Abstract
Simple SummaryA vast number of molecules are involved in regulating metabolism in mammals. Among these molecules, Sirtuins play pivotal roles in the regulation of metabolism. Sirtuins are a family of seven members that are expressed in several tissues/organs and connect the inner and outer environment of the mammalian body to ensure a proper balance of metabolic activities. Deregulation of Sirtuins can be involved in a disturbed balance that is found in metabolic diseases such as obesity and cancer. The level and function of Sirtuins differ per tissue/organ and among mammals and shall be taken into account when envisioning administration of drugs that may affect Sirtuin activity. This systematic review provides an overview of the function of Sirtuins in six metabolic tissues/organs, and of the relevant processes that they regulate. Both healthy and metabolic disease conditions are discussed.Sirtuins are a family of highly conserved NAD+-dependent proteins and this dependency links Sirtuins directly to metabolism. Sirtuins’ activity has been shown to extend the lifespan of several organisms and mainly through the post-translational modification of their many target proteins, with deacetylation being the most common modification. The seven mammalian Sirtuins, SIRT1 through SIRT7, have been implicated in regulating physiological responses to metabolism and stress by acting as nutrient sensors, linking environmental and nutrient signals to mammalian metabolic homeostasis. Furthermore, mammalian Sirtuins have been implicated in playing major roles in mammalian pathophysiological conditions such as inflammation, obesity and cancer. Mammalian Sirtuins are expressed heterogeneously among different organs and tissues, and the same holds true for their substrates. Thus, the function of mammalian Sirtuins together with their substrates is expected to vary among tissues. Any therapy depending on Sirtuins could therefore have different local as well as systemic effects. Here, an introduction to processes relevant for the actions of Sirtuins, such as metabolism and cell cycle, will be followed by reasoning on the system-level function of Sirtuins and their substrates in different mammalian tissues. Their involvement in the healthy metabolism and metabolic disorders will be reviewed and critically discussed.
Highlights
Since their discovery, proteins of the mammalian Sirtuin family have been in the spotlight because of their ability to regulate and influence pivotal cellular and molecular processes
Sirtuins act through gene regulation, and through post-translational modification of key proteins that are involved in metabolism, such as the AMP-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K), the mammalian target of rapamycin, the peroxisome proliferator-activated receptor (PPAR) proteins, and several cell cycle proteins such as cyclins and cyclin-dependent kinases (CDKs) and forkhead box (FOX) transcription factors
The role of PI3K/AKT related to insulin response and glucose metabolism has been described earlier; importantly, activated AKT regulates a number of important players in the cell cycle: it inhibits p27Kip1 and localizes FOXO to the cytoplasm [207,208]
Summary
Proteins of the mammalian Sirtuin family have been in the spotlight because of their ability to regulate and influence pivotal cellular and molecular processes. These include aging, metabolism and disease development, among others. Not all the molecular regulations involving Sirtuins’ function have been elucidated Such knowledge might provide insight into how metabolism is regulated in a healthy organism, as well as how metabolic disorders may occur due to Sirtuins’ deregulation. This systematic review attempts to elucidate the specific role that interactions between Sirtuins and their prominent interaction partners play in different mammalian tissues, namely the heart, liver, adipose tissue, skeletal muscle, pancreas and the brain, in relation to metabolism and metabolic disorders
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