Mammalian Sirt1: insights on its biological functions

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Mammalian Sirt1: insights on its biological functions Empty Mammalian Sirt1: insights on its biological functions

Post by Cr6 on Tue Apr 26, 2016 1:01 am

Mammalian Sirt1: insights on its biological functions

Cell Communication and Signaling20119:11
DOI: 10.1186/1478-811X-9-11
©  Rahman and Islam; licensee BioMed Central Ltd. 2011
Received: 8 November 2010
Accepted: 8 May 2011
Published: 8 May 2011


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Sirt1 (mammalian) is a member of the sirtuin family [1]. It is a nicotinamide adenosine dinucleotide (NAD)-dependent deacetylase and removes acetyl groups from many histone and nonhistone proteins [2]. Sirt1 can deacetylate a variety of substrates and is, therefore, involved in a broad range of physiological functions, including control of gene expression, metabolism and aging [1, 3, 4]. Sirt1 catalyzes an enzymatic reaction that generates nicotinamide and the acetyl group of the substrate is transferred to cleaved NAD, generating a unique metabolite, O-acetyl-ADP ribose [2]. The list of Sirt1 substrates is continuously growing and includes several transcription factors: the tumor suppressor protein p53, members of the FoxO family (forkhead box factors regulated by insulin/Akt), HES1 (hairy and enhancer of split 1), HEY2 (hairy/enhancer-of-split related with YRPW motif 2), PPARγ (peroxisome proliferator-activated receptor gamma), CTIP2 [chicken ovalbumin upstream promoter transcription factor (COUPTF)- interacting protein 2], p300, PGC-1α (PPARγ coactivator), and NF-κB (nuclear factor kappa B) [14]. In this review we will discuss some of the most relevant biological and pathophysiological functions of Sirt1 [1].

Biological functions

Sirt1 and obesity-associated metabolic diseases

Hepatic metabolic derangements are key components in the development of fatty liver, insulin resistance, and atherosclerosis. Sirt1 is an important regulator of energy homeostasis in response to nutrient availability. Scientists demonstrated that hepatic Sirt1 regulates lipid homeostasis by positively regulating peroxisome proliferators-activated receptor α (PPARα), a nuclear receptor that mediates the adaptive response to fasting and starvation. Hepatocyte-specific deletion of Sirt1 impairs PPARα signaling and decreases fatty acid β-oxidation, whereas overexpression of Sirt1 induces the expression of PPARα targets. Sirt1 interacts with PPARα and is required to activate PPARα coactivator PGC-1α. When challenged with a high-fat diet, liver-specific Sirt1 knockout (KO) mice develop hepatic steatosis, hepatic inflammation, and endoplasmic reticulum stress [5]. Present research data indicate that Sirt1 plays a vital role in the regulation of hepatic lipid homeostasis and that pharmacological activation of Sirt1 may be important for the prevention of obesity associated metabolic diseases [5]. Other research also shows that manipulation of Sirt1 levels in the liver affects the expression of a number of genes involved in glucose and lipid metabolism [6]. Additionally, recent studies demonstrated that modest overexpression of Sirt1 resulted in a protective effect against high fat induced hepatic steatosis and glucose intolerance [7, 8]. Sirt1 orthologs also play a critical role in controlling SREBP-dependent gene regulation governing lipid/cholesterol homeostasis in metazoans in response to fasting cues. These findings may have important biomedical implications for the treatment of metabolic disorders associated with aberrant lipid/cholesterol homeostasis, including metabolic syndrome and atherosclerosis [9]. Sirt1 regulates uncoupling protein 2 (UCP2) in beta cells to affect insulin secretion. Regulation of UCP2 by Sirt1 may also be an important axis that is dysregulated by excess fat to contribute to obesity induced diabetes [10].

Sirt1 is a positive regulator of liver X receptor (LXR) proteins [11, 12], nuclear receptors that function as cholesterol sensors and regulate whole-body cholesterol and lipid homeostasis. LXR acetylation is evident at a single conserved lysine (K432 in LXRα and K433 in LXRβ) adjacent to the ligand-regulated activation domain AF2 [2]. Sirt1 interacts with LXR and promotes deacetylation and subsequent ubiquitination. Mutations of K432 eliminate activation of LXRα by this sirtuin [11]. Loss of Sirt1 in vivo reduces expression of a variety of LXR targets involved in lipid metabolism, including ABCA1, an ATP-binding cassette (ABC) transporter that mediates an early step of HDL biogenesis [2, 11]. Altogether these findings suggest that deacetylation of LXRs by Sirt1 may be a mechanism that affects atherosclerosis and other aging-associated diseases [11].

Above information suggests that Sirt1 is involved in regulation of obesity-associated metabolic diseases through regulating PGC-1α, UCP2 and LXR proteins.

Cancer and Sirt1

It has been shown that Sirt1 is significantly elevated in human prostate cancer [13], acute myeloid leukemia [14], and primary colon cancer [15]. Overexpression of Sirt1 was frequently observed in all kinds of non-melanoma skin cancers including squamous cell carcinoma, basal cell carcinoma, Bowen's disease, and actinic keratosis [16]. Based on the elevated levels of Sirt1 in cancers, it was hypothesized that Sirt1 serves as a tumor promoter [17]. The first evidence of Sirt1 as a tumor promoter came from experiments showing that Sirt1 physically interacts with p53 and attenuates p53-mediated functions through deacetylation of p53 at its C-terminal Lys382 residue [18, 19]. In addition, two recent studies demonstrated that DBC1 (deleted in breast cancer-1), which was initially cloned from a region (8p21) homozygously deleted in breast cancer, forms a stable complex with Sirt1 and inhibits Sirt1 activity, leading to increased levels of p53 acetylation and upregulation of p53-mediated function. Consistently, knockdown of DBC1 by RNA interference (RNAi) promoted Sirt1 mediated deacetylation of p53 and inhibited p53-mediated apoptosis induced by genotoxic stress. These effects were reversed in cells by concomitant RNAi-mediated knockdown of endogenous Sirt1 [20, 21]. Sirt1 is also involved in epigenetic silencing of DNA-hypermethylated tumor suppressor genes (TSGs) in cancer cells (Figure 1). Inhibition of Sirt1 by multiple approaches (pharmacologic, over expression of a dominant negative protein or short interfering RNA) leads to TSG re-expression and a block in tumor-causing networks of cell signaling that are activated by loss of the TSGs in a wide range of cancers. Furthermore, Sirt1 inhibition causes re-expression of the E-cadherin gene (in breast and colon cancer cell lines), whose protein product complexes with β-catenin, and this gene reactivation collectively may suppress the constitutive activation of the WNT signaling pathway [22]. Sirt1 acts as a critical modulator of endothelial angiogenic functions. Inhibition of endogenous Sirt1 gene expression prevents the formation of a vascular-like network in vitro. Overexpression of wild-type Sirt1, but not of a deacetylase-defective mutant of Sirt1 (Sirt1 H363Y) [18, 19], increased the sproutforming and migratory activity of endothelial cells [23].
Mammalian Sirt1: insights on its biological functions 12964_2010_Article_224_Fig1_HTML

Figure 1
Activation and inhibition of many cellular processes by Sirt1.


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