolic control, all the way from yeast to humans. SIRT1 senses changes in intracellular NAD(+) levels, which reflect energy level, and uses this information to adapt the cellular energy output such that it matches cellular energy requirements. The changes induced by SIRT1 activation are generally (but not exclusively) transcriptional in nature and are related to an increase in mitochondrial metabolism and antioxidant protection. These attractive features have validated SIRT1 as a therapeutic target in the management of metabolic disease and prompted an intensive search to identify pharmacological SIRT1 activators. In this review, we first give an overview of the SIRT1 biology with a particular focus on its role in metabolic control. We then analyze the pros and cons of the current strategies used to activate SIRT1 and explore the emerging evidence indicating that modulation of NAD(+) levels could provide an effective way to achieve such goals.

Figure 1. The NAD⁺-dependent SIRT1 deacetylase reaction

SIRT1 uses NAD⁺ as a substrate to remove acetyl groups from a target protein. In addition to the deacetylated substrate, the reaction yields nicotinamide and 2′-O-acetyl-ADP ribose as products.

Figure 2. Relevant domains in the human form of the SIRT1 protein

The figure schematizes the span of the conserved sirtuin homology domain as well as the nuclear localization (NLS) and nuclear exportation signals (NES). The residues subject to phosphorylation, by JNK1 and Cyclin/cdk1, and sumoylation are also indicated.

Figure 3. SIRT1 metabolic targets

SIRT1 deacetylates a large arrav of protein targets involved in metabolic regulation. The bottom part of the figure highlights nuclear targets implicated in transcriptional metabolic adaptations. SIRT1’s cytosolic targets are illustrated in the top part. The full names for the abbreviations can be found on the main text.

Figure 4. Transcriptional regulation of the SIRT1 gene

Many transcription factors influence the transcriptional activity through acting on both the proximal and distal regions of the SIRT1 promotor. Transcriptional regulators in the green part of the boxes positively regulate SIRT1 gene expression, while those in the red part of the boxes act as negative regulators. Of note, the SIRT1 protein can create many feed-forward loops by deacetylating and enhancing the activity of some positive regulators (FOXOs) while deacetylating and/or inactivating repressor complexes (p53, PPARγ, HIC1/CtBP). Full names for the abbreviations can be found in the text.

Figure 5. Resveratrol promotes mitochondrial biogenesis and lipid oxidation gene expression through indirect AMPK and SIRT1 activation

While still a matter of debate, most data currently indicate that the metabolic actions of resveratrol or its metabolites stem from its ability to act as a mild mitochondrial poison, impairing ATP synthesis. The energy stress induced by resveratrol activates AMPK, subsequently stimulating SIRT1 by enhancing NAD⁺ levels. Then, SIRT1 activates key downstream targets through deacetylation (see Section 1.c), ultimately leading to an adaptative potentiation of mitochondrial biogenesis and lipid oxidation pathways. CI-V represent mitochondrial respiratory complexes I-V. The full names for other abbreviations can be found in the main text.

Figure 6. NAD⁺ as a nodal point for metabolic regulation

Most evidence to date points out that NAD⁺ could be rate-limiting for the SIRT1 reaction in diverse conditions. SIRT1 activity would hence be stimulated by interventions which increase NAD⁺ levels, such as AMPK activation, enhancement of NAD⁺ biosynthesis through precursor (NA, NR, NMN) supplementation, or through inhibition of alternative NAD⁺ consuming activities, such as PARPs or CD38. The stimulation of SIRT1 activity by these distinct means improves the capacity of the cells/organism to adapt to external metabolic cues.