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Sirtuins as Players in Cell Metabolism and Functions
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Sirtuins as Players in Cell Metabolism and Functions

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (15 May 2024) | Viewed by 6955

Special Issue Editors

Dr. Antonietta Santoro

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Guest Editor
Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy
Interests: the effects of environmental pollutants on human health; the role of the endocannabinoid system in the processes of carcinogenicity, inflammation, neurogenesis and neuronal differentiation
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Rosaria Meccariello

E-Mail Website
Guest Editor
Department of Movement and Wellness Sciences, Parthenope University of Naples, Via Medina 40, I-80133 Naples, Italy
Interests: endocannabinoid system; endocannabinoids–GnRH–steroids crosstalk; kisspeptins; reproduction; HPG axis; spermatogenesis; spermatozoa; endocrine disruptors; epigenetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Sirtuins or silent information regulator 2 (SIR2) proteins are a family of deacetylases discovered in the 1970s in yeast. Since their discovery, sirtuins have been found in organisms ranging from bacteria to plants, and animals. Different forms of sirtuins are present in the cytoplasm, nucleus and mitochondria thus suggesting a key role for these proteins in regulating cell functions and metabolism. Sirtuins are also epigenetic erasers catalyzing post-translational deacetylation of other proteins in response to environmental cues, thus affecting gene silencing, cell survival, proliferation, and differentiation. Although the precise mechanisms of action of these proteins are still unknown, sirtuins’ dysregulation has been related to the pathogenesis of different diseases and new insights are emerging which suggest that sirtuins are involved in redox signaling, immunomodulation, neurodegeneration, aging, cancer, and reproduction. This highlights their potential to be targeted in pharmacological approaches based on sirtuins’ modulators. Therefore, this Special Issue welcomes comprehensive reviews and research papers which aim to provide an up-to-date report on the role of sirtuins in cell metabolism and functions with particular emphasis on molecular mechanisms and epigenetic effects in living organisms as well as their therapeutic potential in experimental model systems and humans.

Dr. Antonietta Santoro
Prof. Dr. Rosaria Meccariello
Guest Editors

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Keywords

  • sirtuins
  • epigenetics effects
  • SIRT modulators
  • neurodegeneration
  • neuroprotection and neuroimmunology
  • control of reproduction
  • cell metabolism
  • ageing
  • immunomodulation

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Published Papers (6 papers)

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Research

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16 pages, 3086 KiB  
Article
Unveiling Novel Mechanism of CIDEB in Fatty Acid Synthesis Through ChIP-Seq and Functional Analysis in Dairy Goat
by Qiuya He, Weiwei Yao, Jiao Wu, Yingying Xia, Yuanmiao Lei and Jun Luo
Int. J. Mol. Sci. 2024, 25(20), 11318; https://doi.org/10.3390/ijms252011318 - 21 Oct 2024
Viewed by 474
Abstract
Goat milk is abundant in nutrients, particularly in milk fats, which confer health benefits to humans. Exploring the regulatory mechanism of fatty acid synthesis is highly important to understand milk composition manipulation. In this study, we used chromatin immunoprecipitation sequencing (ChIP-seq) on goat [...] Read more.
Goat milk is abundant in nutrients, particularly in milk fats, which confer health benefits to humans. Exploring the regulatory mechanism of fatty acid synthesis is highly important to understand milk composition manipulation. In this study, we used chromatin immunoprecipitation sequencing (ChIP-seq) on goat mammary glands at different lactation stages which revealed a novel lactation regulatory factor: cell death-inducing DFFA-like effector B (CIDEB). RT-qPCR results revealed that CIDEB was significantly upregulated during lactation in dairy goats. CIDEB overexpression significantly increased the expression levels of genes involved in fatty acid synthesis (ACACA, SCD1, p < 0.05; ELOVL6, p < 0.01), lipid droplet formation (XDH, p < 0.05), and triacylglycerol (TAG) synthesis (DGAT1, p < 0.05; GPAM, p < 0.01) in goat mammary epithelial cells (GMECs). The contents of lipid droplets, TAG, and cholesterol were increased (p < 0.05) in CIDEB-overexpressing GMECs, and knockdown of CIDEB led to the opposite results. In addition, CIDEB knockdown significantly decreased the proportion of C16:0 and total C18:2. Luciferase reporter assays indicated that X-box binding protein 1 (XBP1) promoted CIDEB transcription via XBP1 binding sites located in the CIDEB promoter. Furthermore, CIDEB knockdown attenuated the stimulatory effect of XBP1 on lipid droplet accumulation. Collectively, these findings elucidate the critical regulatory roles of CIDEB in milk fat synthesis, thus providing new insights into improving the quality of goat milk. Full article
(This article belongs to the Special Issue Sirtuins as Players in Cell Metabolism and Functions)
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13 pages, 3650 KiB  
Article
Sirtuin 1 Inhibits Fatty Acid Synthesis through Forkhead Box Protein O1-Mediated Adipose Triglyceride Lipase Expression in Goat Mammary Epithelial Cells
by Qiuya He, Weiwei Yao, Li Lv, Xuelin Zhang, Jiao Wu and Jun Luo
Int. J. Mol. Sci. 2024, 25(18), 9923; https://doi.org/10.3390/ijms25189923 - 14 Sep 2024
Viewed by 510
Abstract
Sirtuin 1 (SIRT1) is a key upstream regulator of lipid metabolism; however, the molecular mechanisms by which SIRT1 regulates milk fat synthesis in dairy goats remain unclear. This study aimed to investigate the regulatory roles of SIRT1 in modulating lipid metabolism in goat [...] Read more.
Sirtuin 1 (SIRT1) is a key upstream regulator of lipid metabolism; however, the molecular mechanisms by which SIRT1 regulates milk fat synthesis in dairy goats remain unclear. This study aimed to investigate the regulatory roles of SIRT1 in modulating lipid metabolism in goat mammary epithelial cells (GMECs) and its impact on the adipose triglyceride lipase (ATGL) promoter activity using RNA interference (RNAi) and gene overexpression techniques. The results showed that SIRT1 is significantly upregulated during lactation compared to the dry period. Additionally, SIRT1 knockdown notably increased the expressions of genes related to fatty acid synthesis (SREBP1, SCD1, FASN, ELOVL6), triacylglycerol (TAG) production (DGAT2, AGPAT6), and lipid droplet formation (PLIN2). Consistent with the transcriptional changes, SIRT1 knockdown significantly increased the intracellular contents of TAG and cholesterol and the lipid droplet abundance in the GMECs, while SIRT1 overexpression had the opposite effects. Furthermore, the co-overexpression of SIRT1 and Forkhead box protein O1 (FOXO1) led to a more pronounced increase in ATGL promoter activity, and the ability of SIRT1 to enhance ATGL promoter activity was nearly abolished when the FOXO1 binding sites (FKH1 and FKH2) were mutated, indicating that SIRT1 enhances the transcriptional activity of ATGL via the FKH element in the ATGL promoter. Collectively, our data reveal that SIRT1 enhances the transcriptional activity of ATGL through the FOXO1 binding sites located in the ATGL promoter, thereby regulating lipid metabolism. These findings provide novel insights into the role of SIRT1 in fatty acid metabolism in dairy goats. Full article
(This article belongs to the Special Issue Sirtuins as Players in Cell Metabolism and Functions)
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19 pages, 7304 KiB  
Article
Does Selection for Longevity in Acheta domesticus Involve Sirtuin Activity Modulation and Differential Response to Activators (Resveratrol and Nanodiamonds)?
by Patrycja Ziętara, Barbara Flasz and Maria Augustyniak
Int. J. Mol. Sci. 2024, 25(2), 1329; https://doi.org/10.3390/ijms25021329 - 22 Jan 2024
Viewed by 1162
Abstract
Sirtuins, often called “longevity enzymes”, are pivotal in genome protection and DNA repair processes, offering insights into aging and longevity. This study delves into the potential impact of resveratrol (RV) and nanodiamonds (NDs) on sirtuin activity, focusing on two strains of house crickets [...] Read more.
Sirtuins, often called “longevity enzymes”, are pivotal in genome protection and DNA repair processes, offering insights into aging and longevity. This study delves into the potential impact of resveratrol (RV) and nanodiamonds (NDs) on sirtuin activity, focusing on two strains of house crickets (Acheta domesticus): the wild-type and long-lived strains. The general sirtuin activity was measured using colorimetric assays, while fluorescence assays assessed SIRT1 activity. Additionally, a DNA damage test and a Kaplan–Meier survival analysis were carried out. Experimental groups were fed diets containing either NDs or RV. Notably, the long-lived strain exhibited significantly higher sirtuin activity compared to the wild-type strain. Interestingly, this heightened sirtuin activity persisted even after exposure to RVs and NDs. These findings indicate that RV and NDs can potentially enhance sirtuin activity in house crickets, with a notable impact on the long-lived strain. This research sheds light on the intriguing potential of RV and NDs as sirtuin activators in house crickets. It might be a milestone for future investigations into sirtuin activity and its potential implications for longevity within the same species, laying the groundwork for broader applications in aging and lifespan extension research. Full article
(This article belongs to the Special Issue Sirtuins as Players in Cell Metabolism and Functions)
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17 pages, 102345 KiB  
Article
Epigenomics Analysis of the Suppression Role of SIRT1 via H3K9 Deacetylation in Preadipocyte Differentiation
by Youzhualamu Yang, Wei Peng, Xiaolong Su, Binglin Yue, Shi Shu, Jikun Wang, Changqi Fu, Jincheng Zhong and Hui Wang
Int. J. Mol. Sci. 2023, 24(14), 11281; https://doi.org/10.3390/ijms241411281 - 10 Jul 2023
Cited by 3 | Viewed by 1734
Abstract
Sirtuin 1 (SIRT1) overexpression significantly inhibits lipid deposition during yak intramuscular preadipocyte (YIMA) differentiation; however, the regulatory mechanism remains unknown. We elucidated the role of SIRT1 in YIMA differentiation using lentivirus-mediated downregulation technology and conducted mRNA-seq and ChIP-seq assays using H3K9ac [...] Read more.
Sirtuin 1 (SIRT1) overexpression significantly inhibits lipid deposition during yak intramuscular preadipocyte (YIMA) differentiation; however, the regulatory mechanism remains unknown. We elucidated the role of SIRT1 in YIMA differentiation using lentivirus-mediated downregulation technology and conducted mRNA-seq and ChIP-seq assays using H3K9ac antibodies after SIRT1 overexpression in order to reveal SIRT1 targets during YIMA adipogenesis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed in order to identify the functional annotation of common genes. In addition, a potential target of SIRT1 was selected to verify its effects on the differentiation and proliferation of YIMAs. SIRT1 interfered with lipid deposition and promoted YIMA differentiation. In total, 143,518 specific peaks were identified after SIRT1 overexpression, where genes associated with downregulation peaks were enriched in transcription, gene expression, lipid-related processes, and classical lipid-related pathways. The H3K9ac signal in the whole genome promoter region (2 kb upstream and downstream of the transcription start site (TSS)) was weakened, and the peaks were distributed across all gene functional regions. Genes that lost signals in their TSS region or gene body region were enriched in both biological processes and pathways associated with lipogenesis. The ChIP-seq results revealed 714 common differential genes in mRNA-seq, which were enriched in “MAPK signaling”, “lipid and atherosclerosis”, “mTOR signaling”, and “FoxO signaling” pathways. A total of 445 genes were downregulated in both their H3K9ac signals and mRNA expression, and one of their most significantly enriched pathways was FoxO signaling. Nine genes (FBP2, FPGT, HSD17B11, KCNJ15, MAP3K20, SLC5A3, TRIM23, ZCCHC10, and ZMYM1) lost the H3K9ac signal in their TSS regions and had low mRNA expression, and three genes (KCNJ15, TGM3, and TRIM54) had low expression but lost their H3K9ac signal in the gene body region. The interference of TRIM23 significantly inhibited fat deposition during preadipocyte differentiation and promoted cell proliferation by increasing S-phase cell numbers. The present study provides new insights into the molecular mechanism of intramuscular fat content deposition and the epigenetic role of SIRT1 in adipocyte differentiation. Full article
(This article belongs to the Special Issue Sirtuins as Players in Cell Metabolism and Functions)
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Review

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23 pages, 1747 KiB  
Review
The Role of Mitochondrial Sirtuins (SIRT3, SIRT4 and SIRT5) in Renal Cell Metabolism: Implication for Kidney Diseases
by Florian Juszczak, Thierry Arnould and Anne-Emilie Declèves
Int. J. Mol. Sci. 2024, 25(13), 6936; https://doi.org/10.3390/ijms25136936 - 25 Jun 2024
Cited by 1 | Viewed by 1327
Abstract
Kidney diseases, including chronic kidney disease (CKD), diabetic nephropathy, and acute kidney injury (AKI), represent a significant global health burden. The kidneys are metabolically very active organs demanding a large amount of ATP. They are composed of highly specialized cell types in the [...] Read more.
Kidney diseases, including chronic kidney disease (CKD), diabetic nephropathy, and acute kidney injury (AKI), represent a significant global health burden. The kidneys are metabolically very active organs demanding a large amount of ATP. They are composed of highly specialized cell types in the glomerulus and subsequent tubular compartments which fine-tune metabolism to meet their numerous and diverse functions. Defective renal cell metabolism, including altered fatty acid oxidation or glycolysis, has been linked to both AKI and CKD. Mitochondria play a vital role in renal metabolism, and emerging research has identified mitochondrial sirtuins (SIRT3, SIRT4 and SIRT5) as key regulators of renal cell metabolic adaptation, especially SIRT3. Sirtuins belong to an evolutionarily conserved family of mainly NAD+-dependent deacetylases, deacylases, and ADP-ribosyl transferases. Their dependence on NAD+, used as a co-substrate, directly links their enzymatic activity to the metabolic status of the cell. In the kidney, SIRT3 has been described to play crucial roles in the regulation of mitochondrial function, and the antioxidative and antifibrotic response. SIRT3 has been found to be constantly downregulated in renal diseases. Genetic or pharmacologic upregulation of SIRT3 has also been associated with beneficial renal outcomes. Importantly, experimental pieces of evidence suggest that SIRT3 may act as an important energy sensor in renal cells by regulating the activity of key enzymes involved in metabolic adaptation. Activation of SIRT3 may thus represent an interesting strategy to ameliorate renal cell energetics. In this review, we discuss the roles of SIRT3 in lipid and glucose metabolism and in mediating a metabolic switch in a physiological and pathological context. Moreover, we highlight the emerging significance of other mitochondrial sirtuins, SIRT4 and SIRT5, in renal metabolism. Understanding the role of mitochondrial sirtuins in kidney diseases may also open new avenues for innovative and efficient therapeutic interventions and ultimately improve the management of renal injuries. Full article
(This article belongs to the Special Issue Sirtuins as Players in Cell Metabolism and Functions)
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Other

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8 pages, 763 KiB  
Brief Report
SIRT1 Serum Concentrations in Lipodystrophic Syndromes
by Luisa Salvatori, Silvia Magno, Giovanni Ceccarini, Rossella Tozzi, Savina Contini, Caterina Pelosini, Ferruccio Santini, Lucio Gnessi and Stefania Mariani
Int. J. Mol. Sci. 2024, 25(9), 4785; https://doi.org/10.3390/ijms25094785 - 27 Apr 2024
Viewed by 922
Abstract
Lipodystrophies (LDs) are rare, complex disorders of the adipose tissue characterized by selective fat loss, altered adipokine profile and metabolic impairment. Sirtuins (SIRTs) are class III NAD+-dependent histone deacetylases linked to fat metabolism. SIRT1 plays a critical role in metabolic health [...] Read more.
Lipodystrophies (LDs) are rare, complex disorders of the adipose tissue characterized by selective fat loss, altered adipokine profile and metabolic impairment. Sirtuins (SIRTs) are class III NAD+-dependent histone deacetylases linked to fat metabolism. SIRT1 plays a critical role in metabolic health by deacetylating target proteins in tissue types including liver, muscle, and adipose. Circulating SIRT1 levels have been found to be reduced in obesity and increased in anorexia nervosa and patients experiencing weight loss. We evaluated circulating SIRT1 levels in relation to fat levels in 32 lipodystrophic patients affected by congenital or acquired LDs compared to non-LD subjects (24 with anorexia nervosa, 22 normal weight, and 24 with obesity). SIRT1 serum levels were higher in LDs than normal weight subjects (mean ± SEM 4.18 ± 0.48 vs. 2.59 ± 0.20 ng/mL) and subjects with obesity (1.7 ± 0.39 ng/mL), whereas they were close to those measured in anorexia nervosa (3.44 ± 0.46 ng/mL). Our findings show that within the LD group, there was no relationship between SIRT1 levels and the amount of body fat. The mechanisms responsible for secretion and regulation of SIRT1 in LD deserve further investigation. Full article
(This article belongs to the Special Issue Sirtuins as Players in Cell Metabolism and Functions)
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