SIRTUINS 4º part

SIRT1 regulates various metabolic processes that allow the cell to adapt to nutrient stress and has a pivotal role in aging-related metabolic diseases. In response to fasting, SIRT1 modulates gluconeogenesis in the liver through deacetylation of important factors, such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), forkhead box protein O1 (FOXO1) and cAMP response element-binding (CREB)-regulated transcription coactivator 2 (CRTC2) (Brunet et al., 2004; Liu et al., 2008; Motta et al., 2004; Rodgers et al., 2005). In the early phase of fasting, CRTC2 is activated through its acetylation by the co-activator CBP/p300, which then promotes transcription of gluconeogenic genes. If fasting is prolonged, SIRT1 deacetylates both CRTC2 and FOXO1, which leads to a switch from activation of early gluconeogenic genes through CRTC2 to the activation of genes involved in the late phase of gluconeogenesis through FOXO1 (Liu et al., 2008). Deacetylation of PGC-1α by SIRT1 not only controls gluconeogenesis, but also fatty acid oxidation in coordination with peroxisome proliferator-activated receptor alpha (PPARα) (Purushotham et al., 2009). PGC1α also regulates mitochondria biogenesis and oxidative phosphorylation, and it has been proposed that these effects are mediated through the AMP-activated protein kinase (AMPK)–SIRT1–PGC1α pathway (Canto et al., 2009; Iwabu et al., 2010). SIRT1 also targets other nuclear receptors, such as the liver X receptor LXRα and the farnesoid X receptor (FXR), which regulate hepatic metabolic processes (Kemper et al., 2009; Li et al., 2007b). SIRT1 deacetylates LXRα and promotes its ubiquitylation, which results in its activation and induction of cholesterol efflux (Li et al., 2007b). In white adipose tissue, SIRT1 regulates fat mobilization through the repression of peroxisome proliferator-activated receptor gamma (PPARγ) by binding to its cofactors, the nuclear receptor co-repressor (NCoR) and silencing mediator of retinoid and thyroid hormone receptors (SMRT) (Picard et al., 2004). In pancreatic β cells, SIRT1 regulates glucose-stimulated insulin secretion through the synthesis of uncoupling protein 2 (UCP2) (Bordone et al., 2006; Moynihan et al., 2005). Transgenic mice that specifically overexpress SIRT1 in pancreatic β cells (the so-called BESTO mice) have improved glucose tolerance when fed with a high fat diet (HFD) (Moynihan et al., 2005). In addition, mice that overexpress SIRT1 from a bacterial artificial chromosome (BAC) construct (the so-called SIRT1 BAC mice) are also protected against HFD-induced type 2 diabetes (Banks et al., 2008; Pfluger et al., 2008). Consistent with these results, compounds that are able to activate SIRT1, such as resveratrol and SRT1720, protect mice from HFD-induced metabolic disorders (Baur et al., 2006; Feige et al., 2008; Lagouge et al., 2006; Milne et al., 2007). In humans, genetic variation in SIRT1 was shown to be correlated with obesity and type 2 diabetes in studies of Dutch populations (Zillikens et al., 2009b; Zillikens et al., 2009a). Taken together, these findings provide strong evidence that SIRT1 has significant roles in metabolic diseases, such as type 2 diabetes and obesity, and controlling SIRT1 activity with nutrients or small molecules could be a valuable treatment strategy.

A number of studies have revealed that SIRT1 mediates different stress responses, including inflammation, hypoxic stress, heat shock and genotoxic stress, and inflammation in particular is a highly important cause of aging and aging related diseases. SIRT1 can suppress inflammation through its effect on nuclear factor-κB (NF-κB) (Yeung et al., 2004); it physically interacts with its RelA subunit and deacetylates lysine 310, which inactivates NF-κB, thereby inhibiting the expression of its target genes. By contrast, during hypoxic condition, SIRT1 activates hypoxia inducible factor 2 alpha (HIF2α) through its deacetylation and thus initiates hypoxic stress responses (Dioum et al., 2009). However, SIRT1 also deacetylates HIF1α at lysine 647 – which, in this case, inhibits its activity – to control glycolysis in response to hypoxic conditions (Lim et al., 2010). During hypoxia, NAD level gradually decrease and, subsequently, SIRT1 is deactivated. Therefore, it has been speculated that SIRT1 triggers a switch from HIF2α to HIF1α activation to coordinate metabolism, vascular formation and hypoxic stress responses (Lim et al., 2010).

SIRT1 is also involved in the transmission of the heat shock response through the heat shock factor protein1 (HSF1) (Westerheide et al., 2009). Upon protein-damage stress that is associated with the accumulation of misfolded proteins, SIRT1 deacetylates and, thereby, positively regulates HSF1 activity, which promotes the transcription of heat shock response genes (Westerheide et al., 2009). Thus, SIRT1 acts as a sensor of various stresses and organizes the survival signals in response to these stresses.

Cardiovascular diseases increase with aging and are also closely influenced by the metabolism. Several lines of evidence show that SIRT1 has pivotal roles in cardiovascular functions. For example, transgenic mice that overexpress SIRT1 in the heart, are protected against age-related cardiac hypertrophy as well as ischemia or reperfusion injury (Alcendor et al., 2007; Hsu et al., 2010). SIRT1 also regulates vascular endothelial cell functions through deacetylation of endothelial nitric oxide synthase (eNOS) (Mattagajasingh et al., 2007). In addition, activation of SIRT1 with resveratrol can ameliorate heart ischemia or reperfusion injury and also improve vascular functions (Orallo et al., 2002). SIRT1 also functions in reactive oxygen species (ROS)-mediated cell death through deacetylation of poly (ADP-ribose) polymerase 1 (PARP1) and, furthermore, deletion of SIRT1 results in the promotion of cardiomyocyes cell death during heart failure (Pillai et al., 2005; Kolthur-Seetharam et al., 2006).