scholarly journals A Molecular Perspective on Sirtuin Activity

2020 ◽  
Vol 21 (22) ◽  
pp. 8609 ◽  
Author(s):  
Carla S. S. Teixeira ◽  
Nuno M. F. S. A. Cerqueira ◽  
Pedro Gomes ◽  
Sérgio F. Sousa
Keyword(s):  
Metabolic Diseases ◽  
Research Field ◽  
Special Focus ◽  
Lysine Acetylation ◽  
Protein Acetylation ◽  
Considerable Effort ◽  
Special Group ◽  
Amino Terminal ◽  
Age Related ◽  
Lysine Deacetylases

The protein acetylation of either the α-amino groups of amino-terminal residues or of internal lysine or cysteine residues is one of the major posttranslational protein modifications that occur in the cell with repercussions at the protein as well as at the metabolome level. The lysine acetylation status is determined by the opposing activities of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), which add and remove acetyl groups from proteins, respectively. A special group of KDACs, named sirtuins, that require NAD+ as a substrate have received particular attention in recent years. They play critical roles in metabolism, and their abnormal activity has been implicated in several diseases. Conversely, the modulation of their activity has been associated with protection from age-related cardiovascular and metabolic diseases and with increased longevity. The benefits of either activating or inhibiting these enzymes have turned sirtuins into attractive therapeutic targets, and considerable effort has been directed toward developing specific sirtuin modulators. This review summarizes the protein acylation/deacylation processes with a special focus on the current developments in the sirtuin research field.

Mutations of Nuclear and Mitochondrial Genomes as Potential Targets for the Treatment of Metabolic Syndrome

2018 ◽  
Vol 24 (15) ◽  
pp. 1711-1716 ◽  
Author(s):  
Elena V. Galitsyna ◽  
Andrey V. Zhelankin ◽  
Igor A. Sobenin ◽  
Alexander N. Orekhov
Keyword(s):  
Metabolic Syndrome ◽  
Mitochondrial Dna ◽  
Affect Regulation ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Mitochondrial Genomes ◽  
Special Focus ◽  
Age Related ◽  
The Individual

In addition to external factors, such as exercise, food and the environment, genetic predisposition makes great contribution to the development of metabolic disorders and cardiovascular disease. This review is aimed to examine the genetic basis of complex metabolic disorders conventionally described as "metabolic syndrome" (MetS), with the special focus on currently known mutations in the nuclear and mitochondrial genomes, which are associated with both the individual components of MetS and combinations thereof, and also on the studies of the relationship of MetS phenotype as a binary trait. The defects in the mitochondrial genome should be considered as one of the possible genetic reasons leading to MetS. It is known that mitochondrial dysfunction is closely associated with metabolic disorders, as mitochondria are the center of energy metabolism. Consequently, the changes in mitochondrial genes and their functions affect regulation of metabolism. Until now, the role of mitochondrial DNA damage in the development of cardiovascular diseases, age-related and metabolic disorders is still poorly understood. The results of performed studies would help assessing the role of mitochondrial DNA mutations in susceptibility to metabolic syndrome and related metabolic diseases.

scholarly journals The Orphan Nuclear Receptor 4A1: A Potential New Therapeutic Target for Metabolic Diseases

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Lei Zhang ◽  
Qun Wang ◽  
Wen Liu ◽  
Fangyan Liu ◽  
Ailing Ji ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Nuclear Receptor ◽  
Metabolic Diseases ◽  
Early Response ◽  
Orphan Receptor ◽  
Special Focus ◽  
Orphan Nuclear Receptor ◽  
Physiological Functions ◽  
The Impact

Orphan nuclear receptor 4A1 (NR4A1) is a transcriptional factor of the nuclear orphan receptor (NR4A) superfamily that has sparked interest across different research fields in recent years. Several studies have demonstrated that ligand-independent NR4A1 is an immediate-early response gene and the protein product is rapidly induced by a variety of stimuli. Hyperfunction or dysfunction of NR4A1 is implicated in various metabolic processes, including carbohydrate metabolism, lipid metabolism, and energy balance, in major metabolic tissues, such as liver, skeletal muscle, pancreatic tissues, and adipose tissues. No endogenous ligands for NR4A1 have been identified, but numerous compounds that bind and activate or inactivate nuclear NR4A1 or induce cytoplasmic localization of NR4A1 have been identified. This review summarizes recent advances in our understanding of the molecular biology and physiological functions of NR4A1. And we focus on the physiological functions of NR4A1 receptor to the development of the metabolic diseases, with a special focus on the impact on carbohydrate and lipid metabolism in skeletal muscle, liver, adipose tissue, and islet.

SGLT2 inhibitors as calorie restriction-mimetics: insights on longevity pathways and age-related diseases

Endocrinology ◽  
2021 ◽  
Author(s):  
Caroline W S Hoong ◽  
Marvin W J Chua
Keyword(s):  
Calorie Restriction ◽  
Stress Resistance ◽  
Target Genes ◽  
Metabolic Diseases ◽  
Vascular Inflammation ◽  
Sglt2 Inhibitors ◽  
Acid Oxidation ◽  
The Metabolic Syndrome ◽  
Age Related ◽  
Energy Deprivation

Abstract SGLT2 inhibitors induce glycosuria, reduce insulin levels, promote fatty acid oxidation and ketogenesis. By promoting a nutrient deprivation state, SGLT2 inhibitors upregulate the energy deprivation sensors AMPK and SIRT1, inhibit the nutrient sensors mTOR and insulin/IGF-1, and modulate the closely-linked HIF-2α/HIF-1α pathways. Phosphorylation of AMPK and upregulation of adiponectin and PPAR-α favour a reversal of the metabolic syndrome which have been linked to suppression of chronic inflammation. Downregulation of insulin/IGF1 pathways and mTOR signalling from a reduction in glucose and circulating amino acids promote cellular repair mechanisms including autophagy and proteostasis which confer cellular stress resistance and attenuate cellular senescence. SIRT1, another energy sensor activated by NAD+ in nutrient-deficient states, is reciprocally activated by AMPK, and can deacetylate and activate transcription factors such as PCG-1α, TFAM and NRF2 that regulate mitochondrial biogenesis. FOXO3 transcription factor which target genes in stress resistance, is also activated by AMPK and SIRT1. Modulation of these pathways by SGLT2 inhibitors have been shown to alleviate metabolic diseases, attenuate vascular inflammation and arterial stiffness, improve mitochondrial function and reduce oxidative stress-induced tissue damage. Compared to other calorie restriction mimetics such as metformin, rapamycin, resveratrol and NAD+ precursors, SGLT2 inhibitors appear to be the most promising in the treatment of ageing-related diseases, due to its regulation of multiple longevity pathways that closely resemble that achieved by calorie restriction, and their established efficacy in reduction in cardiovascular events and all-cause mortality. Evidence is compelling for the role of SGLT2 inhibitors as a calorie restriction mimetic in anti-ageing therapeutics.

scholarly journals La sénescence en passe d’être vaincue ?

2018 ◽  
Vol 34 (10) ◽  
pp. 885-890 ◽  
Author(s):  
Bertrand Jordan
Keyword(s):  
Murine Model ◽  
Clinical Studies ◽  
Research Field ◽  
Positive Effects ◽  
Age Related ◽  
Active Research

Senescent cells are involved in many age-related diseases, and the effects of their elimination by “senolytic” drugs is an active research field. A recent paper describes a convenient murine model of induced senescence and uses it to convincingly demonstrate the positive effects of senolytics on performance and lifespan. Clinical studies have already been initiated; this approach hold promise to eventually improve human “healthspan”.

scholarly journals Comment on ‘YcgC represents a new protein deacetylase family in prokaryotes’

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Magdalena Kremer ◽  
Nora Kuhlmann ◽  
Marius Lechner ◽  
Linda Baldus ◽  
Michael Lammers
Keyword(s):  
Lysine Acetylation ◽  
Post Translational Modification ◽  
Donor Molecule ◽  
Acetyl Coa ◽  
Lysine Deacetylases ◽  
Protein Deacetylase ◽  
New Protein

Lysine acetylation is a post-translational modification that is conserved from bacteria to humans. It is catalysed by the activities of lysine acetyltransferases, which use acetyl-CoA as the acetyl-donor molecule, and lysine deacetylases, which remove the acetyl moiety. Recently, it was reported that YcgC represents a new prokaryotic deacetylase family with no apparent homologies to existing deacetylases (Tu et al., 2015). Here we report the results of experiments which demonstrate that YcgC is not a deacetylase.

Comprehensive analysis of protein acetylation and glucose metabolism inmouse brains infected with rabies virus

2021 ◽  
Author(s):  
Jie Pei ◽  
Yueming Yuan ◽  
Dayong Tian ◽  
Fei Huang ◽  
Chengguang Zhang ◽  
...  
Keyword(s):  
Immune Response ◽  
Enzyme Activity ◽  
Glucose Metabolism ◽  
Infected Mouse ◽  
Rabies Virus ◽  
Comprehensive Analysis ◽  
Energy Requirements ◽  
Lysine Acetylation ◽  
Protein Acetylation ◽  
Substrate Level

Rabies, caused by rabies virus (RABV), is a widespread zoonosis that is nearly 100% fatal. Alteration of the metabolic environment affects viral replication and the immune response during viral infection. In this study, glucose uptake was increased in mouse brains at the late stage of infection with different RABV strains (lab-attenuated CVS strain and wild-type DRV strain). To illustrate the mechanism underlying glucose metabolism alteration, comprehensive analysis of lysine acetylation and target analysis of energy metabolites in mouse brains infected with CVS and DRV strains were performed. A total of 156 acetylated sites and 115 acetylated proteins were identified as significantly different during RABV infection. Compared to CVS- and mock-infected mice, the lysine acetylation levels of glycolysis and tricarboxylic acid (TCA) cycle enzymes were decreased, and enzyme activity was upregulated in DRV-infected mouse brains. Metabolomic analysis revealed that high levels of oxaloacetate (OAA) in RABV-infected mouse brains. Specifically, the OAA level in CVS-infected mouse brains was higher than that in DRV-infected mouse brains, which contributed to the enhancement of the metabolic rate at the substrate level. Finally, we confirmed that OAA could reduce excessive neuroinflammation in CVS-infected mouse brains by inhibiting JNK and P38 phosphorylation. Taken together, this study provides fresh insight into the different strategies the host adapts to regulate glucose metabolism for energy requirements after different RABV strain infection and suggest that OAA treatment could be a potential strategy to prevent neural damage during RABV infection. IMPORTANCE Both viral replication and the host immune response are highly energy-dependent. It is important to understand how the rabies virus affects energy metabolism in the brain. Glucose is the direct energy source for cell metabolism. Previous studies have revealed that there is some association between acetylation and metabolic processes. In this study, comprehensive protein acetylation and glucose metabolism analysis were conducted to compare glucose metabolism in mouse brains infected with different RABV strains. Our study demonstrates that the regulation of enzyme activity by acetylation and OAA accumulation at the substrate level are two strategies for the host to respond to the energy requirements after RABV infection. Our study also indicates the potential role OAA could play in neuronal protection by suppressing excessive neuroinflammation.

Deep learning based prediction of reversible HAT/HDAC-specific lysine acetylation

2019 ◽  
Vol 21 (5) ◽  
pp. 1798-1805 ◽  
Author(s):  
Kai Yu ◽  
Qingfeng Zhang ◽  
Zekun Liu ◽  
Yimeng Du ◽  
Xinjiao Gao ◽  
...  
Keyword(s):  
Deep Learning ◽  
Protein Interactions ◽  
Web Server ◽  
Data Sets ◽  
Lysine Acetylation ◽  
Protein Acetylation ◽  
Protein Protein Interactions ◽  
Cellular Processes ◽  
Protein Lysine Acetylation ◽  
Specific Regulation

Abstract Protein lysine acetylation regulation is an important molecular mechanism for regulating cellular processes and plays critical physiological and pathological roles in cancers and diseases. Although massive acetylation sites have been identified through experimental identification and high-throughput proteomics techniques, their enzyme-specific regulation remains largely unknown. Here, we developed the deep learning-based protein lysine acetylation modification prediction (Deep-PLA) software for histone acetyltransferase (HAT)/histone deacetylase (HDAC)-specific acetylation prediction based on deep learning. Experimentally identified substrates and sites of several HATs and HDACs were curated from the literature to generate enzyme-specific data sets. We integrated various protein sequence features with deep neural network and optimized the hyperparameters with particle swarm optimization, which achieved satisfactory performance. Through comparisons based on cross-validations and testing data sets, the model outperformed previous studies. Meanwhile, we found that protein–protein interactions could enrich enzyme-specific acetylation regulatory relations and visualized this information in the Deep-PLA web server. Furthermore, a cross-cancer analysis of acetylation-associated mutations revealed that acetylation regulation was intensively disrupted by mutations in cancers and heavily implicated in the regulation of cancer signaling. These prediction and analysis results might provide helpful information to reveal the regulatory mechanism of protein acetylation in various biological processes to promote the research on prognosis and treatment of cancers. Therefore, the Deep-PLA predictor and protein acetylation interaction networks could provide helpful information for studying the regulation of protein acetylation. The web server of Deep-PLA could be accessed at http://deeppla.cancerbio.info.

The origin of intermuscular adipose tissue and its pathophysiological implications

2009 ◽  
Vol 297 (5) ◽  
pp. E987-E998 ◽  
Author(s):  
Roberto Vettor ◽  
Gabriella Milan ◽  
Chiara Franzin ◽  
Marta Sanna ◽  
Paolo De Coppi ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Metabolic Diseases ◽  
High Plasma ◽  
Stem Cell Population ◽  
Phenotypic Switch ◽  
Mesenchymal Progenitors ◽  
Intermuscular Adipose Tissue ◽  
Pathological Conditions ◽  
Age Related ◽  
Mitochondrial Ros

The intermuscular adipose tissue (IMAT) is a depot of adipocytes located between muscle bundles. Several investigations have recently been carried out to define the phenotype, the functional characteristics, and the origin of the adipocytes present in this depot. Among the different mechanisms that could be responsible for the accumulation of fat in this site, the dysdifferentiation of muscle-derived stem cells or other mesenchymal progenitors has been postulated, turning them into cells with an adipocyte phenotype. In particular, muscle satellite cells (SCs), a heterogeneous stem cell population characterized by plasticity and self-renewal that allow muscular growth and regeneration, can acquire features of adipocytes, including the abilities to express adipocyte-specific genes and accumulate lipids. Failure to express the transcription factors that direct mesenchymal precursors into fully differentiated functionally specialized cells may be responsible for their phenotypic switch into the adipogenic lineage. We proved that human SCs also possess a clear adipogenic potential that could explain the presence of mature adipocytes within skeletal muscle. This occurs under some pathological conditions (i.e., primary myodystrophies, obesity, hyperglycemia, high plasma free fatty acids, hypoxia, etc.) or as a consequence of thiazolidinedione treatment or simply because of a sedentary lifestyle or during aging. Several pathways and factors (PPARs, WNT growth factors, myokines, GEF-GAP-Rho, p66shc, mitochondrial ROS production, PKCβ) could be implicated in the adipogenic conversion of SCs. The understanding of the molecular pathways that regulate muscle-to-fat conversion and SC behavior could explain the increase in IMAT depots that characterize many metabolic diseases and age-related sarcopenia.

scholarly journals Identification of Lysine Acetylation Sites on MERS-CoV Replicase pp1ab

2020 ◽  
Vol 19 (8) ◽  
pp. 1303-1309 ◽  
Author(s):  
Lin Zhu ◽  
Sin-Yee Fung ◽  
Guangshan Xie ◽  
Lok-Yin Roy Wong ◽  
Dong-Yan Jin ◽  
...  
Keyword(s):  
Viral Proteins ◽  
Bioinformatic Analysis ◽  
Hek293 Cells ◽  
Lysine Acetylation ◽  
Protein Acetylation ◽  
Conservation Level ◽  
Life Threatening ◽  
Infected Cells ◽  
Orbitrap Analysis ◽  
First Time

MERS is a life-threatening disease and MERS-CoV has the potential to cause the next pandemic. Protein acetylation is known to play a crucial role in host response to viral infection. Acetylation of viral proteins encoded by other RNA viruses have been reported to affect viral replication. It is therefore of interest to see whether MERS-CoV proteins are also acetylated. Viral proteins obtained from infected cells were trypsin-digested into peptides. Acetylated peptides were enriched by immunoprecipitation and subject to nano-LC-Orbitrap analysis. Bioinformatic analysis was performed to assess the conservation level of identified acetylation sites and to predict the upstream regulatory factors. A total of 12 acetylation sites were identified from 7 peptides, which all belong to the replicase polyprotein pp1ab. All identified acetylation sites were found to be highly conserved across MERS-CoV sequences in NCBI database. Upstream factors, including deacetylases of the SIRT1 and HDAC families as well as acetyltransferases of the TIP60 family, were predicted to be responsible for regulating the acetylation events identified. Western blotting confirms that acetylation events indeed occur on pp1ab protein by expressing NSP4 in HEK293 cells. Acetylation events on MERS-CoV viral protein pp1ab were identified for the first time, which indicate that MERS-CoV might use the host acetylation machinery to regulate its enzyme activity and to achieve optimal replication. Upstream factors were predicted, which might facilitate further analysis of the regulatory mechanism of MERS-CoV replication.

Sign in / Sign up

Export Citation Format

Share Document