Sirtuins as regulators of metabolism and healthspan

Abstract

Since the beginning of the century, the mammalian sirtuin protein family (comprising SIRT1-SIRT7) has received much attention for its regulatory role, mainly in metabolism and ageing. Sirtuins act in different cellular compartments: they deacetylate histones and several transcriptional regulators in the nucleus, but also specific proteins in other cellular compartments, such as in the cytoplasm and in mitochondria. As a consequence, sirtuins regulate fat and glucose metabolism in response to physiological changes in energy levels, thereby acting as crucial regulators of the network that controls energy homeostasis and as such determines healthspan.

Figure 1. Regulation of sirtuin expression and activity.

a | Various transcription factors regulate sirtuin expression. FOXO1, PPARα, PPARβ/δ and CREB enhance SIRT1 (in green), whereas PPARγ, ChREBP, PARP2 and HIC1 repress SIRT1 expression (in red). Only CREB, ChREBP and PARP2 were also shown to possess this activity in vivo. Sirt1 expression is also repressed by the miRNAs miR-34a and miR-199a. b | Reversible post-translational modifications affect SIRT1 activity. The cyclinB/Cdk1 complex phosphorylates (P) SIRT1 thereby allowing cell cycle progression. Activation of JNK by reactive oxygen species (ROS) results in SIRT1 phosphorylation and subsequent deacetylation of histone H3, but not p53. Genotoxic stress, for instance by UV light or H2O2 exposure, results in desumoylation of SIRT1, inactiving it. Sumoylation (sumo) by a yet unidentified enzyme activates SIRT1. c | Complex formation with other proteins influences SIRT1 enzymatic activity. A complex of NCoR1 and SIRT1 blocks the transcriptional activity of PPARγ. Genotoxic and metabolic (high-fat diet) stress induce DBC1-SIRT1 complex formation, by which DBC1 inactivates SIRT1. Fasting relieves this inactivation. The LSD1-SIRT1 complex represses Notch target gene expression by demethylation and deacetylation of specific histones, but is derepressed by activation of the Notch pathway. Complex formation with AROS activates SIRT1. d | Controlling the levels of the cofactor NAD⁺ governs SIRT1 function. NAD⁺ levels are increased by providing precursors nicotinic acid (NA), nicotinamide (NAM) or nicotinamide riboside (NR), inhibiting its breakdown by means of PARP or CD38 inhibition, or by AMPK activation following energy stress or treatment with the AMPK activator resveratrol. Increased NAD⁺ levels subsequently lead to sirtuin activation.

Figure 2. Overview of sirtuins’ role in the regulation of pathways involved in glucose metabolism.

Red arrows indicate activating effects whereas blue bars denote inhibiting functions. Colored symbols show metabolic processes, genes or proteins, which are affected by the nuclear function(s) of SIRT1 or SIRT6. The involvement of certain specific sirtuins in the control of particular metabolic pathway is indicated with white oval.

Figure 3. Overview of sirtuins’ role in the regulation of lipid metabolism.

Red arrows indicate activating effects whereas blue bars denote inhibiting functions. Colored symbols show metabolic processes, genes or proteins, which are affected by the nuclear function(s) of SIRT1 or SIRT6. The involvement of certain specific sirtuins in the control of particular metabolic pathway is indicated with white oval.

Figure 4. The association of sirtuin activity with metabolic health.

a | Sirtuins influence glucose and lipid metabolism in several tissues. SIRT1 inhibits adipogenesis in 3T3L1 adipocytes. In addition, SIRT1 decreases fat storage by enhances lipolysis through PPARγ in WAT. In pancreas, SIRT1 increases insulin secretion by repressing the transcription of UCP2. In skeletal muscle, SIRT1 attenuates glycolysis via PGC1α and enhances lipid utilization by stimulating PGC1α and PPARα. In the liver, SIRT1 decreases glycolysis via HIF1α and PGC1α and lowers lipid accumulation by suppressing lipid synthesis via SREBP-1c and promoting lipid utilization through PGC1α and PPARα. In addition, SIRT1 regulates hepatic glucose production via PGC1α, CRTC2 and FOXO1, although its exact role in this process is under debate. Using SIRT3 whole-body knock-out mice, it has been demonstrated that during energy limitation, SIRT3 suppresses glycolysis via HIF1α, promotes fatty acid oxidation through LCAD, IDH2 and NDUFA9, protects from ROS by stimulating SOD2 and increases ketone body formation through HMGCS2. Based on in vitro studies, SIRT3 promotes cellular respiration in brown adipocytes via SDH. b | In response to calorie restriction and exercise, the induction of SIRT1 stimulates mitochondrial activity, leading to improved metabolism and disease prevention. During energy limitation, low ATP levels activate AMPK, which in turn induces SIRT1 by increasing NAD⁺ levels. SIRT1 increases mitochondrial activity by decreasing acetylation levels of PGC1α. During calorie excess and sedentary life-style, cellular ATP levels increase, whereas NAD⁺ levels decrease, thereby inhibiting SIRT1. As a result, PGC1α remains acetylated, which leads to decreased mitochondrial activity, predisposing to the development of metabolic diseases.