Review
Regulation of SIRT1 in cellular functions: Role of polyphenols

https://doi.org/10.1016/j.abb.2010.05.003Get rights and content

Abstract

Sirtuin 1 (SIRT1) is known to deacetylate histones and non-histone proteins including transcription factors thereby regulating metabolism, stress resistance, cellular survival, cellular senescence/aging, inflammation-immune function, endothelial functions, and circadian rhythms. Naturally occurring dietary polyphenols, such as resveratrol, curcumin, quercetin, and catechins, have antioxidant and anti-inflammatory properties via modulating different pathways, such as NF-κB- and mitogen activated protein kinase-dependent signaling pathways. In addition, these polyphenols have also been shown to activate SIRT1 directly or indirectly in a variety of models. Therefore, activation of SIRT1 by polyphenols is beneficial for regulation of calorie restriction, oxidative stress, inflammation, cellular senescence, autophagy/apoptosis, autoimmunity, metabolism, adipogenesis, circadian rhythm, skeletal muscle function, mitochondria biogenesis and endothelial dysfunction. In this review, we describe the regulation of SIRT1 by dietary polyphenols in various cellular functions in response to environmental and pro-inflammatory stimuli.

Introduction

Sirtuins, the class III histone deacetylases (HDACs), are widely distributed and have been shown to regulate a variety of physiopathological processes, such as inflammation, cellular senescence/aging, cellular apoptosis/proliferation, differentiation, metabolism, stem cell pluripotency, and cell cycle regulation. There are seven mammalian enzymes belonging to class III HDACs: SIRT1 to SIRT7. The details of localization, main functions, and substrate of SIRT1 to SIRT7 are given in Table 1. The best characterized and well-studied among the human sirtuins is sirtuin1 (SIRT1), a nuclear protein reported to regulate critical metabolic and physiological processes [1], [2], [3], [4], [5] (Fig. 1). SIRT1, a mammalian ortholog of yeast silent information regulator 2 (Sir2), plays an important role in regulation of pathogenesis of chronic including diabetes, chronic inflammatory pulmonary diseases, neurodegenerative, cardiovascular and chronic renal diseases. Sir2 is the first to be reported to extend lifespan up to 70% in yeast, fly and the nematode via maintaining silent chromatin by deacetylating core histones [6], [7], [8], [9], [10]. The mechanism in regulation of SIRT1 or Sir2 on these processes is due to its ability to deacetylate histones and non-histone proteins, such as nuclear factor (NF)-κB, forkhead box class O (FOXO) 3, p53, peroxisome proliferator-activated receptor (PPAR)-γ, PPAR-γ coactivator 1α (PGC-1α), and endothelial nitric oxide synthase (eNOS) [2], [3], [4].

Polyphenols, such as resveratrol, quercetin, and catechins, have been shown to activate SIRT1 either directly or indirectly in vitro and in vivo[11], [12], [13], [14], [15], [16]. Hence, the activation of SIRT1 by polyphenols would be beneficial in therapeutic intervention of a variety of chronic diseases. This review focuses on cellular and biological functions of SIRT1 and its regulation by polyphenols. Understanding the role and mechanisms of polyphenols in SIRT1 regulation and cellular functions will help in identification of pharmacological agents for their possible use as nutraceuticals in management of chronic diseases.

Section snippets

SIRT1 regulation by nicotinamide adenine dinucleotide (NAD+)

Unlike class I and II HDACs, SIRT1 activity requires NAD+ as cofactor and is not inhibited by trichostatin A [17]. SIRT1 removes acetyl groups from proteins by transferring the acetyl group to NAD+, generating two metabolites; 2′-O-acetyl-ADP-ribose and nicotinamide (NAM). Thus, the deacetylating activity of SIRT1 can be inhibited by the reaction product, NAM [8], [9], [18], [19]. There are two different routes of NAD+ biosynthesis in yeast and mammalian cells i.e. de novo production and

Polyphenols and SIRT1 activators

Polyphenols are secondary metabolites of plants and represent a vast group of compounds having aromatic ring(s), characterized by presence of one or more hydroxyl groups with varying structural complexities. The most widely distributed group of plant phenolics are flavonoids. The flavonoids subclasses comprise of flavonols, flavones, isoflavones, antocyanidins, and others. The commonly studied dietary polyphenols, such as resveratrol, quercetin, and catechins, have been reported to possess

In calorie restriction (CR)

Sir2 has been identified as one of the key proteins in not only establishing the transcriptional silencing via deacetylating histone H4 at lys16 (K16), but also extending the lifespan in yeast, C. elegans, and drosophila [9], [70]. CR is the major mechanism known to extend the lifespan of organisms. Activation and regulation of SIRT1 has been extensively studied in understanding the underlying mechanism of CR-mediated lifespan extension. Activation of Sir2 or mammalian SIRT1 has been shown to

Conclusions and future directions

The yeast Sir2 or mammalian ortholog SIRT1 has been identified as key regulator of lifespan in several model organisms. Activation of SIRT1 by polyphenols have beneficial effects on regulation of CR, oxidative stress, inflammation, adipogenesis, cellular senescence, autophagy, apoptosis, differentiaton, circadian rhythm, autoimmunity, stem cell pluripotency skeletal muscle function, metabolism, mitochondria biogenesis, and endothelial dysfunction. However, the molecular mechanism of these

Acknowledgments

This study was supported by the NIH 1R01HL085613, 1R01HL097751, 1R01HL092842 and NIEHS Environmental Health Science Center Grant P30-ES01247.

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