SIRT1

SIRT1 (silent information regulator two protein) is a type III protein deacetylase that regulates a variety of important metabolic and physiologic processes including stress resistance, metabolism, apoptosis and energy balance. It reverses cholesterol transport and reduces risk for development of atherosclerosis and cardiovascular disease. The following review highlights the potential role of SIRT1 on cardiovascular biology and function.

Adult neurogenesis plays increasingly recognized roles in brain homeostasis and repair and is profoundly affected by energy balance and nutrients. We found that the expression of Hes-1 (hairy and enhancer of split 1) is modulated in neural stem and
progenitor cells (NSCs) by extracellular glucose through the coordinated action of CREB (cyclic AMP responsive element binding protein) and Sirt-1 (Sirtuin 1), two cellular nutrient sensors. Excess glucose reduced CREB-activated Hes-1 expression
and results in impaired cell proliferation. CREB-deficient NSCs expanded poorly in vitro and did not respond to glucose availability. Elevated glucose also promoted Sirt-1-dependent repression of the Hes-1 promoter. Conversely, in low glucose, CREB replaced Sirt-1 on the chromatin associated with the Hes-1 promoter enhancing Hes-1 expression and cell proliferation. Thus, the glucose-regulated antagonism between CREB and Sirt-1 for Hes-1 transcription participates in the metabolic regulation of neurogenesis.

The sirtuin family comprises seven NAD+-dependent deacetylases which control the overall health of organisms through the regulation of pleiotropic metabolic pathways. Sirtuins are important modulators of adipose tissue metabolism and their expression is higher in lean than obese subjects. At present, the role of sirtuins in adipose-derived stem cells has not been investigated yet. Therefore, in this study, we evaluated the expression of the complete panel of sirtuins in adipose-derived stem cells isolated from both subcutaneous and visceral fat of non-obese and obese subjects. We aimed at investigating the influence of obesity on sirtuins’ levels, their role in obesity-associated inflammation, and the relationship with the peroxisome proliferator-activated receptor delta, which also plays functions in adipose tissue metabolism. The mRNA levels in the four types of adipose-derived stem cells were evaluated by quantitative polymerase chain reaction, in untreated cells and also after 8 h of hypoxia exposure. Correlations among sirtuins’ expression and clinical and molecular parameters were also analyzed. We found that sirtuin1–6 exhibited significant higher mRNA expression in visceral adipose-derived stem cells compared to subcutaneous adipose-derived stem cells of non-obese subjects. Sirtuin1–6 levels were markedly reduced in visceral adipose-derived stem cells of obese patients. Sirtuins’ expression in visceral adipose-derived stem cells correlated negatively with body mass index and C-reactive protein and positively with peroxisome proliferator-activated receptor delta. Finally, only in the visceral adipose-derived stem cells of obese patients hypoxia-induced mRNA expression of all of the sirtuins. Our results highlight that sirtuins’ levels in adipose-derived stem cells are consistent with protective effects against visceral obesity and inflammation, and suggest a transcriptional mechanism through which acute hypoxia up-regulates sirtuins in the visceral adipose-derived stem cells of obese patients.

Background and objectives: Sirtuin-1 (SIRT1) is a conserved a NAD +-dependent protein deacetylase essential for cellular metabolism and defence against oxidative stress and endothelial dysfunction. This study aimed to compare effects of 8 weeks of aerobic and combined training on serum level of SIRT1 and PGC1-α in coronary artery bypass graft patients. Methods: In this semi-experimental study, 45 non-active men (mean age 47.4 ± 3.3 years) who had undergone coronary artery bypass graft surgery were randomly divided into three groups: aerobic training, combined resistance and aerobic training and control. Trainings were performed at 80% of maximum heart rate, three sessions a week for 8 weeks. Blood samples were collected 24 hours before the first exercise session and 48 hours after the last training session. T-test and one-way analysis of variance were used for assessment of within-group and between-group differences, respectively. P-values less than 0.05 were considered as statistically significant. Results: The 8-week aerobic and combined training increased serum levels of SIRT1 and PGC-1α compared with the control group, and significantly decreased the weight of subjects (p=0.001). There was no significant difference in serum levels of SIRT1 and PGC-1α between the two training groups (P≥0.05). Conclusion: Both combined and aerobic training significantly improve the SIRT1 and PGC-1α levels in coronary artery bypass graft patients.

Background and Objectives: Cardiac rehabilitation improves functional capacity of post-coronary artery bypass grafting (CABG) patients. Therefore, the aim of this study was to evaluate effects of eight weeks of cardiac rehabilitation on serum levels of sirutin1 (SIRT1) and functional capacity of post-CABG patients. Methods: Forty-five non-active men (mean age: 47.4 ± 3.3 years, duration of disease: 150 ± 69.12 months) were randomly divided into three equal groups: aerobic exercise, combined (resistance and aerobic) exercise and control. The subjects performed trainings at 60-75% of maximum heart rate, three sessions a week for eight weeks. Blood samples were collected 24 hours before the first exercise session and 48 hours after the last exercise session. Data were analyzed with SPSS 16.0 using one-way ANOVA and the Tukey post hoc test. P-values less than 0.05 were considered statistically significant. Results: Aerobic and combined exercise increased serum SIRT1 levels and functional capacity. There was no significant decrease in body mass index (P=0.06). The SIRT1 level did not differ significantly between the two exercise groups after the intervention (P=0.91). There were significant difference between the study groups in terms of the travelled distance (P<0.034). Conclusion: Both combined and aerobic exercise can increase serum levels of SIRT1, reduce body mass index and improve functional capacity in CABG patients.

Lin28 is a small RNA-binding protein that plays an important role in regulating developmental timing, stem cell reprogramming, and oncogenesis. However, the significance of the effect of post-translational modifications on Lin28 activity is not fully understood. In this study, we demonstrated that PCAF directly interacted with and acetylated Lin28. We also showed that the acetylation of Lin28 can be specifically reversed by the deacetylase SIRT1. These findings suggest that the PCAF/SIRT1 balance plays an important role in regulating Lin28 activity. Furthermore, we found that the cold shock domain of Lin28 is the major target of PCAF-mediated acetylation, which leads to a severe reduction in the Lin28 protein levels and an increase in the level of mature let-7a. This study provides the first demonstration that post-translational modification regulates Lin28 activity during let-7a biogenesis and sheds light on the regulation of Lin28 in ES cells and carcinogenesis.

Sirtuins, the mammalian homologs of the silent information regulator 2 gene of Saccharomyces cerevisiae, are members of the NAD(+)-dependent family of histone deacetylases. In vertebrates, 7 sirtuins have been described, with different cellular localizations and target proteins. Glucose and lipid metabolism are among the processes regulated by these enzymes. In ruminants, gluconeogenesis is the main biochemical pathway by which glucose is obtained. Because sirtuins in bovines have not been studied, the aim of this work was to obtain sequences coding for the 7 sirtuins and determine the expression patterns of sirtuin1 (Sirt1) and sirtuin3 (Sirt3) in the liver, muscle, and adipose tissue of calves and bulls. Using PCR amplification, we obtained sirtuin gene sequences and reported them to the National Center for Biotechnology Information GenBank. Characteristic sequence motifs corresponding to the sirtuin catalytic core domain were found, including the active and zinc-binding sites. Relative expression patterns of Sirt1 and Sirt3 in liver, muscle, and adipose tissue were quantified by real-time PCR, normalizing to the geometric mean of the housekeeping genes cyclophilin A and β-actin. Expression of Sirt1 was less in liver and muscle, whereas it was greater in adipose tissue of adult animals, with statistical differences (P=0.0071) only in the latter. In the case of Sirt3, expression was greater in all 3 adult tissues, but statistical differences were found only in liver (P=0.0141) and muscle (P=0.0017). The greatest expression was observed in liver for Sirt1 and in muscle for Sirt3, whereas the least expression was in muscle for Sirt1 and in adipose tissue for Sirt3. In other species, sirtuin expression (both Sirt1 and Sirt3) in liver is reported to be the greatest among these 3 tissues, a pattern different from what we measured. These differences in expression can be associated with metabolic differences between nonruminant and ruminant species. However, further research on the relationship between bovine sirtuins and ruminant metabolism is required for a better understanding of these fields.

Background and Objectives: Sirtuin (SIRT), Fibroblast Growth Factor21 (FGF21) and Fetuin A are proteins that cause a wide range of metabolic disorders such as type 2 diabetes mellitus (T2DM). On the other hand, regular physical activity is known to play a key role in prevention and management of T2DM. Thus, this study investigated the effect of vigorous aerobic exercise on serum levels of metabolic parameters including SIRT1, FGF21 and Fetuin A in women with T2DM. Methods: The study was performed on 28 randomly selected women with T2DM who were divided into an exercise group and a control group. The training intervention consisted eight weeks of vigorous aerobic exercise (three times a week at 70-80% of maximum heart rate). The serum levels of SIRT1, FGF21 and Fetuin A were evaluated before the first session and 48 hours after the last session. Paired sample t-test and independent t-test were used to analyze within and between group differences, respectively. All statistical analyses were performed in SPSS (version 19) at significance of 0.05. Results: The eight-week aerobic training caused a significant reduction in body weight, body mass index, insulin resistance, low-density lipoprotein, fasting blood sugar, triglycerides and Fetuin A of women with T2DM. In addition, it caused a significant increase in SIRT1 and FGF21 levels. There was no significant difference in the level of high-density lipoprotein and cholesterol between the two groups. Conclusion: As a non-pharmacological therapy, regular aerobic exercise might improve the metabolic parameters, SIRT1, FGF21, and Fetuin A in women with T2DM.

Sirtuins (Sirt) are NAD-dependent
deacetylases that are activated by the antioxidants resveratrol
(RSV) and lipoic acid (LA). The objective of
this study was to determine in bovine liver and muscle
slice cultures the effect of RSV and LA treatment on
the expresssion of Sirt1, Sirt3, peroxisome proliferator-
activated receptor γ coactivator 1α (PPARGC1A),
and the forkhead box O transcription factors FoxO1
and FoxO3 as well as other factors involved in glucose
and lipid metabolism and related to Sirt activity.
Tissue slices from crossbred bulls were treated during
60 min with 40 or 80 μM RSV and 30, 100, 300,
or 1,000 μM LA under restricted conditions (Krebs-
Ringer buffer without nutrients) and fed conditions
(2.5 mM propionate in combination with 1 nM glucagon)
for liver slices or with 0.01 μM epinephrine for
muscle slices. Quantitative real-time PCR was used
to analyze the expression of the mRNA for the genes
studied and western blot analysis for the expression
of the protein for Sirt1. Our results show that the
expression of the mRNA for Sirt1 was enhanced by
RSV in liver under restriction (P ≤ 0.0112) and by
LA in muscle, more under restriction (P ≤ 0.0121)
than after epinephrine administration (P < 0.0001).
Sirt3 is affected in a dose-dependent manner by both
compounds in both tissues and under both metabolic
conditions (P ≤ 0.0452). The expression of the protein
for Sirt1 was increased by LA in both tissues under
restricted conditions (P = 0.0026 and P = 0.0201,
respectively) but in liver also in fed conditions (P =
0.0016). Genes involved in the antioxidant response
were upregulated in both tissues. These results indicate
that bovine Sirt respond differently to RSV and
LA stimulation than monogastric Sirt do and that
gluconeogenesis in ruminants is not related to Sirt to
the same degree as in monogastric species. However,
these results provide information about the possible
role of Sirt in ruminant metabolism.

Background: Hepatic steatosis is among the most common causes of chronic liver diseases, although established effective treatments are not evident.  Previous studies reported that Kurozu improved hypercholesterolemia and carbohydrate metabolism. However, the effect of Kurozu on the incidence of hepatic steatosis is not clear.
Objective: The effect of Kurozu on the onset of hepatic steatosis by administering a high-fat diet (HFD) for 110 weeks was evaluated in C57BL/6J mice.
Methods: HFD treatment for 110 weeks accelerated the onset of hepatic steatosis more than a standard diet, whereas concentrated Kurozu (CK) supplementation ameliorated the effect of an HFD feeding. The effect of supplementation with resveratrol in an HFD on the onset of hepatic steatosis was also evaluated. To elucidate the mechanism of the effect of Kurozu on the expression of lipid metabolism genes, acute treatment for 10 days with Kurozu was also examined.
Results: Supplementation with resveratrol in HFD-fed mice did not ameliorate hepatic steatosis. Body weights were significantly lower in the CK + HFD and Resveratrol + HFD groups than in the control HFD group in middle age. No significant differences in all-cause mortality were observed following supplementation with CK or resveratrol. CK and resveratrol supplements significantly inhibited decreases in dehydroepiandrosterone sulphate serum levels at postnatal week 120. CK and resveratrol supplements did not affect the survival of mice. The ingestion of Kurozu for 10 days significantly elevated the expression levels of Sirt1, Pgc-1α, Lpin1, and Igfbp1 in the liver.
Conclusion: These results suggest that ingesting CK may delay the onset of hepatic steatosis HFD feeding causes.

Diabetic nephropathy is a leading cause of end-stage renal failure. Approximately
20-40% patients with diabetes mellitus will develop nephropathy with a significant proportion
requiring regular dialysis or kidney transplantation. The International Diabetes Federation
estimates that 366 million people had diabetes worldwide in 2011 and 552 million people will
have this disease by 2030.1 The increasing incidence of diabetes elevates diabetic nephropathy
to one of the most important current public health issues, representing a significant burden on
the health system.2 Despite current interventional strategies being intensively implemented,
the number of patients with diabetes requiring renal replacement therapy for end-stage renal
disease is growing.3 Current treatments of diabetic nephropathy slow its progression,3 so the
optimal therapeutic strategy to arrest or reverse the nephropathy is needed urgently. As multiple
risk factors and their interactions promote the development of diabetic nephropathy, targeting
a single factor may be ineffective in the treatment of this disease; thus, optimal treatments by
targeting multiple factors need to be developed to arrest or reverse the diabetic nephropathy.