SIRT1 Activation by Natural Phytochemicals: An Overview (original) (raw)
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Role of Sirtuin 1 in metabolic regulation
Drug Discovery Today, 2010
Sirtuin proteins are an evolutionarily conserved family of NAD +-dependent protein deacetylases. Originally discovered in yeast as gene-silencing proteins, they subsequently emerged as key regulators of life span in yeast and other lower species. Recent identification and characterization of mammalian Sirtuin homologs have revealed a widespread spectrum of biological activities in gene regulation linked to cell survival, cell apoptosis and metabolism. These findings have stimulated several drug discovery efforts. Here, we review current knowledge of the biological functions and possible pharmacological implications of Sirtuin 1, the most characterized member of the mammalian Sirtuin family, in glucose and fat metabolism.
Sirtuin functions and modulation: from chemistry to the clinic
Clinical Epigenetics, 2016
Sirtuins are NAD +-dependent histone deacetylases regulating important metabolic pathways in prokaryotes and eukaryotes and are involved in many biological processes such as cell survival, senescence, proliferation, apoptosis, DNA repair, cell metabolism, and caloric restriction. The seven members of this family of enzymes are considered potential targets for the treatment of human pathologies including neurodegenerative diseases, cardiovascular diseases, and cancer. Furthermore, recent interest focusing on sirtuin modulators as epigenetic players in the regulation of fundamental biological pathways has prompted increased efforts to discover new small molecules able to modify sirtuin activity. Here, we review the role, mechanism of action, and biological function of the seven sirtuins, as well as their inhibitors and activators.
Redox Biology, 2019
Sirtuin-1 (SirT1) catalyzes NAD +-dependent protein lysine deacetylation and is a critical regulator of energy and lipid metabolism, mitochondrial biogenesis, apoptosis, and senescence. Activation of SirT1 mitigates metabolic perturbations associated with diabetes and obesity. Pharmacologic molecules, cellular redox, and nutritional states can regulate SirT1 activity. Technical barriers against measuring endogenous SirT1 activity have limited characterization of SirT1 in disease and its activation by small molecules. Herein, we developed a relative quantitative mass spectrometrybased technique for measuring endogenous SirT1 activity (RAMSSAY/RelAtive Mass Spectrometry Sirt1 Activity assaY) in cell and tissue homogenates using a biotin-labeled, acetylated p53-derived peptide as a substrate. We demonstrate that oxidative and metabolic stress diminish SirT1 activity in the hepatic cell line HepG2. Moreover, pharmacologic molecules including nicotinamide and EX-527 attenuate SirT1 activity; purported activators of SirT1, the polyphenol S17834, the polyphenol resveratrol, or the non-polyphenolic Sirtris compound SRT1720, failed to activate endogenous SirT1 significantly. Furthermore, we provide evidence that feeding a high fat high sucrose diet (HFHS) to mice inhibits endogenous SirT1 activity in mouse liver. In summary, we introduce a robust, specific and sensitive mass spectrometry-based assay for detecting and quantifying endogenous SirT1 activity using a biotin-labeled peptide in cell and tissue lysates. With this assay, we determine how pharmacologic molecules and metabolic and oxidative stress regulate endogenous SirT1 activity. The assay may also be adapted for other sirtuin isoforms.
Sirtuin 1 and Sirtuin 3: Physiological Modulators of Metabolism
Physiological Reviews, 2012
The sirtuins are a family of highly conserved NAD ϩ -dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes. Two sirtuins that are central to the control of metabolic processes are mammalian sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), which are localized to the nucleus and mitochondria, respectively. Both are activated by high NAD ϩ levels, a condition caused by low cellular energy status. By deacetylating a variety of proteins that induce catabolic processes while inhibiting anabolic processes, SIRT1 and SIRT3 coordinately increase cellular energy stores and ultimately maintain cellular energy homeostasis. Defects in the pathways controlled by SIRT1 and SIRT3 are known to result in various metabolic disorders. Consequently, activation of sirtuins by genetic or pharmacological means can elicit multiple metabolic benefits that protect mice from diet-induced obesity, type 2 diabetes, and nonalcoholic fatty liver disease.
Molecular and Cellular Endocrinology, 2009
Calorie restriction (CR) is a non-genetic manipulation that reliably results in extended lifespan of several species ranging from yeast to dogs. The lifespan extension effect of CR has been strongly associated with an increased level and activation of the Sir2 histone deacetylase and its mammalian ortholog Sirt1. This association led to the search for potential Sirt1-activating, life-extending molecules. This review briefly outlines the experimental findings on resveratrol and other dietary activators of Sirt1.
Regulation of SIRT1 in cellular functions: Role of polyphenols
Archives of Biochemistry and Biophysics, 2010
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, and 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.
International Journal of Molecular Sciences
Sirtuins (SIRTs), enzymes from the family of NAD+-dependent histone deacetylases, play an important role in the functioning of the body at the cellular level and participate in many biochemical processes. The multi-directionality of SIRTs encourages scientists to undertake research aimed at understanding the mechanisms of their action and the influence that SIRTs have on the organism. At the same time, new substances are constantly being sought that can modulate the action of SIRTs. Extensive research on the expression of SIRTs in various pathological conditions suggests that regulation of their activity may have positive results in supporting the treatment of certain metabolic, neurodegenerative or cancer diseases or this connected with oxidative stress. Due to such a wide spectrum of activity, SIRTs may also be a prognostic markers of selected pathological conditions and prove helpful in assessing their progression, especially by modulating their activity. The article presents and...
International Journal of Molecular Sciences, 2021
Natural products have long been used as drugs to treat a wide array of human diseases. The lead compounds discovered from natural sources are used as novel templates for developing more potent and safer drugs. Natural products produce biological activity by binding with biological macromolecules, since natural products complement the protein-binding sites and natural product–protein interactions are already optimized in nature. Sirtuin 6 (SIRT6) is an NAD+ dependent histone deacetylase enzyme and a unique Sirtuin family member. It plays a crucial role in different molecular pathways linked to DNA repair, tumorigenesis, glycolysis, gluconeogenesis, neurodegeneration, cardiac hypertrophic responses, etc. Thus, it has emerged as an exciting target of several diseases such as cancer, neurodegenerative diseases, aging, diabetes, metabolic disorder, and heart disease. Recent studies have shown that natural compounds can act as modulators of SIRT6. In the current review, a list of natural ...
Sirtuins: novel targets for metabolic disease
Current opinion in investigational drugs (London, England : 2000), 2008
Sirtuins represent a novel family of enzymes that are collectively well situated to help regulate nutrient sensing and utilization, metabolic rate and ultimately metabolic disease. Activation of one of these enzymes, SIRT1, leads to enhanced activity of multiple proteins, including peroxisome-proliferator activated receptor coactivator-1alpha (PGC-1alpha), which helps to mediate some of the in vitro and in vivo effects of sirtuins. As such, enhanced SIRT1 activity decreases glucose levels, improves insulin sensitivity, increases mitochondrial number and function, decreases adiposity, improves exercise tolerance and potentially lowers body weight. SRT-501 is a proprietary formulation of resveratrol with improved bioavailability. As such, SRT-501 represents the first in a novel class of SIRT1 activators that has proven to be safe and well-tolerated in humans. Clinical trials in type 2 diabetic patients are currently underway.