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Sirtuin Signaling Pathway

Figure1. Sirtuin signaling pathway.

Sirtuin overview

Post-translational modifications play an important role in cells, such as DNA recognition, protein-protein interactions, catalytic activity, and protein stability. Protein acetylation/deacetylation is a histone covalent modification that is mainly catalyzed by histone acetylase and histone deacetylase, respectively. There are four types of HDAC, and sirtuin belongs to the third class of HDAC, which is homologous to the yeast transcriptional repressor Sir2. The Sirtuin protein family plays an important role in different cellular processes such as apoptosis, mitochondrial biosynthesis, lipid metabolism, fatty acid oxidation, cellular stress response, insulin secretion, and aging.

Sirtuin family

The yeast silencing regulator 2 (Sir2) protein and sirtuin in other prokaryotic and eukaryotic organisms are a class of proteins that belong to deacetylases and/or ADP ribose that are highly conserved depending on NAD+. As early as 1979, it was discovered that the sir2 gene plays a very important role in maintaining the mating type of yeast, the length of telomeres, and the generation of rDNA-encoded DNA repeats. The reason why researchers are paying more and more attention to the sirtuin protein family is that it has been found that Sir2 plays an important role in life regulation. The sir2 gene can extend the lifespan of the yeast by inhibiting genomic instability. Knocking out the sir2 gene can significantly shorten the lifespan of the yeast, while an additional sir2 gene copy can extend the yeast life by about 40%. It was subsequently found that Sir2.1, a homolog of Sir2 overexpressing in the nematode, prolonged the lifespan of nematodes by 50%, and similar phenomena were found in fruit flies. The Sirtuin protein family also plays an important role in the life extension process caused by caloric restriction, but studies in the online insect and fruit fly in 2011 questioned the relationship between Sir2 and lifespan. The Sirtuin protein family is a NAD+-dependent protein deacetylase and/or ADP ribosyltransferase, suggesting that the sirtuin protein family may act as a receptor for NAD+ and is closely related to glycolipid metabolism. At the same time, due to the discovery of the important role of Sir2 in calorie restriction, research on the sirtuin protein family has also become a hot spot in the field of metabolism. The Sirtuin protein family is involved in a series of physiological and pathological processes in living organisms and is closely related to glycolipid metabolism, lifespan regulation, stress response, inflammatory response, and tumor formation. The mammalian sirtuin protein family has seven members (SIRT1~SIRT7), all of which have highly conserved NAD+ binding domains and catalytic domains, and the different N-terminus and C-terminus allow them to bind to different substrates. The Sirtuin protein family regulates acetylation and/or ADP ribosyl modification of a variety of proteins. The Sirtuin protein family has different subcellular localizations. SIRT1, SIRT 6 and SIRT 7 are mainly located in the nucleus, SIRT3, SIRT4, and SIRT5 are located in the mitochondria, while SIRT2 is mainly distributed in the cytoplasm. The subcellular localization of these proteins also depends on cell type, status, and intermolecular interactions, such as SIRT1 and SIRT2, which shuttle between the nucleus and cytoplasm and interact with proteins in the nucleus and cytoplasm.

Sirtuin signaling pathway

  1. Sirtuin signaling pathway cascade
    SIRT1 in the liver primarily regulates gluconeogenesis, glycolysis, insulin sensitivity, fatty acid oxidation, and cholesterol metabolism. In the event of excess energy, the liver can store energy by synthesizing glycogen and forming lipid droplets. Recent studies have shown that SIRT1 is widely involved in glycolipid metabolism in the liver. In the case of short-term starvation, SIRT1 can inhibit the gluconeogenesis key factor TORC2, thereby inhibiting gluconeogenesis and lowering blood glucose concentration. Under long-term starvation conditions, SIRT1 deacetylates and activates PGC1-α and PPARα, which promotes oxidation of fatty acids and improves glucose homeostasis. In the long-term starvation state, SIRT1 also promotes gluconeogenesis and inhibits glycolysis by deacetylating FOXO1 and STAT3. SIRT1 is also involved in the regulation of insulin sensitivity in hepatocytes. Overexpression of SIRT1 by the adenovirus in the liver can alleviate endoplasmic reticulum stress in obese mice, improve insulin sensitivity, and alleviate fatty liver. In addition, SIRT1 regulates glycolipid metabolism by deacetylating CREB. The use of adenovirus to reduce the expression of SIRT1 in the liver of mice leads to a decrease in the expression of fatty acid oxidation-related genes in starvation. Specific knockdown of the fourth exon of the sirt1 gene in mouse liver results in the expression of a SIRT1 protein in the liver of mice that is deficient in enzyme activity. This mouse induces fatty acid oxidation in the liver when induced by a high-fat diet. The ability is weakened, and it is more prone to dyslipoproteinemia, fatty liver, inflammatory response and endoplasmic reticulum stress induced by a high-fat diet. Knocking out the fifth and sixth exons of the sirt1 gene in the liver of mice resulted in fatty liver in the normal diet. SIRT1 also regulates transcription factors such as LXR, FXR, and SREBP to regulate lipid and cholesterol metabolism. LXR and FXR are important receptors for cholesterol and bile acid, and they are all activated by deacetylation of SIRT1. SREBP is a key regulator of lipid synthesis and cholesterol synthesis, and they can also be deacetylated by SIRT1. Some small molecule compounds, such as resveratrol, increase the enzymatic activity of SIRT1, and both in vivo and in vitro experiments have shown that these compounds inhibit the expression of downstream genes SREBP. In summary, these findings suggest that SIRT1 in the liver plays an important role in glycolipid metabolism, and activation of SIRT1 may be useful in the treatment of metabolic diseases. The brain can regulate the metabolic balance of the whole body through the nervous and endocrine systems. Calorie restriction and starvation both increase the expression of SIRT1 in the hypothalamus. Deletion of SIRT1 in the mouse brain results in defects in the anterior pituitary cells, and the pituitary does not respond to caloric restriction; neuronal activity in the hypothalamus is enhanced after mouse brain-specific overexpression of SIRT1. These results suggest that SIRT1 in the brain affects the secretion of hypothalamic/pituitary hormones and participates in the process of calorie restriction to delay aging in mammals. SIRT1 is involved in the regulation of rhythms. SIRT1 binds to CLOCK/BMAL1 and regulates the expression of rhythmic genes by deacetylating PER2 and BMAL1, but it is not clear whether the SIRT1 protein level or its enzyme activity has a rhythmic change. NADT, the rate-limiting enzyme of NAD+ biosynthesis, can be directly regulated by CLOCK/BMAL1, which may be the molecular mechanism of NAD+ and SIRT1 enzyme activity rhythm changes. These studies link CLOCK/BMAL1, NAMPT, NAD+, and SIRT1 to provide a possible molecular mechanism for the regulation of metabolic rhythms.
  2. Pathway regulation and clinical research
    Many reports indicate that SIRT1 is involved in several metabolic pathways including fat production, insulin secretion, glucose synthesis, and mitochondrial biosynthesis, suggesting that activation of SIRT1 may have a good effect on obese or diabetic patients. As mentioned above, energy limitation can increase the expression of SIRT1 and prolong life. Several new SIRT1 agonists, including resveratrol, have been discovered through chemical library screening, which appears to mimic certain effects of energy limitation in a variety of organisms. At present, new compounds have been found to act in the same way as resveratrol in vitro and animal disease models. From this point of view, SIRT1 activators have good application prospects in many therapeutic fields including type 2 diabetes, inflammation, neurodegenerative diseases, and heart diseases. Modification of SIRT1 activity and other sirtuin enzymes may provide a new platform for drug development. At present, the treatment of diabetes has great deficiencies, such as weight gain and hypoglycemia and pancreatic juice failure after chronic treatment. The data so far show that SIRT1 agonists can increase glucose homeostasis without the above side effects. However, SIRT1 is a novel target, and its agonist needs further research in the field of clinical therapy. Sirtuins also play an important role in vascular biology, which may regulate age-related atherosclerosis. This effect may be due in part to the regulation of lipid and cholesterol metabolism, including the regulation of nuclear receptor LXR activity by SIRT1. In addition, when SIRT1 is deleted in endothelial cells, the vascular effects after ischemic injury will be destroyed. SIRT1 also deacetylates nitric oxide synthase (NOS), an important regulator of angiotensin in endothelial cells, to regulate its activity. However, the results are interesting because, in the mouse model, energy limitation has been shown to promote mitochondrial biosynthesis via a NOS-dependent pathway. Other sirtuins can also affect vascular physiology, such as SIRT7-deficient mice exhibiting cardiovascular abnormalities, and the important vasoconstrictor, angiotensin II, regulates SIRT3 expression. It fully demonstrates the role of sirtuins in aging-related diseases and further discovery of downstream target proteins requires more work, and this type of protein may become a new and effective therapeutic target for limiting life-threatening diseases.

References:

  1. Bonda D J, Lee H G, Camins A, et al. The sirtuin pathway in ageing and Alzheimer disease: mechanistic and therapeutic consideration. Lancet Neurology. 2011, 10(3):275-279.
  2. Rangarajan P, Karthikeyan A, Lu J, et al. Sirtuin 3 regulates Foxo3a-mediated antioxidant pathway in microglia. Neuroscience. 2015, 311:398-414.
  3. Mouchiroud L, Houtkooper R H, Moullan N, et al. The NAD + /Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling. Cell. 2013, 154(2):430-441.
  4. Fifel K. Sirtuin 3: a molecular pathway linking sleep deprivation to neurological diseases. Journal of Neuroscience. 2014, 34(28):9179-81.
  5. Jamal J, Mustafa M R, Wong P F. Paeonol protects against premature senescence in endothelial cells by modulating Sirtuin 1 pathway. Journal of Ethnopharmacology. 2014, 154(2):428-436.

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