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Liu J, Zhen L, Yu D, Wang W. EFFECT AND REGULATORY MECHANISM OF SIRT6 ON POSTCARDIAC ARREST BRAIN INJURY IN RATS. Shock 2025; 63:648-655. [PMID: 39749948 DOI: 10.1097/shk.0000000000002545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
ABSTRACT Aims: Brain injury occupies the predominant cause of neurological dysfunction and mortality after successful cardiopulmonary resuscitation (CPR) from cardiac arrest (CA). This study investigates the role and mechanism of Sirtuin 6 (SIRT6) in postcardiac arrest brain injury in rats. Methods: All rats were subjected to asphyxial CA followed by CPR. Two weeks before modeling, rats were infected with lentivirus containing oe-SIRT6 and oe-FOXO1 through lateral ventricular injection. qRT-PCR and Western blot quantified SIRT6 and FOXO1 expressions in brain tissues. Neurological deficit scores evaluated the neural function of rats at different time points, and Water Maze Test assessed the changes in short-term learning and memory abilities. The survival status of rats 7 days after modeling was recorded. The pathological changes in brain tissues, inflammatory factors, and apoptosis were evaluated by H&E staining, ELISA, and TUNEL, respectively. Ch-IP measured the enrichment of SIRT6 and H3K9ac in the FOXO1 promoter. Results: SIRT6 was poorly expressed while FOXO1 was highly expressed in CA/CPR rats. Elevation of SIRT6 expression alleviated neural function, behavioral ability, and survival rate, as well as abated pathological damage, inflammatory responses, and cell apoptosis in CA/CPR rats. Mechanistically, SIRT6 curbed FOXO1 transcription and expression by lowering the H3K9ac level in the FOXO1 promoter; FOXO1 overexpression abolished the improvement effect of SIRT6 overexpression on brain injury in CA/CPR rats. Conclusions: Elevation of SIRT6 expression restrained the FOXO1 expression by diminishing the H3K9ac level in the FOXO1 promoter, thereby mitigating postcardiac arrest brain injury in rats.
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Affiliation(s)
- Jianxiong Liu
- Department of Emergency Medicine, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
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Akter R, Noor F, Tonmoy HS, Ahmed A. Potential of SIRT6 modulators in targeting molecular pathways involved in cardiovascular diseases and their treatment-A comprehensive review. Biochem Pharmacol 2025; 233:116787. [PMID: 39894306 DOI: 10.1016/j.bcp.2025.116787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 01/09/2025] [Accepted: 01/28/2025] [Indexed: 02/04/2025]
Abstract
Cardiovascular disease (CVD) is the leading cause of mortality and morbidity, accounting for major public health concerns worldwide. CVD poses an immense burden on the global healthcare system and economy. Ischemic heart disease, stroke, heart failure, atherosclerosis, and hypertension are the major diseases belonging to CVDs and ischemic heart diseases and stroke contribute to most CVD-induced deaths. Previously published review articles focused on the role of SIRT6 in CVDs but did not focus on the important role of SIRT6 in modulating the signaling pathways involved in CVDs and targeting them to treat CVDs. Thus, this review aims to identify and delineate the major signaling pathways that are involved in CVDs and whether SIRT6 can modulate those pathways to improve and treat CVDs. Alongside possible applications of small molecule modulators of SIRT6 in cardiovascular disease treatment have been comprehensively analyzed.
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Affiliation(s)
- Raushanara Akter
- School of Pharmacy, KHA 224 Bir Uttam Rafiqul Islam Avenue, Merul Badda, BRAC University, Dhaka 1212, Bangladesh.
| | - Fouzia Noor
- School of Pharmacy, KHA 224 Bir Uttam Rafiqul Islam Avenue, Merul Badda, BRAC University, Dhaka 1212, Bangladesh
| | - Hasan Shahriyer Tonmoy
- School of Pharmacy, KHA 224 Bir Uttam Rafiqul Islam Avenue, Merul Badda, BRAC University, Dhaka 1212, Bangladesh
| | - Ashfaq Ahmed
- School of Pharmacy, KHA 224 Bir Uttam Rafiqul Islam Avenue, Merul Badda, BRAC University, Dhaka 1212, Bangladesh
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Zaretsky A, Venzor AG, Eremenko E, Stein D, Smirnov D, Rabuah Y, Dryer R, Kriukov D, Kaluski-Kopatch S, Einav M, Khrameeva E, Toiber D. SIRT6-dependent functional switch via K494 modifications of RE-1 silencing transcription factor. Cell Death Dis 2024; 15:798. [PMID: 39511137 PMCID: PMC11543946 DOI: 10.1038/s41419-024-07160-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 10/08/2024] [Accepted: 10/15/2024] [Indexed: 11/15/2024]
Abstract
RE-1 silencing transcription factor (REST) is a key repressor of neural genes. REST is upregulated under stress signals, aging and neurodegenerative diseases, but although it is upregulated, its function is lost in Alzheimer's Disease. However, why it becomes inactive remains unclear. Here, we show that the NAD-dependent deacetylase SIRT6 regulates REST expression, location and activity. In the absence of SIRT6, REST is overexpressed but mislocalized, leading to a partial loss of its activity and causing it to become toxic. SIRT6 deficiency abrogates REST and EZH2 interaction, perturbs the location of REST to the heterochromatin Lamin B ring, and leads to REST target gene overexpression. SIRT6 reintroduction or REST methyl-mimic K494M expression rescues this phenotype, while an acetyl-mimic mutant loses its function even in WT cells. Our studies define a novel regulatory switch where, depending on SIRT6 presence, the function of REST is regulated by post-translational modifications on K494 (Ac/me), affecting neuronal gene expression. In WT cells (left), REST functions as a repressor due to its methylation, which allows proper localization and interaction with EZH2. In SIRT6 KO cells (right), REST is overexpressed, but it is mislocalized and acetylated instead of methylated, impairing its interaction with EZH2. REST localizes in the cytoplasm in autophagosomes. The overall increase in REST without SIRT6 results in non-functional and toxic REST proteins. During aging, SIRT6 declines in the brain, while REST is upregulated to protect it. In pathological aging, where SIRT6 levels are very low, the increase in REST without SIRT6 results in non-functional and toxic REST.
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Affiliation(s)
- Adam Zaretsky
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
| | - Alfredo Garcia Venzor
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
| | - Ekaterina Eremenko
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
| | - Daniel Stein
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
| | - Dmitrii Smirnov
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Moscow, 121205, Russia
| | - Yuval Rabuah
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
| | - Rebecca Dryer
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
| | - Dmitrii Kriukov
- Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Moscow, 121205, Russia
| | - Shai Kaluski-Kopatch
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
| | - Monica Einav
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
| | - Ekaterina Khrameeva
- Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Moscow, 121205, Russia
| | - Debra Toiber
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.
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Wei Y, Wang X, Ma Z, Xiang P, Liu G, Yin B, Hou L, Shu P, Liu W, Peng X. Sirt6 regulates the proliferation of neural precursor cells and cortical neurogenesis in mice. iScience 2024; 27:108706. [PMID: 38288355 PMCID: PMC10823065 DOI: 10.1016/j.isci.2023.108706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 11/07/2023] [Accepted: 12/07/2023] [Indexed: 01/31/2024] Open
Abstract
Sirt6, a member of the class III histone deacetylases (HDACs), functions in the regulation of genomic stability, DNA repair, cancer, metabolism and aging. Sirt6 deficiency is lethal, and newborn SIRT6-null cynomolgus monkeys show unfinished brain development. After the generation of a cortex-specific Sirt6 conditional knockout mouse model, we investigated the specific deletion of Sirt6 in NPCs at E10.5. This study found that Sirt6 deficiency causes excessive proliferation of neural precursor cells (NPCs) and retards differentiation. The results suggest that endogenous Sirt6 in NPCs regulates histone acetylation and limits stemness-related genes, including Notch1, in order to participate in NPC fate determination. These findings help elucidate Sirt6's role in brain development and in NPC fate determination while providing data on species generality and differentiation.
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Affiliation(s)
- Yufei Wei
- State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Xinhuan Wang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Zhihua Ma
- State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Pan Xiang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Gaoao Liu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Bin Yin
- State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Lin Hou
- State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Pengcheng Shu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Wei Liu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Xiaozhong Peng
- State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
- Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China
- State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
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Jia J, Tao W, Chen T, Zhong Q, Sun J, Xu Y, Sui X, Chen C, Zhang Z. SIRT6 Improves Hippocampal Neurogenesis Following Prolonged Sleep Deprivation Through Modulating Energy Metabolism in Developing rats. Mol Neurobiol 2024; 61:883-899. [PMID: 37668962 DOI: 10.1007/s12035-023-03585-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 08/14/2023] [Indexed: 09/06/2023]
Abstract
OBJECTIVE Prolonged sleep deprivation is known to have detrimental effects on the hippocampus during development or in adulthood. Furthermore, it is well-established that sleep deprivation disrupts energy metabolism broadly. SIRT6 is a critical regulator of energy metabolism in both central and peripheral tissues. This study aims to investigate the role of SIRT6 in modulating hippocampal neurogenesis following sleep deprivation during development, and elucidate the underlying mechanism. METHODS Male Sprague-Dawley rats, aged three weeks, were subjected to 2 weeks of sleep deprivation using the modified multiple platform method. Metabolomic profiling was carried out using the liquid chromatography-electrospray ionization-tandem mass spectrometry (LC‒ESI‒MS/MS). To investigate the role of SIRT6 in energy metabolism, the rats were administered with either the SIRT6-specific inhibitor, OSS128167, or SIRT6-overexpressing adeno-associated virus (AAV). Hippocampal neurogenesis was assessed by immunostaining with markers for neural stem cells (SOX2), immature neurons [doublecortin (DCX)] and newborn cells (BrdU). Sparse labeling of adult neurons was used to determine the density of dendritic spines in the dentate gyrus (DG). The Y-maze and novel object recognition (NOR) tests were performed to evaluate the spatial and recognition memory. SIRT6 expression was examined using immunofluorescence and western blotting (WB). The inhibition of SIRT6 was confirmed by assessing the acetylation of histone 3 lysine 9 (aceH3K9), a well-known substrate of SIRT6, through WB. RESULTS Sleep deprivation for a period of two weeks leads to inhibited hippocampal neurogenesis, reduced density of dendritic spines in the DG, and impaired memory, accompanied by decreased SIRT6 expression and disrupted energy metabolism. Similar to sleep deprivation, administration of OSS128167 significantly decreased energy metabolism, leading to reduced neurogenesis and memory dysfunction. Notably, the abnormal hippocampal energy metabolism, neurogenetic pathological changes and memory dysfunction caused by sleep deprivation were alleviated by SIRT6 overexpression in the DG. CONCLUSION Our results suggest that SIRT6 plays a critical role in maintaining energy metabolism homeostasis in the hippocampus after sleep deprivation, promoting hippocampal neurogenesis and enhancing memory during development.
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Affiliation(s)
- Junke Jia
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, 430071, Hubei, China
| | - Wanjiang Tao
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, 430071, Hubei, China
| | - Ting Chen
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, 430071, Hubei, China
| | - Qi Zhong
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, 430071, Hubei, China
| | - Jiahui Sun
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, 430071, Hubei, China
| | - Yutong Xu
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, 430071, Hubei, China
| | - Xiaokai Sui
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, 430071, Hubei, China
| | - Chang Chen
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, 430071, Hubei, China.
| | - Zongze Zhang
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, 430071, Hubei, China.
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Jain R, Epstein JA. Epigenetics. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1441:341-364. [PMID: 38884720 DOI: 10.1007/978-3-031-44087-8_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2024]
Abstract
Epigenetics is the study of heritable changes to the genome and gene expression patterns that are not caused by direct changes to the DNA sequence. Examples of these changes include posttranslational modifications to DNA-bound histone proteins, DNA methylation, and remodeling of nuclear architecture. Collectively, epigenetic changes provide a layer of regulation that affects transcriptional activity of genes while leaving DNA sequences unaltered. Sequence variants or mutations affecting enzymes responsible for modifying or sensing epigenetic marks have been identified in patients with congenital heart disease (CHD), and small-molecule inhibitors of epigenetic complexes have shown promise as therapies for adult heart diseases. Additionally, transgenic mice harboring mutations or deletions of genes encoding epigenetic enzymes recapitulate aspects of human cardiac disease. Taken together, these findings suggest that the evolving field of epigenetics will inform our understanding of congenital and adult cardiac disease and offer new therapeutic opportunities.
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Affiliation(s)
- Rajan Jain
- Departments of Medicine and Cell and Developmental Biology, Institute for Regenerative Medicine, Epigenetics Institute and the Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
| | - Jonathan A Epstein
- Departments of Medicine and Cell and Developmental Biology, Institute for Regenerative Medicine, Epigenetics Institute and the Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
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Zhu J, Cheng X, Naumovski N, Hu L, Wang K. Epigenetic regulation by quercetin: a comprehensive review focused on its biological mechanisms. Crit Rev Food Sci Nutr 2023; 65:627-646. [PMID: 38062765 DOI: 10.1080/10408398.2023.2278760] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2025]
Abstract
Epigenetics regulates gene expression and play significant roles across diverse disease states. Epigenetics mechanisms, including DNA methylation, histone modifications, microRNAs/lncRNA, and N6-methyladenosine (m6A) RNA methylation, elicit heritable but reversible modifications in gene expression without modifying the DNA sequence. Recent research suggests that certain natural phytochemicals with chemopreventive properties have the potential to function as epigenetic regulators. Quercetin, a derivative of natural flavonoid glycosides and a constituent of the human diet, is linked to a variety of health benefits including anti-inflammatory, anticancer activity, antiapoptotic, antihypertensive, and neuroprotective effects. Recent findings suggest that quercetin possesses the ability to modulate canonical biochemical signaling pathways and exert an impact on epigenetic networks. This review aims to synthesize the most recent research findings that elucidate the potential biological effects of quercetin and its influence on in vitro and in vivo models via epigenetic mechanisms. In light of our findings, it is evident that quercetin possesses the potential to function as an exemplary instance of naturally derived phytochemicals, which can be effectively employed as a pivotal constituent in functional foods and dietary supplements aimed at the amelioration of various ailments. More specifically, its mechanism of action involves the alteration of diverse epigenetic targets.
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Affiliation(s)
- Jinfeng Zhu
- School for Radiological and interdisciplinary Sciences (RAD-X) and Collaborative Innovation Centre of Radiation Medicine of Jiangsu Higher Education Institutions. Soochow University, Suzhou, China
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Roma, Italy
| | - Xiaju Cheng
- School for Radiological and interdisciplinary Sciences (RAD-X) and Collaborative Innovation Centre of Radiation Medicine of Jiangsu Higher Education Institutions. Soochow University, Suzhou, China
| | - Nenad Naumovski
- Discipline of Nutrition and Dietetics, Faculty of Health, University of Canberra, Bruce, Canberra, ACT, Australia
- Functional Foods and Nutrition Research (FFNR) Laboratory, University of Canberra, Ngunnawal Country, Canberra, ACT, Australia
- University of Canberra Research Institute for Sport and Exercise (UCRISE), University of Canberra, Canberra, ACT, Australia
- Department of Nutrition-Dietetics, Harokopio University, Athens, Greece
| | - Lin Hu
- School for Radiological and interdisciplinary Sciences (RAD-X) and Collaborative Innovation Centre of Radiation Medicine of Jiangsu Higher Education Institutions. Soochow University, Suzhou, China
| | - Kai Wang
- State Key Laboratory of Resource Insects, Institute of Apicultural Research, Chinese Academy of Agricultural Sciences, Beijing, China
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Deng Q, Li H, Yue X, Guo C, Sun Y, Ma C, Gao J, Wu Y, Du B, Yang J, Zhang C, Zhang W. Smooth muscle liver kinase B1 inhibits foam cell formation and atherosclerosis via direct phosphorylation and activation of SIRT6. Cell Death Dis 2023; 14:542. [PMID: 37607939 PMCID: PMC10444762 DOI: 10.1038/s41419-023-06054-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 08/01/2023] [Accepted: 08/08/2023] [Indexed: 08/24/2023]
Abstract
Foam cell formation is a hallmark of the early phase of atherosclerosis. Growing evidence has demonstrated that vascular smooth muscle cells (VSMCs) comprise a considerable proportion of foam cells. Liver kinase B1 (LKB1) plays a crucial part in cardiovascular diseases. However, the role of LKB1 in VSMC-derived foam cell formation and atherosclerosis remains unclear. To explore the effects of LKB1 on VSMC-derived foam cell formation and atherosclerosis, we generated smooth muscle-specific LKB1 knockout (LKB1SMKO) mice by crossbreeding LKB1flox/flox mice with SM22α-CreERT2 mice. LKB1 expression decreased in plaque-loaded aortas and oxidized low-density lipoprotein (oxLDL)-treated VSMCs. Compared with controls, atherosclerosis development was exacerbated in LKB1SMKO mice via the promotion of VSMC-derived foam cell formation. Conversely, LKB1 overexpression inhibited lipid uptake and foam cell formation in VSMCs. Mechanistically, LKB1 binds to SIRT6 and directly phosphorylates and activates it, thereby reducing lectin-like oxLDL receptor-1 (LOX-1) via SIRT6-dependent histone deacetylation. Finally, adeno-associated virus (AAV)-mediated LOX-1 deficiency in smooth muscle ameliorated atherosclerosis in LKB1SMKO mice. Our findings suggest that LKB1 may modulate VSMC-derived foam cell formation and atherosclerosis via the phosphorylation and activation of SIRT6.
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Affiliation(s)
- Qiming Deng
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Hongxuan Li
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
| | - Xiaolin Yue
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Chenghu Guo
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Yuanyuan Sun
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Chang Ma
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Jiangang Gao
- School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, China
| | - Yue Wu
- Department of Cardiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Bin Du
- Department of Cardiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jianmin Yang
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Cheng Zhang
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
| | - Wencheng Zhang
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
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9
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Gao S, Yang Q, Peng Y, Kong W, Liu Z, Li Z, Chen J, Bao M, Li X, Zhang Y, Bian X, Jin L, Zhang H, Zhang Y, Sanchis D, Yan F, Ye J. SIRT6 regulates obesity-induced oxidative stress via ENDOG/SOD2 signaling in the heart. Cell Biol Toxicol 2023; 39:1489-1507. [PMID: 35798905 DOI: 10.1007/s10565-022-09735-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 06/07/2022] [Indexed: 12/06/2022]
Abstract
The sirtuin 6 (SIRT6) participates in regulating glucose and lipid homeostasis. However, the function of SIRT6 in the process of cardiac pathogenesis caused by obesity-associated lipotoxicity remains to be unveiled. This study was designed to elucidate the role of SIRT6 in the pathogenesis of cardiac injury due to nutrition overload-induced obesity and explore the downstream signaling pathways affecting oxidative stress in the heart. In this study, we used Sirt6 cardiac-specific knockout murine models treated with a high-fat diet (HFD) feeding to explore the function and mechanism of SIRT6 in the heart tissue during HFD-induced obesity. We also took advantage of neonatal cardiomyocytes to study the role and downstream molecules of SIRT6 during HFD-induced injury in vitro, in which intracellular oxidative stress and mitochondrial content were assessed. We observed that during HFD-induced obesity, Sirt6 loss-of-function aggravated cardiac injury including left ventricular hypertrophy and lipid accumulation. Our results evidenced that upon increased fatty acid uptake, SIRT6 positively regulated the expression of endonuclease G (ENDOG), which is a mitochondrial-resident molecule that plays an important role in mitochondrial biogenesis and redox homeostasis. Our results also showed that SIRT6 positively regulated superoxide dismutase 2 (SOD2) expression post-transcriptionally via ENDOG. Our study gives a new sight into SIRT6 beneficial role in mitochondrial biogenesis of cardiomyocytes. Our data also show that SIRT6 is required to reduce intracellular oxidative stress in the heart triggered by high-fat diet-induced obesity, involving the control of ENDOG/SOD2.
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Affiliation(s)
- Shuya Gao
- Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, 210006, China
| | - Qingchen Yang
- Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, 210006, China
| | - Yue Peng
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210006, China
| | - Weixian Kong
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210006, China
| | - Zekun Liu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210006, China
| | - Zhe Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
| | - Jiawen Chen
- Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, 210006, China
| | - Mengmeng Bao
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210006, China
| | - Xie Li
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210006, China
| | - Yubin Zhang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210006, China
| | - Xiaohong Bian
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210006, China
| | - Liang Jin
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210006, China
| | - Hanwen Zhang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210006, China
| | - Yuexin Zhang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210006, China
| | - Daniel Sanchis
- Institut de Recerca Biomedica de Lleida (IRBLLEIDA), Universitat de Lleida, Edifici Biomedicina-I, Av. Rovira Roure 80, 25198, Lleida, Spain.
| | - Fangrong Yan
- Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, 210006, China.
| | - Junmei Ye
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210006, China.
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10
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Sun C, Bai S, Liang Y, Liu D, Liao J, Chen Y, Zhao X, Wu B, Huang D, Chen M, Wu D. The role of Sirtuin 1 and its activators in age-related lung disease. Biomed Pharmacother 2023; 162:114573. [PMID: 37018986 DOI: 10.1016/j.biopha.2023.114573] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/10/2023] [Accepted: 03/21/2023] [Indexed: 04/05/2023] Open
Abstract
Aging is a major driving factor in lung diseases. Age-related lung disease is associated with downregulated expression of SIRT1, an NAD+-dependent deacetylase that regulates inflammation and stress resistance. SIRT1 acts by inducing the deacetylation of various substrates and regulates several mechanisms that relate to lung aging, such as genomic instability, lung stem cell exhaustion, mitochondrial dysfunction, telomere shortening, and immune senescence. Chinese herbal medicines have many biological activities, exerting anti-inflammatory, anti-oxidation, anti-tumor, and immune regulatory effects. Recent studies have confirmed that many Chinese herbs have the effect of activating SIRT1. Therefore, we reviewed the mechanism of SIRT1 in age-related lung disease and explored the potential roles of Chinese herbs as SIRT1 activators in the treatment of age-related lung disease.
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11
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Astrocytic SIRT6 is a potential anti-depression and anti-anxiety target. Prog Neuropsychopharmacol Biol Psychiatry 2023; 123:110702. [PMID: 36565979 DOI: 10.1016/j.pnpbp.2022.110702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 11/20/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
Sirtuin 6 (SIRT6) is a nuclear silencing information regulator that is widely expressed in brain. Inhibition of SIRT6 in the brain induced antidepressant effects in rodents. However, SIRT6 knockout in neurons induced developmental retardation and cognitive impairments. In this study, a mouse strain of astrocyte conditional knockout SIRT6 (AKO) was constructed. Unlike whole brain SIRT6 knockout mice, AKO mice did not show growth retardation. We showed that SIRT6 knockout in astrocytes did not impair the learning and memory ability of mice. Chronic unpredictable mild stress (CUMS) was used to evaluate the anti-depression and anti-anxiety effects in mice. In tail suspension test and forced swimming test, AKO mice did not show depression like phenotype induced by CUMS. In addition, knockout of SIRT6 in astrocytes alleviated the high anxiety level induced by CUMS in light and dark box test, open field test and elevated cross maze test. Three box social test showed that the deletion of SIRT6 in astrocytes changed the social preference of mice. Re-expression of SIRT6 in astrocytes mediated by adeno-associated virus reversed the social preference of AKO mice, but the re-expression also eliminated the anti-depression and anti-anxiety effects in AKO mice. Deletion of SIRT6 in astrocytes change the purine metabolic homeostasis of medial prefrontal cortex in mice. The results of transcriptomics and metabolomics analysis showed that the deletion of SIRT6 would change the purine metabolic pathway of cultured astrocytes and increase the contents of inosine and the second messenger cyclic adenosine monophosphate in astrocytes. In conclusion, knockout of SIRT6 in astrocytes induced anti-depression and anti-anxiety effects in mice without impairing the development and cognitive ability of mice.
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12
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Fu W, Xiao Z, Chen Y, Pei J, Sun Y, Zhang Z, Wu H, Pei Y, Wei S, Wang Y, Wang D. Molecular integrative study on interaction domains of nuclear factor erythroid 2-related factor 2 with sirtuin 6. Biochimie 2023; 211:68-77. [PMID: 36924820 DOI: 10.1016/j.biochi.2023.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 02/08/2023] [Accepted: 03/09/2023] [Indexed: 03/16/2023]
Abstract
Oxidative stress is one of the elements causing aging and related diseases. Inhibiting Nrf2 activity or increasing oxidative pressure can replicate the deficits of premature aging. SIRT6 is one of the few proteins that can regulate both life span and aging. Deletion of SIRT6 in human cells impairs the antioxidant capacity of cells, which results in the accumulation of intracellular reactive oxygen species and DNA oxidation products. Characterization of the binding of Nrf2 with SIRT6 is critical for understanding the modulation of Nrf2-correlated cell activities by SIRT6. The yeast two-hybrid experiments showed that the binding of Nrf2 with SIRT6 is mediated by Neh1 and Neh3 domains. The elimination of the Neh1 and Neh3 domains decreased the binding stability and free energy, according to the molecular dynamic analysis. The roles of theses domains in mediating the binding were confirmed by co-immunoprecipitation. In cells transfected with the small interfering RNA (siRNA) targeting the Nrf2 Neh1 domain and plasmids overexpressing domain-mutant Nrf2, it was discovered that Nrf2 lost its activity to stimulate the transcription of antioxidant genes in the absence of Neh1 and Neh3 domains.
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Affiliation(s)
- Wanmeng Fu
- Laboratory of Biopharmaceuticals and Molecular Pharmacology, School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan, 570228, China
| | - Zhengpan Xiao
- Laboratory of Biopharmaceuticals and Molecular Pharmacology, School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan, 570228, China
| | - Yibo Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, 999078, China
| | - Jinli Pei
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
| | - Yan Sun
- Laboratory of Biopharmaceuticals and Molecular Pharmacology, School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan, 570228, China
| | - Zhuandan Zhang
- Laboratory of Biopharmaceuticals and Molecular Pharmacology, School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan, 570228, China
| | - Hao Wu
- Central Laboratory, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, 315046, China
| | - Yechun Pei
- Laboratory of Biopharmaceuticals and Molecular Pharmacology, School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan, 570228, China
| | - Shuangshuang Wei
- Laboratory of Biopharmaceuticals and Molecular Pharmacology, School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan, 570228, China
| | - Yuerong Wang
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Dayong Wang
- Laboratory of Biopharmaceuticals and Molecular Pharmacology, School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan, 570228, China; Key Laboratory of Tropical Biological Resources of the Ministry of Education of China, Hainan University, Haikou, Hainan, 570228, China; One Health Collaborative Innovation Center, Hainan University, Haikou, Hainan, 570228, China.
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13
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Guo Z, Li P, Ge J, Li H. SIRT6 in Aging, Metabolism, Inflammation and Cardiovascular Diseases. Aging Dis 2022; 13:1787-1822. [PMID: 36465178 PMCID: PMC9662279 DOI: 10.14336/ad.2022.0413] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 04/13/2022] [Indexed: 07/28/2023] Open
Abstract
As an important NAD+-dependent enzyme, SIRT6 has received significant attention since its discovery. In view of observations that SIRT6-deficient animals exhibit genomic instability and metabolic disorders and undergo early death, SIRT6 has long been considered a protein of longevity. Recently, growing evidence has demonstrated that SIRT6 functions as a deacetylase, mono-ADP-ribosyltransferase and long fatty deacylase and participates in a variety of cellular signaling pathways from DNA damage repair in the early stage to disease progression. In this review, we elaborate on the specific substrates and molecular mechanisms of SIRT6 in various physiological and pathological processes in detail, emphasizing its links to aging (genomic damage, telomere integrity, DNA repair), metabolism (glycolysis, gluconeogenesis, insulin secretion and lipid synthesis, lipolysis, thermogenesis), inflammation and cardiovascular diseases (atherosclerosis, cardiac hypertrophy, heart failure, ischemia-reperfusion injury). In addition, the most recent advances regarding SIRT6 modulators (agonists and inhibitors) as potential therapeutic agents for SIRT6-mediated diseases are reviewed.
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Affiliation(s)
- Zhenyang Guo
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, China.
| | - Peng Li
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, China.
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, China.
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Hua Li
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, China.
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
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14
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Metformin alleviates HFD-induced oxidative stress in hepatocyte via activating SIRT6/PGC-1α/ENDOG signaling. Clin Sci (Lond) 2022; 136:1711-1730. [DOI: 10.1042/cs20220242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 10/13/2022] [Accepted: 10/31/2022] [Indexed: 12/05/2022]
Abstract
Abstract
Metformin is accepted as a first-line drug for the therapy of Type 2 diabetes (T2D), while its mechanism is still controversial. In the present study, by taking advantage of mouse model of high-fat-diet (HFD)-induced obesity and primary mouse hepatocytes (PMHCs) as well as human hepatocyte L02 cell line, we aimed to investigate the involvement of SIRTs during the application of metformin for the therapy of T2D. Our data evidenced that during HFD-induced obesity, there was elevation of nucleus protein acetylation. Analysis of liver tissue showed that among all SIRT members, SIRT6 expression was significantly down-regulated during HFD feeding, which was sustained to regular level with metformin administration. Our result also showed that SIRT6 suppressed intracellular oxidative stress upon FAs stimulation in PMHCs and L02 cells. Mechanistically, SIRT6, but not SIRT1 promoted PGC-1α expression. We further prove that ENDOG is downstream of PGC-1α. In addition, we evidenced that ENDOG protects hepatocytes from lipid-induced oxidative stress, and down-regulation of Endog blunted the protective role of metformin in defending against FAs-induced oxidative stress. Our study established a novel mechanism of metformin in counteracting lipid-induced hepatic injury via activating SIRT6/PGC-1α/ENDOG signaling, thus providing novel targets of metformin in the therapy of T2D.
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15
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Zhang Q, Zhang J, Lei T, Liang Z, Dong X, Sun L, Zhao Y. Sirt6-mediated epigenetic modification of DNA accessibility is essential for Pou2f3-induced thymic tuft cell development. Commun Biol 2022; 5:544. [PMID: 35668088 PMCID: PMC9170729 DOI: 10.1038/s42003-022-03484-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 05/11/2022] [Indexed: 11/09/2022] Open
Abstract
AbstractThymic epithelial cells (TECs) are essential for the production of self-tolerant T cells. The newly identified thymic tuft cells are regulated by Pou2f3 and represent important elements for host type 2 immunity. However, epigenetic involvement in thymic tuft cell development remains unclear. We performed single-cell ATAC-seq of medullary TEC (mTEC) and established single-cell chromatin accessibility profiling of mTECs. The results showed that mTEC III cells can be further divided into three groups (Late Aire 1, 2, and 3) and that thymic tuft cells may be derived from Late Aire 2 cells. Pou2f3 is expressed in both Late Aire 2 cells and thymic tuft cells, while Pou2f3-regulated genes are specifically expressed in thymic tuft cells with simultaneous opening of chromatin accessibility, indicating the involvement of epigenetic modification in this process. Using the epigenetic regulator Sirt6-defect mouse model, we found that Sirt6 deletion increased Late Aire 2 cells and decreased thymic tuft cells and Late Aire 3 cells without affecting Pou2f3 expression. However, Sirt6 deletion reduced the chromatin accessibility of Pou2f3-regulated genes in thymic tuft cells, which may be caused by Sirt6–mediated regulation of Hdac9 expression. These data indicate that epigenetic regulation is indispensable for Pou2f3-mediated thymic tuft cell development.
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16
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Garcia-Venzor A, Toiber D. SIRT6 Through the Brain Evolution, Development, and Aging. Front Aging Neurosci 2021; 13:747989. [PMID: 34720996 PMCID: PMC8548377 DOI: 10.3389/fnagi.2021.747989] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 09/16/2021] [Indexed: 12/19/2022] Open
Abstract
During an organism's lifespan, two main phenomena are critical for the organism's survival. These are (1) a proper embryonic development, which permits the new organism to function with high fitness, grow and reproduce, and (2) the aging process, which will progressively undermine its competence and fitness for survival, leading to its death. Interestingly these processes present various similarities at the molecular level. Notably, as organisms became more complex, regulation of these processes became coordinated by the brain, and failure in brain activity is detrimental in both development and aging. One of the critical processes regulating brain health is the capacity to keep its genomic integrity and epigenetic regulation-deficiency in DNA repair results in neurodevelopmental and neurodegenerative diseases. As the brain becomes more complex, this effect becomes more evident. In this perspective, we will analyze how the brain evolved and became critical for human survival and the role Sirt6 plays in brain health. Sirt6 belongs to the Sirtuin family of histone deacetylases that control several cellular processes; among them, Sirt6 has been associated with the proper embryonic development and is associated with the aging process. In humans, Sirt6 has a pivotal role during brain aging, and its loss of function is correlated with the appearance of neurodegenerative diseases such as Alzheimer's disease. However, Sirt6 roles during brain development and aging, especially the last one, are not observed in all species. It appears that during the brain organ evolution, Sirt6 has gained more relevance as the brain becomes bigger and more complex, observing the most detrimental effect in the brains of Homo sapiens. In this perspective, we part from the evolution of the brain in metazoans, the biological similarities between brain development and aging, and the relevant functions of Sirt6 in these similar phenomena to conclude with the evidence suggesting a more relevant role of Sirt6 gained in the brain evolution.
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Affiliation(s)
- Alfredo Garcia-Venzor
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Debra Toiber
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
- The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, Israel
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17
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Hammond-Martel I, Verreault A, Wurtele H. Chromatin dynamics and DNA replication roadblocks. DNA Repair (Amst) 2021; 104:103140. [PMID: 34087728 DOI: 10.1016/j.dnarep.2021.103140] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/18/2021] [Accepted: 05/20/2021] [Indexed: 11/27/2022]
Abstract
A broad spectrum of spontaneous and genotoxin-induced DNA lesions impede replication fork progression. The DNA damage response that acts to promote completion of DNA replication is associated with dynamic changes in chromatin structure that include two distinct processes which operate genome-wide during S-phase. The first, often referred to as histone recycling or parental histone segregation, is characterized by the transfer of parental histones located ahead of replication forks onto nascent DNA. The second, known as de novo chromatin assembly, consists of the deposition of new histone molecules onto nascent DNA. Because these two processes occur at all replication forks, their potential to influence a multitude of DNA repair and DNA damage tolerance mechanisms is considerable. The purpose of this review is to provide a description of parental histone segregation and de novo chromatin assembly, and to illustrate how these processes influence cellular responses to DNA replication roadblocks.
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Affiliation(s)
- Ian Hammond-Martel
- Centre de recherche de l'Hôpital Maisonneuve-Rosemont, 5415 boulevard de l'Assomption, Montreal, H1T 2M4, Canada
| | - Alain Verreault
- Institute for Research in Immunology and Cancer, Université de Montréal, P.O. Box 6128, Succursale Centre-Ville, Montreal, H3C 3J7, Canada; Département de Pathologie et Biologie Cellulaire, Université de Montréal, 2900 Edouard Montpetit Blvd, Montreal, H3T 1J4, Canada
| | - Hugo Wurtele
- Centre de recherche de l'Hôpital Maisonneuve-Rosemont, 5415 boulevard de l'Assomption, Montreal, H1T 2M4, Canada; Département de Médecine, Université de Montréal, Université de Montréal, 2900 Edouard Montpetit Blvd, Montreal, H3T 1J4, Canada.
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18
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Maissan P, Mooij EJ, Barberis M. Sirtuins-Mediated System-Level Regulation of Mammalian Tissues at the Interface between Metabolism and Cell Cycle: A Systematic Review. BIOLOGY 2021; 10:194. [PMID: 33806509 PMCID: PMC7999230 DOI: 10.3390/biology10030194] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/20/2021] [Accepted: 02/25/2021] [Indexed: 02/06/2023]
Abstract
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.
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Affiliation(s)
- Parcival Maissan
- Synthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands;
| | - Eva J. Mooij
- Systems Biology, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, Surrey, UK;
- Centre for Mathematical and Computational Biology, CMCB, University of Surrey, Guildford GU2 7XH, Surrey, UK
| | - Matteo Barberis
- Synthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands;
- Systems Biology, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, Surrey, UK;
- Centre for Mathematical and Computational Biology, CMCB, University of Surrey, Guildford GU2 7XH, Surrey, UK
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19
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Tang Q, Liu Q, Yang X, Wu T, Huang C, Zhang J, Zhang Z, Zhang G, Zhao Y, Zhou J, Huang H, Xia Y, Yan J, Li Y, He J. Sirtuin 6 supra-physiological overexpression in hypothalamic pro-opiomelanocortin neurons promotes obesity via the hypothalamus-adipose axis. FASEB J 2021; 35:e21408. [PMID: 33583107 DOI: 10.1096/fj.202002607] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 01/19/2021] [Indexed: 02/05/2023]
Abstract
Sirtuin 6 (Sirt6), a member of the Sirtuin family, has important roles in maintaining glucose and lipid metabolism. Our previous studies demonstrated that the deletion of Sirt6 in pro-opiomelanocortin (POMC)-expressing cells by the loxP-Cre system resulted in severe obesity and hepatic steatosis. However, whether overexpression of Sirt6 in hypothalamic POMC neurons could ameliorate diet-induced obesity is still unknown. Thus, we generated mice specifically overexpressing Sirt6 in hypothalamic POMC neurons (PSOE) by stereotaxic injection of Cre-dependent adeno-associated viruses into the arcuate nucleus of Pomc-Cre mice. PSOE mice showed increased adiposity and decreased energy expenditure. Furthermore, thermogenesis of BAT and lipolysis of WAT were both impaired, caused by reduced sympathetic nerve innervation and activity in adipose tissues. Mechanistically, Sirt6 overexpression decreasing STAT3 acetylation, thus lowering POMC expression in the hypothalamus underlined the observed phenotypes in PSOE mice. These results demonstrate that Sirt6 overexpression specifically in the hypothalamic POMC neurons exacerbates diet-induced obesity and metabolic disorders via the hypothalamus-adipose axis.
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Affiliation(s)
- Qin Tang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
| | - Qinhui Liu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
| | - Xuping Yang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Tong Wu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Cuiyuan Huang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Jinhang Zhang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Zijing Zhang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Guorong Zhang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Yingnan Zhao
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Jian Zhou
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Hui Huang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Yan Xia
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Jiamin Yan
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Yanping Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
| | - Jinhan He
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
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20
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Liu G, Chen H, Liu H, Zhang W, Zhou J. Emerging roles of SIRT6 in human diseases and its modulators. Med Res Rev 2021; 41:1089-1137. [PMID: 33325563 PMCID: PMC7906922 DOI: 10.1002/med.21753] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/27/2020] [Accepted: 11/01/2020] [Indexed: 12/13/2022]
Abstract
The biological functions of sirtuin 6 (SIRT6; e.g., deacetylation, defatty-acylation, and mono-ADP-ribosylation) play a pivotal role in regulating lifespan and several fundamental processes controlling aging such as DNA repair, gene expression, and telomeric maintenance. Over the past decades, the aberration of SIRT6 has been extensively observed in diverse life-threatening human diseases. In this comprehensive review, we summarize the critical roles of SIRT6 in the onset and progression of human diseases including cancer, inflammation, diabetes, steatohepatitis, arthritis, cardiovascular diseases, neurodegenerative diseases, viral infections, renal and corneal injuries, as well as the elucidation of the related signaling pathways. Moreover, we discuss the advances in the development of small molecule SIRT6 modulators including activators and inhibitors as well as their pharmacological profiles toward potential therapeutics for SIRT6-mediated diseases.
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Affiliation(s)
- Gang Liu
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
| | - Haiying Chen
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
| | - Hua Liu
- Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Wenbo Zhang
- Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Jia Zhou
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
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21
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Lasigliè D. Sirtuins and the prevention of immunosenescence. VITAMINS AND HORMONES 2021; 115:221-264. [PMID: 33706950 DOI: 10.1016/bs.vh.2020.12.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Aging of hematopoietic stem cells (HSCs) has been largely described as one underlying cause of senescence of the immune-hematopoietic system (immunosenescence). A set of well-defined hallmarks characterizes aged HSCs contributing to unbalanced hematopoiesis and aging-associated functional alterations of both branches of the immune system. In this chapter, the contribution of sirtuins, a family of conserved NAD+ dependent deacetylases with key roles in metabolism, genome integrity, aging and lifespan, to immunosenescence, will be addressed. In particular, the role of SIRT6 will be deeply analyzed highlighting a multifaceted part of this deacetylase in HSCs aging as well as in the immunosenescence of dendritic cells (DCs). These and other emerging data are currently paving the way for future design and development of rejuvenation means aiming at rescuing age-related changes in immune function in the elderly and combating age-associated hematopoietic diseases.
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Affiliation(s)
- Denise Lasigliè
- Istituto Comprensivo "Franco Marro", Ministero dell'Istruzione Ministero dell'Università e della Ricerca (M.I.U.R), Villar Perosa, TO, Italy.
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22
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Hypothalamic Actions of SIRT1 and SIRT6 on Energy Balance. Int J Mol Sci 2021; 22:ijms22031430. [PMID: 33572672 PMCID: PMC7866978 DOI: 10.3390/ijms22031430] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/14/2021] [Accepted: 01/28/2021] [Indexed: 02/07/2023] Open
Abstract
Sirtuins are NAD+ dependent deacetylases that regulate a large number of physiological processes. These enzymes are highly conserved and act as energy sensors to coordinate different metabolic responses in a controlled manner. At present, seven mammalian sirtuins (SIRT 1-7) have been identified, with SIRT1 and SIRT6 shown to exert their metabolic actions in the hypothalamus, both with crucial roles in eliciting responses to dampen metabolic complications associated with obesity. Therefore, our aim is to compile the current understanding on the role of SIRT1 and SIRT6 in the hypothalamus, especially highlighting their actions on the control of energy balance.
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Matsuno H, Tsuchimine S, Fukuzato N, O'Hashi K, Kunugi H, Sohya K. Sirtuin 6 is a regulator of dendrite morphogenesis in rat hippocampal neurons. Neurochem Int 2021; 145:104959. [PMID: 33444676 DOI: 10.1016/j.neuint.2021.104959] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 12/15/2020] [Accepted: 01/05/2021] [Indexed: 01/14/2023]
Abstract
Sirtuin 6 (SIRT6), a member of the Sirtuin family, acts as nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase, mono-adenosine diphosphate (ADP)-ribosyltransferase, and fatty acid deacylase, and plays critical roles in inflammation, aging, glycolysis, and DNA repair. Accumulating evidence has suggested that SIRT6 is involved in brain functions such as neuronal differentiation, neurogenesis, and learning and memory. However, the precise molecular roles of SIRT6 during neuronal circuit formation are not yet well understood. In this study, we tried to elucidate molecular roles of SIRT6 on neurite development by using primary-cultured hippocampal neurons. We observed that SIRT6 was abundantly localized in the nucleus, and its expression was markedly increased during neurite outgrowth and synaptogenesis. By using shRNA-mediated SIRT6-knockdown, we show that both dendritic length and the number of dendrite branches were significantly reduced in the SIRT6-knockdown neurons. Microarray and subsequent gene ontology analysis revealed that reducing SIRT6 caused the downregulation of immediate early genes (IEGs) and alteration of several biological processes including MAPK (ERK1/2) signaling. We found that nuclear accumulation of phosphorylated ERK1/2 was significantly reduced in SIRT6-knockdown neurons. Overexpression of SIRT6 promoted dendritic length and branching, but the mutants lacking deacetylase activity had no significant effect on the dendritic morphology. Collectively, the presented findings reveal a role of SIRT6 in dendrite morphogenesis, and suggest that SIRT6 may act as an important regulator of ERK1/2 signaling pathway that mediates IEG expression, which leads to dendritic development.
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Affiliation(s)
- Hitomi Matsuno
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan.
| | - Shoko Tsuchimine
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan
| | - Noriko Fukuzato
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan
| | - Kazunori O'Hashi
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan; Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-8310, Japan
| | - Hiroshi Kunugi
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan; Department of Psychiatry, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, 173-8605, Japan
| | - Kazuhiro Sohya
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan.
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24
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Li Z, Xu K, Zhao S, Guo Y, Chen H, Ni J, Liu Q, Wang Z. SPATA4 improves aging-induced metabolic dysfunction through promotion of preadipocyte differentiation and adipose tissue expansion. Aging Cell 2021; 20:e13282. [PMID: 33314576 PMCID: PMC7811838 DOI: 10.1111/acel.13282] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 10/25/2020] [Accepted: 10/28/2020] [Indexed: 12/13/2022] Open
Abstract
Spermatogenesis‐associated protein 4 (SPATA4) is conserved across multiple species. However, the function of this gene remains largely unknown. In this study, we generated Spata4 transgenic mice to explore tissue‐specific function of SPATA4. Spata4 overexpression mice displayed increased subcutaneous fat tissue compared with wild‐type littermates at an old age, while this difference was not observed in younger mice. Aging‐induced ectopic fat distribution, inflammation, and insulin resistance were also significantly attenuated by SPATA4. In vitro, SPATA4 promoted preadipocyte differentiation through activation of the ERK1/2 and C/EBPβ pathway and increased the expression of adipokines. These data suggest SPATA4 can regulate lipid accumulation in a tissue‐specific manner and improve aging‐induced dysmetabolic syndromes. Clarifying the mechanism of SPATA4 functioning in lipid metabolism might provide novel therapeutic targets for disease interventions.
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Affiliation(s)
- Zhongchi Li
- Protein Science Key Laboratory of the Ministry of Education School of Pharmaceutical Sciences Tsinghua University Beijing China
| | - Kang Xu
- Protein Science Key Laboratory of the Ministry of Education School of Pharmaceutical Sciences Tsinghua University Beijing China
| | - Sen Zhao
- Key Laboratory of Big Data for Spinal Deformities Peking Union Medical College Hospital Beijing China
| | - Yannan Guo
- Protein Science Key Laboratory of the Ministry of Education School of Pharmaceutical Sciences Tsinghua University Beijing China
| | - Huiling Chen
- Protein Science Key Laboratory of the Ministry of Education School of Pharmaceutical Sciences Tsinghua University Beijing China
| | - Jianquan Ni
- School of Medicine Tsinghua University Beijing China
| | - Qingfei Liu
- Protein Science Key Laboratory of the Ministry of Education School of Pharmaceutical Sciences Tsinghua University Beijing China
| | - Zhao Wang
- Protein Science Key Laboratory of the Ministry of Education School of Pharmaceutical Sciences Tsinghua University Beijing China
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25
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Carreño M, Bresque M, Machado MR, Santos L, Durán R, Vitturi DA, Escande C, Denicola A. Nitro-fatty acids as activators of hSIRT6 deacetylase activity. J Biol Chem 2020; 295:18355-18366. [PMID: 33122195 PMCID: PMC7939442 DOI: 10.1074/jbc.ra120.014883] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 10/16/2020] [Indexed: 12/21/2022] Open
Abstract
Sirtuin 6, SIRT6, is critical for both glucose and lipid homeostasis and is involved in maintaining genomic stability under conditions of oxidative DNA damage such as those observed in age-related diseases. There is an intense search for modulators of SIRT6 activity, however, not many specific activators have been reported. Long acyl-chain fatty acids have been shown to increase the weak in vitro deacetylase activity of SIRT6 but this effect is modest at best. Herein we report that electrophilic nitro-fatty acids (nitro-oleic acid and nitro-conjugated linoleic acid) potently activate SIRT6. Binding of the nitro-fatty acid to the hydrophobic crevice of the SIRT6 active site exerted a moderate activation (2-fold at 20 μm), similar to that previously reported for non-nitrated fatty acids. However, covalent Michael adduct formation with Cys-18, a residue present at the N terminus of SIRT6 but absent from other isoforms, induced a conformational change that resulted in a much stronger activation (40-fold at 20 μm). Molecular modeling of the resulting Michael adduct suggested stabilization of the co-substrate and acyl-binding loops as a possible additional mechanism of SIRT6 activation by the nitro-fatty acid. Importantly, treatment of cells with nitro-oleic acid promoted H3K9 deacetylation, whereas oleic acid had no effect. Altogether, our results show that nitrated fatty acids can be considered a valuable tool for specific SIRT6 activation, and that SIRT6 should be considered as a molecular target for in vivo actions of these anti-inflammatory nitro-lipids.
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Affiliation(s)
- Mara Carreño
- Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, and Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay
| | - Mariana Bresque
- Laboratorio de Patologías del Metabolismo y el Envejecimiento, Institut Pasteur de Montevideo, Montevideo, Uruguay
| | - Matías R Machado
- Laboratorio de Simulaciones Biomoleculares, Institut Pasteur de Montevideo, Montevideo, Uruguay
| | - Leonardo Santos
- Laboratorio de Patologías del Metabolismo y el Envejecimiento, Institut Pasteur de Montevideo, Montevideo, Uruguay
| | - Rosario Durán
- Unidad de Bioquímica y Proteómica Analíticas, Institut Pasteur de Montevideo, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay
| | - Darío A Vitturi
- Department of Pharmacology and Chemical Biology; Heart, Lung, Blood and Vascular Medicine Institute, and Center for Critical Care Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Carlos Escande
- Laboratorio de Patologías del Metabolismo y el Envejecimiento, Institut Pasteur de Montevideo, Montevideo, Uruguay.
| | - Ana Denicola
- Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, and Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay.
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26
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Rasha F, Mims BM, Castro-Piedras I, Barnes BJ, Grisham MB, Rahman RL, Pruitt K. The Versatility of Sirtuin-1 in Endocrinology and Immunology. Front Cell Dev Biol 2020; 8:589016. [PMID: 33330467 PMCID: PMC7717970 DOI: 10.3389/fcell.2020.589016] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 10/27/2020] [Indexed: 12/13/2022] Open
Abstract
Sirtuins belong to the class III family of NAD-dependent histone deacetylases (HDAC) and are involved in diverse physiological processes that range from regulation of metabolism and endocrine function to coordination of immunity and cellular responses to stress. Sirtuin-1 (SIRT1) is the most well-studied family member and has been shown to be critically involved in epigenetics, immunology, and endocrinology. The versatile roles of SIRT1 include regulation of energy sensing metabolic homeostasis, deacetylation of histone and non-histone proteins in numerous tissues, neuro-endocrine regulation via stimulation of hypothalamus-pituitary axes, synthesis and maintenance of reproductive hormones via steroidogenesis, maintenance of innate and adaptive immune system via regulation of T- and B-cell maturation, chronic inflammation and autoimmune diseases. Moreover, SIRT1 is an appealing target in various disease contexts due to the promise of pharmacological and/or natural modulators of SIRT1 activity within the context of endocrine and immune-related disease models. In this review we aim to provide a broad overview on the role of SIRT1 particularly within the context of endocrinology and immunology.
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Affiliation(s)
- Fahmida Rasha
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Brianyell McDaniel Mims
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Isabel Castro-Piedras
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Betsy J. Barnes
- Laboratory of Autoimmune and Cancer Research, Center for Autoimmune Musculoskeletal and Hematopoietic Disease, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Department of Molecular Medicine and Department of Pediatrics, Zucker School of Medicine at Hofstra-Northwell, Hempstead, NY, United States
| | - Matthew B. Grisham
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | | | - Kevin Pruitt
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, United States
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27
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Identification of the subtype-selective Sirt5 inhibitor balsalazide through systematic SAR analysis and rationalization via theoretical investigations. Eur J Med Chem 2020; 206:112676. [PMID: 32858418 DOI: 10.1016/j.ejmech.2020.112676] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/17/2020] [Accepted: 07/18/2020] [Indexed: 12/30/2022]
Abstract
We report here an extensive structure-activity relationship study of balsalazide, which was previously identified in a high-throughput screening as an inhibitor of Sirt5. To get a closer understanding why this compound is able to inhibit Sirt5, we initially performed docking experiments comparing the binding mode of a succinylated peptide as the natural substrate and balsalazide with Sirt5 in the presence of NAD+. Based on the evidence gathered here, we designed and synthesized 13 analogues of balsalazide, in which single functional groups were either deleted or slightly altered to investigate which of them are mandatory for high inhibitory activity. Our study confirms that balsalazide with all its given functional groups is an inhibitor of Sirt5 in the low micromolar concentration range and structural modifications presented in this study did not increase potency. While changes on the N-aroyl-β-alanine side chain eliminated potency, the introduction of a truncated salicylic acid part minimally altered potency. Calculations of the associated reaction paths showed that the inhibition potency is very likely dominated by the stability of the inhibitor-enzyme complex and not the type of inhibition (covalent vs. non-covalent). Further in-vitro characterization in a trypsin coupled assay determined that the tested inhibitors showed no competition towards NAD+ or the synthetic substrate analogue ZKsA. In addition, investigations for subtype selectivity revealed that balsalazide is a subtype-selective Sirt5 inhibitor, and our initial SAR and docking studies pave the way for further optimization.
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28
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Liu Q, Zhu X, Lindström M, Shi Y, Zheng J, Hao X, Gustafsson CM, Liu B. Yeast mismatch repair components are required for stable inheritance of gene silencing. PLoS Genet 2020; 16:e1008798. [PMID: 32469861 PMCID: PMC7286534 DOI: 10.1371/journal.pgen.1008798] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 06/10/2020] [Accepted: 04/26/2020] [Indexed: 11/19/2022] Open
Abstract
Alterations in epigenetic silencing have been associated with ageing and tumour formation. Although substantial efforts have been made towards understanding the mechanisms of gene silencing, novel regulators in this process remain to be identified. To systematically search for components governing epigenetic silencing, we developed a genome-wide silencing screen for yeast (Saccharomyces cerevisiae) silent mating type locus HMR. Unexpectedly, the screen identified the mismatch repair (MMR) components Pms1, Mlh1, and Msh2 as being required for silencing at this locus. We further found that the identified genes were also required for proper silencing in telomeres. More intriguingly, the MMR mutants caused a redistribution of Sir2 deacetylase, from silent mating type loci and telomeres to rDNA regions. As a consequence, acetylation levels at histone positions H3K14, H3K56, and H4K16 were increased at silent mating type loci and telomeres but were decreased in rDNA regions. Moreover, knockdown of MMR components in human HEK293T cells increased subtelomeric DUX4 gene expression. Our work reveals that MMR components are required for stable inheritance of gene silencing patterns and establishes a link between the MMR machinery and the control of epigenetic silencing.
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Affiliation(s)
- Qian Liu
- Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan, Goteborg, Sweden
| | - Xuefeng Zhu
- Institute of Biomedicine, University of Gothenburg, Goteborg, Sweden
- * E-mail: (XZ); (BL)
| | - Michelle Lindström
- Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan, Goteborg, Sweden
| | - Yonghong Shi
- Institute of Biomedicine, University of Gothenburg, Goteborg, Sweden
| | - Ju Zheng
- Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan, Goteborg, Sweden
- Department of Biology, Functional Biology, KU Leuven, Heverlee, Belgium
| | - Xinxin Hao
- Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan, Goteborg, Sweden
| | | | - Beidong Liu
- Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan, Goteborg, Sweden
- Center for Large-scale cell-based screening, Faculty of Science, University of Gothenburg, Medicinaregatan, Goteborg, Sweden
- * E-mail: (XZ); (BL)
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29
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Amsalem Z, Arif T, Shteinfer-Kuzmine A, Chalifa-Caspi V, Shoshan-Barmatz V. The Mitochondrial Protein VDAC1 at the Crossroads of Cancer Cell Metabolism: The Epigenetic Link. Cancers (Basel) 2020; 12:cancers12041031. [PMID: 32331482 PMCID: PMC7226296 DOI: 10.3390/cancers12041031] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 04/14/2020] [Accepted: 04/17/2020] [Indexed: 12/29/2022] Open
Abstract
Carcinogenesis is a complicated process that involves the deregulation of epigenetics, resulting in cellular transformational events, such as proliferation, differentiation, and metastasis. Most chromatin-modifying enzymes utilize metabolites as co-factors or substrates and thus are directly dependent on such metabolites as acetyl-coenzyme A, S-adenosylmethionine, and NAD+. Here, we show that using specific siRNA to deplete a tumor of VDAC1 not only led to reprograming of the cancer cell metabolism but also altered several epigenetic-related enzymes and factors. VDAC1, in the outer mitochondrial membrane, controls metabolic cross-talk between the mitochondria and the rest of the cell, thus regulating the metabolic and energetic functions of mitochondria, and has been implicated in apoptotic-relevant events. We previously demonstrated that silencing VDAC1 expression in glioblastoma (GBM) U-87MG cell-derived tumors, resulted in reprogramed metabolism leading to inhibited tumor growth, angiogenesis, epithelial-mesenchymal transition and invasiveness, and elimination of cancer stem cells, while promoting the differentiation of residual tumor cells into neuronal-like cells. These VDAC1 depletion-mediated effects involved alterations in transcription factors regulating signaling pathways associated with cancer hallmarks. As the epigenome is sensitive to cellular metabolism, this study was designed to assess whether depleting VDAC1 affects the metabolism-epigenetics axis. Using DNA microarrays, q-PCR, and specific antibodies, we analyzed the effects of si-VDAC1 treatment of U-87MG-derived tumors on histone modifications and epigenetic-related enzyme expression levels, as well as the methylation and acetylation state, to uncover any alterations in epigenetic properties. Our results demonstrate that metabolic rewiring of GBM via VDAC1 depletion affects epigenetic modifications, and strongly support the presence of an interplay between metabolism and epigenetics.
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Affiliation(s)
- Zohar Amsalem
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (Z.A.); (T.A.); (A.S.-K.)
| | - Tasleem Arif
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (Z.A.); (T.A.); (A.S.-K.)
| | - Anna Shteinfer-Kuzmine
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (Z.A.); (T.A.); (A.S.-K.)
- National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel;
| | - Vered Chalifa-Caspi
- National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel;
| | - Varda Shoshan-Barmatz
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (Z.A.); (T.A.); (A.S.-K.)
- National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel;
- Correspondence: ; Fax: +972-8-647-2992
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30
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Tang Q, Gao Y, Liu Q, Yang X, Wu T, Huang C, Huang Y, Zhang J, Zhang Z, Li R, Pu S, Zhang G, Zhao Y, Zhou J, Huang H, Li Y, Jiang W, Chang Y, He J. Sirt6 in pro-opiomelanocortin neurons controls energy metabolism by modulating leptin signaling. Mol Metab 2020; 37:100994. [PMID: 32278654 PMCID: PMC7215198 DOI: 10.1016/j.molmet.2020.100994] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/28/2020] [Accepted: 04/03/2020] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVE Sirt6 is an essential regulator of energy metabolism in multiple peripheral tissues. However, the direct role of Sirt6 in the hypothalamus, specifically pro-opiomelanocortin (POMC) neurons, controlling energy balance has not been established. Here, we aimed to determine the role of Sirt6 in hypothalamic POMC neurons in the regulation of energy balance and the underlying mechanisms. METHODS For overexpression studies, the hypothalamic arcuate nucleus (ARC) of diet-induced obese mice was targeted bilaterally and adenovirus was delivered by using stereotaxic apparatus. For knockout studies, the POMC neuron-specific Sirt6 knockout mice (PKO mice) were generated. Mice were fed with chow diet or high-fat diet, and body weight and food intake were monitored. Whole-body energy expenditure was determined by metabolic cages. Parameters of body composition and glucose/lipid metabolism were evaluated. RESULTS Sirt6 overexpression in the ARC ameliorated diet-induced obesity. Conversely, selective Sirt6 ablation in POMC neurons predisposed mice to obesity and metabolic disturbances. PKO mice showed an increased fat mass and food intake, while the energy expenditure was decreased. Mechanistically, Sirt6 could modulate leptin signaling in hypothalamic POMC neurons, with Sirt6 deficiency impairing leptin-induced phosphorylation of signal transducer and activator of transcription 3. The effects of leptin on reducing food intake and body weight and leptin-stimulated lipolysis were also impaired. Moreover, Sirt6 inhibition diminished the leptin-induced depolarization of POMC neurons. CONCLUSIONS Our results reveal a key role of Sirt6 in POMC neurons against energy imbalance, suggesting that Sirt6 is an important molecular regulator for POMC neurons to promote negative energy balance.
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Affiliation(s)
- Qin Tang
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Yong Gao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, China
| | - Qinhui Liu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Xuping Yang
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Tong Wu
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Cuiyuan Huang
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Ya Huang
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Jinhang Zhang
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Zijing Zhang
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Rui Li
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Shiyun Pu
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Guorong Zhang
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Yingnan Zhao
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Jian Zhou
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Hui Huang
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Yanping Li
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Wei Jiang
- Molecular Medicine Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Yongsheng Chang
- Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China.
| | - Jinhan He
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China; Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
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Hypothalamic NAD +-Sirtuin Axis: Function and Regulation. Biomolecules 2020; 10:biom10030396. [PMID: 32143417 PMCID: PMC7175325 DOI: 10.3390/biom10030396] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 02/29/2020] [Accepted: 03/02/2020] [Indexed: 02/06/2023] Open
Abstract
The rapidly expanding elderly population and obesity endemic have become part of continuing global health care problems. The hypothalamus is a critical center for the homeostatic regulation of energy and glucose metabolism, circadian rhythm, and aging-related physiology. Nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase sirtuins are referred to as master metabolic regulators that link the cellular energy status to adaptive transcriptional responses. Mounting evidence now indicates that hypothalamic sirtuins are essential for adequate hypothalamic neuronal functions. Owing to the NAD+-dependence of sirtuin activity, adequate hypothalamic NAD+ contents are pivotal for maintaining energy homeostasis and circadian physiology. Here, we comprehensively review the regulatory roles of the hypothalamic neuronal NAD+-sirtuin axis in a normal physiological context and their changes in obesity and the aging process. We also discuss the therapeutic potential of NAD+ biology-targeting drugs in aging/obesity-related metabolic and circadian disorders.
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Zhang N, Yang X, Yuan F, Zhang L, Wang Y, Wang L, Mao Z, Luo J, Zhang H, Zhu WG, Zhao Y. Increased Amino Acid Uptake Supports Autophagy-Deficient Cell Survival upon Glutamine Deprivation. Cell Rep 2019; 23:3006-3020. [PMID: 29874586 DOI: 10.1016/j.celrep.2018.05.006] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 03/29/2018] [Accepted: 05/02/2018] [Indexed: 12/25/2022] Open
Abstract
Autophagy is a protein degradation process by which intracellular materials are recycled for energy homeostasis. However, the metabolic status and energy source of autophagy-defective tumor cells are poorly understood. Here, our data show that amino acid uptake from the extracellular environment is increased in autophagy-deficient cells upon glutamine deprivation. This elevated amino acid uptake results from activating transcription factor 4 (ATF4)-dependent upregulation of AAT (amino acid transporter) gene expression. Furthermore, we identify SIRT6, a NAD+-dependent histone deacetylase, as a corepressor of ATF4 transcriptional activity. In autophagy-deficient cells, activated NRF2 enhances ATF4 transcriptional activity by disrupting the interaction between SIRT6 and ATF4. In this way, autophagy-deficient cells exhibit increased AAT expression and show increased amino acid uptake. Notably, inhibition of amino acid uptake reduces the viability of glutamine-deprived autophagy-deficient cells, but not significantly in wild-type cells, suggesting reliance of autophagy-deficient tumor cells on extracellular amino acid uptake.
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Affiliation(s)
- Nan Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Xin Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Fengjie Yuan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Luyao Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Yanan Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Lina Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Zebin Mao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Jianyuan Luo
- Department of Medical Genetics, Peking University Health Science Center, Beijing 100191, China
| | - Hongquan Zhang
- Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing 100191, China
| | - Wei-Guo Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; School of Medicine, Shenzhen University, Shenzhen, China
| | - Ying Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
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Kanwal A, Pillai VB, Samant S, Gupta M, Gupta MP. The nuclear and mitochondrial sirtuins, Sirt6 and Sirt3, regulate each other's activity and protect the heart from developing obesity-mediated diabetic cardiomyopathy. FASEB J 2019; 33:10872-10888. [PMID: 31318577 PMCID: PMC6766651 DOI: 10.1096/fj.201900767r] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 06/04/2019] [Indexed: 01/31/2023]
Abstract
Sirtuins (Sirts) are implicated in regulating a myriad of biologic functions ranging from cell growth and metabolism to longevity. Here, we show that nuclear Sirt, Sirt6, and mitochondrial Sirt, Sirt3, regulate each other's activity and protect the heart from developing diabetic cardiomyopathy. We found that expression of both Sirt6 and Sirt3 was reduced in cardiomyocytes treated with palmitate and in hearts of mice fed with a high-fat, high-sucrose (HF-HS) diet to develop obesity and diabetes. Conversely, whole-body overexpressing Sirt6 transgenic (Tg.Sirt6) mice were protected from developing obesity and insulin resistance when fed with the same HF-HS diet. The hearts of Tg.Sirt6 mice were also protected from mitochondrial fragmentation and decline of Sirt3, resulting otherwise from HF-HS diet feeding. Mechanistic studies showed that Sirt3 preserves Sirt6 levels by reducing oxidative stress, whereas Sirt6 maintains Sirt3 levels by up-regulating nuclear respiratory factor 2 (Nrf2)-dependent Sirt3 gene transcription. We found that Sirt6 regulates Nrf2-mediated cardiac gene expression in 2 ways; first, Sirt6 suppresses expression of Kelch-like ECH-associated protein 1 (Keap1), a negative regulator of Nrf2, and second, Sirt6 binds to Nrf2 and antagonizes its interaction with Keap1, thereby stabilizing Nrf2 levels in cardiomyocytes. Together, these studies demonstrate that Sirt6 and Sirt3 maintain each other's activity and protect the heart from developing diabetic cardiomyopathy.-Kanwal, A., Pillai, V. B., Samant, S., Gupta, M., Gupta, M. P. The nuclear and mitochondrial sirtuins, Sirt6 and Sirt3, regulate each other's activity and protect the heart from developing obesity-mediated diabetic cardiomyopathy.
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Affiliation(s)
- Abhinav Kanwal
- Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Vinodkumar B. Pillai
- Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Sadhana Samant
- Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Madhu Gupta
- Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Mahesh P. Gupta
- Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
- Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
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Abstract
The sirtuin family of nicotinamide adenine dinucleotide-dependent deacylases (SIRT1-7) are thought to be responsible, in large part, for the cardiometabolic benefits of lean diets and exercise and when upregulated can delay key aspects of aging. SIRT1, for example, protects against a decline in vascular endothelial function, metabolic syndrome, ischemia-reperfusion injury, obesity, and cardiomyopathy, and SIRT3 is protective against dyslipidemia and ischemia-reperfusion injury. With increasing age, however, nicotinamide adenine dinucleotide levels and sirtuin activity steadily decrease, and the decline is further exacerbated by obesity and sedentary lifestyles. Activation of sirtuins or nicotinamide adenine dinucleotide repletion induces angiogenesis, insulin sensitivity, and other health benefits in a wide range of age-related cardiovascular and metabolic disease models. Human clinical trials testing agents that activate SIRT1 or boost nicotinamide adenine dinucleotide levels are in progress and show promise in their ability to improve the health of cardiovascular and metabolic disease patients.
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Affiliation(s)
- Alice E Kane
- From the Department of Genetics, Harvard Medical School, Boston, MA (A.E.K., D.A.S.)
| | - David A Sinclair
- From the Department of Genetics, Harvard Medical School, Boston, MA (A.E.K., D.A.S.).,Department of Pharmacology, The University of New South Wales, Sydney, Australia (D.A.S.)
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Tang W, Fan Y. SIRT6 as a potential target for treating insulin resistance. Life Sci 2019; 231:116558. [PMID: 31194993 DOI: 10.1016/j.lfs.2019.116558] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 06/04/2019] [Accepted: 06/10/2019] [Indexed: 12/26/2022]
Abstract
AIMS We aimed to explore the role of SIRT6 in Insulin resistance (IR). We are the first to investigate on this crucial relationship in an obese mouse model fed on a high-fat diet (HFD) and an IR model based on the mature 3T3-L1-derived adipocytes. MAIN METHODS Western blotting (WB) and qPCR analysis were performed to evaluate the SIRT6 protein and mRNA expressions in HFD mice as well as IR cells. Injection of adenovirus encoding SIRT6 gene in HFD mice and transfection of pcDNA3-SIRT6 in IR cells increased the glucose uptake levels and insulin sensitivity. KEY FINDINGS The positive regulatory effects of SIRT6 on transient receptor potential vallinoid 1 (TRPV1) in IR cells were confirmed by a mechanistic investigation at both protein and mRNA levels. Further, the overexpression of SIRT6 was found to activate the TRPV1/Calcitonin gene-related peptide (CGRP) signaling and upregulate the glucose transporter (GLUT) expression at protein and mRNA levels. Additionally, administration of the TRPV1 antagonist, SB-705498 repressed the insulin sensitivity upregulated by SIRT6 overexpression accompanied with the inhibition of CGRP and decrease in GLUT proportions. The results also showed that TRPV1 agonist, Capsaicin boosted the SIRT6-induced glucose uptake, CGRP production, and GLUT4 levels. SIGNIFICANCE Overall, SIRT6 was concluded to be involved in the TRPV1-CGRP-GLUT4 signaling axis thus leading to increased glucose uptake and decreased IR in HFD mice and 3T3-L1 adipocytes. Therefore, in terms of obesity and diabetes, SIRT6 is a novel candidate for treating IR.
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Affiliation(s)
- Wei Tang
- Department of Endocrinology, Zhoukou Central Hospital, Zhoukou, Henan, China.
| | - Yingying Fan
- Department of Endocrinology, Zhoukou Central Hospital, Zhoukou, Henan, China
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36
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Foolad F, Khodagholi F, Javan M. Sirtuins in Multiple Sclerosis: The crossroad of neurodegeneration, autoimmunity and metabolism. Mult Scler Relat Disord 2019; 34:47-58. [PMID: 31228716 DOI: 10.1016/j.msard.2019.06.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 05/26/2019] [Accepted: 06/07/2019] [Indexed: 12/17/2022]
Abstract
Multiple Sclerosis (MS) is a challenging and disabling condition particularly in the secondary progressive (SP) phase of this disease. The available treatments cannot ameliorate or stop disease progression in this phase, and there is an urgent need to focus on effective therapies and the molecular pathways involved SPMS. Given the significant impact of neurodegeneration, autoimmunity and metabolic alterations in MS, focusing on the molecules that target these different pathways could help in finding new treatments. Sirtuins (SIRTs) are NAD+ dependent epigenetic and metabolic regulators, which have critical roles in the physiology of central nervous system, immune system and metabolism. Based on these facts, SIRTs are crucial candidates of therapeutic targets in MS and collecting the information related to MS disease for each SIRT individually is noteworthy and highlights the lack of investigation in each part. In this review we summarized the role of different sirtuins as key regulator in neurodegeneration, autoimmunity and metabolism pathways. We also clarify the rationale behind selecting SIRTs as therapeutic targets in MS disease by collecting the researches showing alteration of these proteins in human samples of MS patients and animal model of MS, and also the improvement of modeled animals after SIRT-directed treatments.
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Affiliation(s)
- Forough Foolad
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Fariba Khodagholi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Javan
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
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Kitada M, Ogura Y, Monno I, Koya D. Sirtuins and Type 2 Diabetes: Role in Inflammation, Oxidative Stress, and Mitochondrial Function. Front Endocrinol (Lausanne) 2019; 10:187. [PMID: 30972029 PMCID: PMC6445872 DOI: 10.3389/fendo.2019.00187] [Citation(s) in RCA: 180] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Accepted: 03/06/2019] [Indexed: 01/05/2023] Open
Abstract
The rising incidence of type 2 diabetes mellitus (T2DM) is a major public health concern, and novel therapeutic strategies to prevent T2DM are urgently needed worldwide. Aging is recognized as one of the risk factors for metabolic impairments, including insulin resistance and T2DM. Inflammation, oxidative stress, and mitochondrial dysfunction are closely related to both aging and metabolic disease. Calorie restriction (CR) can retard the aging process in organisms ranging from yeast to rodents and delay the onset of numerous age-related disorders, such as insulin resistance and diabetes. Therefore, metabolic CR mimetics may represent new therapeutic targets for insulin resistance and T2DM. Sirtuin 1 (SIRT1), the mammalian homolog of Sir2, was originally identified as a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase. The activation of SIRT1 is closely associated with longevity under CR, and it is recognized as a CR mimetic. Currently, seven sirtuins have been identified in mammals. Among these sirtuins, SIRT1 and SIRT2 are located in the nucleus and cytoplasm, SIRT3 exists predominantly in mitochondria, and SIRT6 is located in the nucleus. These sirtuins regulate metabolism through their regulation of inflammation, oxidative stress and mitochondrial function via multiple mechanisms, resulting in the improvement of insulin resistance and T2DM. In this review, we describe the current understanding of the biological functions of sirtuins, especially SIRT1, SIRT2, SIRT3, and SIRT6, focusing on oxidative stress, inflammation, and mitochondrial function, which are closely associated with aging.
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Affiliation(s)
- Munehiro Kitada
- Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Japan
- Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, Japan
- *Correspondence: Munehiro Kitada
| | - Yoshio Ogura
- Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Japan
| | - Itaru Monno
- Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Japan
| | - Daisuke Koya
- Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Japan
- Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, Japan
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Gui LS, Raza SHA, Garcia M, Sun YG, Ullah I, Han YC. Genetic variants in the SIRT6 transcriptional regulatory region affect gene activity and carcass quality traits in indigenous Chinese beef cattle (Bos taurus). BMC Genomics 2018; 19:785. [PMID: 30382814 PMCID: PMC6211504 DOI: 10.1186/s12864-018-5149-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 10/08/2018] [Indexed: 01/21/2023] Open
Abstract
Background The aim of this study was to analyze potential influences of polymorphisms within the regulatory region of the bovine SIRT6 gene on carcass quality traits. Expression analyses suggested that SIRT6 gene is predominately expressed in kidney, compared with other tissues. In 535 indigenous Chinese beef cattle, two novel single nucleotide polymorphisms (SNPs) were identified within the promoter region of the SIRT6 gene. Results Association analysis indicated that G allele of the c.-1100 A > G had a positive effect on fat deposition, and the Hap4/4 diplotype had more favourable results than other dipoltypes with respect to the evaluation of carcass quality traits. Furthermore, promoter activity associated with the Hap3 haplotype was measured at higher levels than the Hap1 haplotype, which would be in agreement with the previously described association analysis. Conclusion The SIRT6 promoter variants significantly affect transcriptional levels and subsequently significantly influence bovine intramscular fat content.
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Affiliation(s)
- Lin-Sheng Gui
- State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, Qinghai Province, 810016, People's Republic of China.,College of Agriculture and Animal Husbandry, Qinghai University, Xining, Qinghai Province, 810016, People's Republic of China
| | - Sayed Haidar Abbas Raza
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, People's Republic of China
| | - Matthew Garcia
- Utah State University, School of Animal Dairy and Veterinary Sciences, Logan, UT, 84322, USA
| | - Yong-Gang Sun
- Academy of Animal Science and Veterinary Medicine, Qinghai University, Xining, Qinghai Province, 810016, People's Republic of China
| | - Irfan Ullah
- College of Bio-medical engineering Chongqing University Chongqing, Shapingba 400044, People's Republic of China
| | - Yin-Cang Han
- Academy of Animal Science and Veterinary Medicine, Qinghai University, Xining, Qinghai Province, 810016, People's Republic of China.
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Zhang W, Wan H, Feng G, Qu J, Wang J, Jing Y, Ren R, Liu Z, Zhang L, Chen Z, Wang S, Zhao Y, Wang Z, Yuan Y, Zhou Q, Li W, Liu GH, Hu B. SIRT6 deficiency results in developmental retardation in cynomolgus monkeys. Nature 2018; 560:661-665. [PMID: 30135584 DOI: 10.1038/s41586-018-0437-z] [Citation(s) in RCA: 131] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Accepted: 07/16/2018] [Indexed: 12/18/2022]
Abstract
SIRT6 acts as a longevity protein in rodents1,2. However, its biological function in primates remains largely unknown. Here we generate a SIRT6-null cynomolgus monkey (Macaca fascicularis) model using a CRISPR-Cas9-based approach. SIRT6-deficient monkeys die hours after birth and exhibit severe prenatal developmental retardation. SIRT6 loss delays neuronal differentiation by transcriptionally activating the long non-coding RNA H19 (a developmental repressor), and we were able to recapitulate this process in a human neural progenitor cell differentiation system. SIRT6 deficiency results in histone hyperacetylation at the imprinting control region of H19, CTCF recruitment and upregulation of H19. Our results suggest that SIRT6 is involved in regulating development in non-human primates, and may provide mechanistic insight into human perinatal lethality syndrome.
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Affiliation(s)
- Weiqi Zhang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Institute of Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Haifeng Wan
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Institute of Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Guihai Feng
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Institute of Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Institute of Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Jiaqiang Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Institute of Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Yaobin Jing
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Ruotong Ren
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Institute of Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Zunpeng Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Linlin Zhang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Zhiguo Chen
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Cell Therapy Center, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Shuyan Wang
- Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Cell Therapy Center, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Yong Zhao
- Key Laboratory of Gene Engineering of the Ministry of Education, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Zhaoxia Wang
- Department of Neurology, Peking University First Hospital, Beijing, China
| | - Yun Yuan
- Department of Neurology, Peking University First Hospital, Beijing, China
| | - Qi Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Institute of Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Wei Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. .,University of Chinese Academy of Sciences, Beijing, China. .,Institute of Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
| | - Guang-Hui Liu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. .,University of Chinese Academy of Sciences, Beijing, China. .,Institute of Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, China. .,Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Cell Therapy Center, Xuanwu Hospital Capital Medical University, Beijing, China.
| | - Baoyang Hu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. .,University of Chinese Academy of Sciences, Beijing, China. .,Institute of Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
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Sun L, Marin de Evsikova C, Bian K, Achille A, Telles E, Pei H, Seto E. Programming and Regulation of Metabolic Homeostasis by HDAC11. EBioMedicine 2018; 33:157-168. [PMID: 29958910 PMCID: PMC6085537 DOI: 10.1016/j.ebiom.2018.06.025] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 06/19/2018] [Accepted: 06/21/2018] [Indexed: 12/22/2022] Open
Abstract
Histone deacetylases (HDACs) are enzymes that regulate protein functions by catalyzing the removal of acetyl and acyl groups from lysine residues. They play pivotal roles in governing cell behaviors and are indispensable in numerous biological processes. HDAC11, the last identified and sole member of class IV HDACs, was reported over a decade ago. However, its physiological function remains poorly understood. Here, we report that HDAC11 knockout mice are resistant to high-fat diet-induced obesity and metabolic syndrome, suggesting that HDAC11 functions as a crucial metabolic regulator. Depletion of HDAC11 significantly enhanced insulin sensitivity and glucose tolerance, attenuated hypercholesterolemia, and decreased hepatosteatosis and liver damage. Mechanistically, HDAC11 deficiency boosts energy expenditure through promoting thermogenic capacity, which attributes to the elevation of uncoupling protein 1 (UCP1) expression and activity in brown adipose tissue. Moreover, loss of HDAC11 activates the adiponectin-AdipoR-AMPK pathway in the liver, which may contribute to a reversal in hepatosteatosis. Overall, our findings distinguish HDAC11 as a novel regulator of obesity, with potentially important implications for obesity-related disease treatment.
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Affiliation(s)
- Lei Sun
- George Washington University Cancer Center, USA; Department of Biochemistry & Molecular Medicine, George Washington University School of Medicine & Health Sciences, Washington, DC 20037, USA
| | | | - Ka Bian
- George Washington University Cancer Center, USA; Department of Biochemistry & Molecular Medicine, George Washington University School of Medicine & Health Sciences, Washington, DC 20037, USA
| | - Alexandra Achille
- Moffitt Cancer Center, University of South Florida, Tampa, FL 33612, USA
| | | | - Huadong Pei
- George Washington University Cancer Center, USA; Department of Biochemistry & Molecular Medicine, George Washington University School of Medicine & Health Sciences, Washington, DC 20037, USA
| | - Edward Seto
- George Washington University Cancer Center, USA; Department of Biochemistry & Molecular Medicine, George Washington University School of Medicine & Health Sciences, Washington, DC 20037, USA.
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41
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Gat-Yablonski G, De Luca F. Effect of Nutrition on Statural Growth
. Horm Res Paediatr 2018; 88:46-62. [PMID: 28365689 DOI: 10.1159/000456547] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 01/11/2017] [Indexed: 12/14/2022] Open
Abstract
In children, proper growth and development are often regarded as a surrogate marker for good health. A complex system controls the initiation, rate, and cessation of growth, and thus gives a wonderful example of the interactions between genetics, epigenetics, and environmental factors (especially stress and nutrition). Malnutrition is considered a leading cause of growth attenuation in children. This review summarizes our current knowledge regarding the mechanisms linking nutrition and skeletal growth, including systemic factors, such as insulin, growth hormone, insulin-like growth factor-1, fibroblast growth factor-21, etc., and local mechanisms, including mTOR, miRNAs, and epigenetics. Studying the molecular mechanisms regulating skeletal growth may lead to the establishment of better nutritional and therapeutic regimens for more effective linear growth in children with malnutrition and growth abnormalities.
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Affiliation(s)
- Galia Gat-Yablonski
- The Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Children's Diabetes, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.,Felsenstein Medical Research Center, Petach Tikva, Israel.,Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Francesco De Luca
- Section of Endocrinology and Diabetes, St. Christopher's Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
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Yadav DK, Kumar S, Saloni, Misra S, Yadav L, Teli M, Sharma P, Chaudhary S, Kumar N, Choi EH, Kim HS, Kim MH. Molecular Insights into the Interaction of RONS and Thieno[3,2-c]pyran Analogs with SIRT6/COX-2: A Molecular Dynamics Study. Sci Rep 2018; 8:4777. [PMID: 29556059 PMCID: PMC5859274 DOI: 10.1038/s41598-018-22972-9] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 03/05/2018] [Indexed: 01/21/2023] Open
Abstract
SIRT6 and COX-2 are oncogenes target that promote the expression of proinflammatory and pro-survival proteins through a signaling pathway, which leads to increased survival and proliferation of tumor cells. However, COX-2 also suppresses skin tumorigenesis and their relationship with SIRT6, making it an interesting target for the discovery of drugs with anti-inflammatory and anti-cancer properties. Herein, we studied the interaction of thieno[3,2-c]pyran analogs and RONS species with SIRT6 and COX-2 through the use of molecular docking and molecular dynamic simulations. Molecular docking studies revealed the importance of hydrophobic and hydrophilic amino acid residues for the stability. The molecular dynamics study examined conformational changes in the enzymes caused by the binding of the substrates and how those changes affected the stability of the protein-drug complex. The average RMSD values of the backbone atoms in compounds 6 and 10 were calculated from 1000 ps to 10000 ps and were found to be 0.13 nm for both compounds. Similarly, the radius of gyration values for compounds 6 and 10 were found to be 1.87 ± 0.03 nm and 1.86 ± 0.02 nm, respectively. The work presented here, will be of great help in lead identification and optimization for early drug discovery.
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Affiliation(s)
- Dharmendra K Yadav
- College of Pharmacy, Gachon University of Medicine and Science, 191, Hambangmoe-ro, Yeonsu-gu, Incheon, 21936, Republic of Korea.
| | - Surendra Kumar
- College of Pharmacy, Gachon University of Medicine and Science, 191, Hambangmoe-ro, Yeonsu-gu, Incheon, 21936, Republic of Korea
| | - Saloni
- College of Pharmacy, Gachon University of Medicine and Science, 191, Hambangmoe-ro, Yeonsu-gu, Incheon, 21936, Republic of Korea
| | - Sanjeev Misra
- Department of Biochemistry, All India Institute of Medical Science, Jodhpur, Rajasthan, 342005, India
| | - Lalit Yadav
- Department of Chemistry, Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur, 302017, India
| | - Mahesh Teli
- Faculty of Biochemistry and Molecular Medicine Aapistie, University of Oulu, 7A, Oulu, 90220, Finland
| | - Praveen Sharma
- Department of Biochemistry, All India Institute of Medical Science, Jodhpur, Rajasthan, 342005, India
| | - Sandeep Chaudhary
- Department of Chemistry, Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur, 302017, India
| | - Naresh Kumar
- Plasma Bioscience Research Center/Department of Electrical and Biological Physics, Kwangwoon University, 20 Kwangwon-Ro, Nowon-Gu, Seoul, 139-701, Republic of Korea
- Department of Chemistry, Research group PLASMANT, University of Antwerp, BE-2610, Wilrijk-Antwerp, Belgium
| | - Eun Ha Choi
- Plasma Bioscience Research Center/Department of Electrical and Biological Physics, Kwangwoon University, 20 Kwangwon-Ro, Nowon-Gu, Seoul, 139-701, Republic of Korea
| | - Hyung Sik Kim
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Mi-Hyun Kim
- College of Pharmacy, Gachon University of Medicine and Science, 191, Hambangmoe-ro, Yeonsu-gu, Incheon, 21936, Republic of Korea.
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43
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D'Onofrio N, Servillo L, Balestrieri ML. SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection. Antioxid Redox Signal 2018; 28:711-732. [PMID: 28661724 PMCID: PMC5824538 DOI: 10.1089/ars.2017.7178] [Citation(s) in RCA: 280] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 05/24/2017] [Indexed: 02/06/2023]
Abstract
SIGNIFICANCE Oxidative stress represents the common hallmark of pathological conditions associated with cardiovascular disease (CVD), including atherosclerosis, heart failure, hypertension, aging, diabetes, and other vascular system-related diseases. The sirtuin (SIRT) family, comprising seven proteins (SIRT1-SIRT7) sharing a highly conserved nicotinamide adenine dinucleotide (NAD+)-binding catalytic domain, attracted a great attention for the past few years as stress adaptor and epigenetic enzymes involved in the cellular events controlling aging-related disorder, cancer, and CVD. Recent Advances: Among sirtuins, SIRT1 and SIRT6 are the best characterized for their protective roles against inflammation, vascular aging, heart disease, and atherosclerotic plaque development. This latest role has been only recently unveiled for SIRT6. Of interest, in recent years, complex signaling networks controlled by SIRT1 and SIRT6 common to stress resistance, vascular aging, and CVD have emerged. CRITICAL ISSUES We provide a comprehensive overview of recent developments on the molecular signaling pathways controlled by SIRT1 and SIRT6, two post-translational modifiers proven to be valuable tools to dampen inflammation and oxidative stress at the cardiovascular level. FUTURE DIRECTIONS A deeper understanding of the epigenetic mechanisms through which SIRT1 and SIRT6 act in the signalings responsible for onset and development CVD is a prime scientific endeavor of the upcoming years. Multiple "omic" technologies will have widespread implications in understanding such mechanisms, speeding up the achievement of selective and efficient pharmacological modulation of sirtuins for future applications in the prevention and treatment of CVD. Antioxid. Redox Signal. 28, 711-732.
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Affiliation(s)
- Nunzia D'Onofrio
- Department of Biochemistry, Biophysics and General Pathology, School of Medicine and Surgery, Università degli Studi della Campania , Naples, Italy
| | - Luigi Servillo
- Department of Biochemistry, Biophysics and General Pathology, School of Medicine and Surgery, Università degli Studi della Campania , Naples, Italy
| | - Maria Luisa Balestrieri
- Department of Biochemistry, Biophysics and General Pathology, School of Medicine and Surgery, Università degli Studi della Campania , Naples, Italy
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Abstract
Sirt6 is one of the sirtuin family members, a kind of NAD+-dependent histone deacetylase and ADP-ribose transferase enzyme. It has an important role in physiological and pathological processes, regulating aging, cancer, obesity, insulin resistance, inflammation, and energy metabolism. Recent studies have suggested that reduced Sirt6 action is related to obesity and diabetes. Aging and overnutrition, two major risk factors for obesity and diabetes, lead to decreased Sirt6 level and function, which results in abnormal glucose and lipid metabolism. Whole-body ablation of Sirt6 in mice results in severe hypoglycemia. Sirt6 deficiency leads to liver steatosis and promotes diet-induced obesity and insulin resistance. Sirt6 has a protective effect on obesity and diabetes. This review surveys evidence for an emerging role of Sirt6 as a regulator of metabolism in mammals and summarizes its major functions in obesity and diabetes.
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Affiliation(s)
- Jiangying Kuang
- State Key Laboratory of Biotherapy, Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China.,Department of Cardiology, The Second Hospital of Shandong University, Shandong University, Jinan, China
| | - Lei Chen
- State Key Laboratory of Biotherapy, Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Qin Tang
- State Key Laboratory of Biotherapy, Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Zhang
- State Key Laboratory of Biotherapy, Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Yanping Li
- State Key Laboratory of Biotherapy, Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhan He
- State Key Laboratory of Biotherapy, Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
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45
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Nakajima A, Kawaguchi F, Uemoto Y, Fukushima M, Yoshida E, Iwamoto E, Akiyama T, Kohama N, Kobayashi E, Honda T, Oyama K, Mannen H, Sasazaki S. A genome-wide association study for fat-related traits computed by image analysis in Japanese Black cattle. Anim Sci J 2018; 89:743-751. [DOI: 10.1111/asj.12987] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 11/30/2017] [Indexed: 11/30/2022]
Affiliation(s)
- Ayaka Nakajima
- Laboratory of Animal Breeding and Genetics; Graduate School of Agricultural Science; Kobe University; Kobe Japan
| | - Fuki Kawaguchi
- Laboratory of Animal Breeding and Genetics; Graduate School of Agricultural Science; Kobe University; Kobe Japan
| | - Yoshinobu Uemoto
- Laboratory of Animal Breeding and Genetics; Graduate School of Agricultural Science; Tohoku University; Sendai Japan
| | - Moriyuki Fukushima
- Northern Center of Agricultural Technology; General Technological Center of Hyogo Prefecture for Agriculture, Forest and Fishery; Asago Japan
| | - Emi Yoshida
- Hyogo Prefectural Technology Center for Agriculture, Forestry and Fisheries; Kasai Japan
| | - Eiji Iwamoto
- Hyogo Prefectural Technology Center for Agriculture, Forestry and Fisheries; Kasai Japan
| | - Takayuki Akiyama
- Northern Center of Agricultural Technology; General Technological Center of Hyogo Prefecture for Agriculture, Forest and Fishery; Asago Japan
| | - Namiko Kohama
- Northern Center of Agricultural Technology; General Technological Center of Hyogo Prefecture for Agriculture, Forest and Fishery; Asago Japan
| | - Eiji Kobayashi
- Division of Animal Breeding and Reproduction Research; Institute of Livestock and Grassland Science; National Agriculture and Food Research Organization; Tsukuba Japan
| | - Takeshi Honda
- Food Resources Education & Research Center; Kobe University; Kasai Japan
| | - Kenji Oyama
- Food Resources Education & Research Center; Kobe University; Kasai Japan
| | - Hideyuki Mannen
- Laboratory of Animal Breeding and Genetics; Graduate School of Agricultural Science; Kobe University; Kobe Japan
| | - Shinji Sasazaki
- Laboratory of Animal Breeding and Genetics; Graduate School of Agricultural Science; Kobe University; Kobe Japan
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46
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Yamamoto M, Takahashi Y. The Essential Role of SIRT1 in Hypothalamic-Pituitary Axis. Front Endocrinol (Lausanne) 2018; 9:605. [PMID: 30405528 PMCID: PMC6205959 DOI: 10.3389/fendo.2018.00605] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 09/24/2018] [Indexed: 01/28/2023] Open
Abstract
The endocrine system plays an essential role in the physiological adaptation to malnutrition. The adaptive response of various hormones directs the energy utilization toward the survival functions and away from growth and reproduction. Particularly, the hypothalamic pituitary axis plays an integral and a central role in the regulation of endocrine organs. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase that is activated in response to calorie restriction (CR). SIRT1 is involved in cellular processes via the deacetylation of histone as well as various transcription factors and signal transduction molecules and thereby modulates the endocrine/metabolic functions. There is much evidence to demonstrate clearly that SIRT1 in the hypothalamus, pituitary gland, and other target organs modifies the synthesis, secretion, and activities of hormones and in turn induces the adaptive responses. In this review, we discussed the role of SIRT1 in the hypothalamic pituitary axis and its pathophysiological significance.
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Affiliation(s)
- Masaaki Yamamoto
- Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Yutaka Takahashi
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
- *Correspondence: Yutaka Takahashi
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47
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Song J, Yang B, Jia X, Li M, Tan W, Ma S, Shi X, Feng L. Distinctive Roles of Sirtuins on Diabetes, Protective or Detrimental? Front Endocrinol (Lausanne) 2018; 9:724. [PMID: 30559718 PMCID: PMC6284472 DOI: 10.3389/fendo.2018.00724] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 11/15/2018] [Indexed: 12/21/2022] Open
Abstract
Dysregulation of metabolic pathways leads to type 2 diabetes, characteristic of high glucose concentration caused by insulin resistance. The histone deacetylases sirtuins exhibit remarkable enzymatic activities. Accumulating evidence indicates that sirtuins can be pharmacologically activated to ameliorate diabetes. Here, we evaluated different roles of sirtuins (SIRT1-SIRT7) in diabetes progression and described their involvement in metabolic pathways of skeletal muscle, adipose tissue and liver. The nuclear sirtuins, SIRT1, SIRT6, and SIRT7, regulate the activity of key transcription factors and cofactors in almost all tissues with the cellular responses to energy demands. The mitochondrial sirtuins, SIRT3, SIRT4, and SIRT5, regulate the activity of mitochondrial enzymes in response to fasting and calorie restriction. Moreover, genetic polymorphisms of SIRT1 and SIRT2 have been reported to associate with diabetes development. It's worth noting that SIRT1, SIRT2, SIRT3, and SIRT6 are positive regulators of insulin resistance in most cases. In the opposite, SIRT4 and SIRT7 inhibit insulin secretion and fatty acid oxidation. Identification of SIRT1 activators for diabetes has gained wide attention, such as metformin, resveratrol, and resveratrol derivatives. Randomized, prospective, and large-scale clinical trials are warrant to uncover the responsibilities of SIRTs modulators on diabetes progress.
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Affiliation(s)
- Jie Song
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
- Affiliated Hospital on Integration of Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Bing Yang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiaobin Jia
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Mingyu Li
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Wei Tan
- Affiliated Hospital on Integration of Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shitang Ma
- Life and Health college, Anhui Science and Technology University, Fengyang, China
| | - Xinhong Shi
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Liang Feng
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
- *Correspondence: Liang Feng
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48
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Sipos F, Székely H, Kis ID, Tulassay Z, Műzes G. Relation of the IGF/IGF1R system to autophagy in colitis and colorectal cancer. World J Gastroenterol 2017; 23:8109-8119. [PMID: 29290648 PMCID: PMC5739918 DOI: 10.3748/wjg.v23.i46.8109] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 10/28/2017] [Accepted: 12/04/2017] [Indexed: 02/06/2023] Open
Abstract
Metabolic syndrome (MetS), as a chronic inflammatory disorder has a potential role in the development of inflammatory and cancerous complications of the colonic tissue. The interaction of DNA damage and inflammation is affected by the insulin-like growth factor 1 receptor (IGF1R) signaling pathway. The IGF1R pathway has been reported to regulate autophagy, as well, but sometimes through a bidirectional context. Targeting the IGF1R-autophagy crosstalk could represent a promising strategy for the development of new antiinflammatory and anticancer therapies, and may help for subjects suffering from MetS who are at increased risk of colorectal cancer. However, therapeutic responses to targeted therapies are often shortlived, since a signaling crosstalk of IGF1R with other receptor tyrosine kinases or autophagy exists, leading to acquired cellular resistance to therapy. From a pharmacological point of view, it is attractive to speculate that synergistic benefits could be achieved by inhibition of one of the key effectors of the IGF1R pathway, in parallel with the pharmacological stimulation of the autophagy machinery, but cautiousness is also required, because pharmacologic IGF1R modulation can initiate additional, sometimes unfavorable biologic effects.
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Affiliation(s)
- Ferenc Sipos
- 2nd Department of Internal Medicine, Semmelweis University, Budapest 1088, Hungary
| | - Hajnal Székely
- 2nd Department of Internal Medicine, Semmelweis University, Budapest 1088, Hungary
| | - Imre Dániel Kis
- Faculty of Medicine, Semmelweis University, Budapest 1088, Hungary
| | - Zsolt Tulassay
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest 1088, Hungary
| | - Györgyi Műzes
- 2nd Department of Internal Medicine, Semmelweis University, Budapest 1088, Hungary
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49
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Bae EJ. Sirtuin 6, a possible therapeutic target for type 2 diabetes. Arch Pharm Res 2017; 40:1380-1389. [DOI: 10.1007/s12272-017-0989-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 11/16/2017] [Indexed: 12/27/2022]
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50
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Kaluski S, Portillo M, Besnard A, Stein D, Einav M, Zhong L, Ueberham U, Arendt T, Mostoslavsky R, Sahay A, Toiber D. Neuroprotective Functions for the Histone Deacetylase SIRT6. Cell Rep 2017; 18:3052-3062. [PMID: 28355558 DOI: 10.1016/j.celrep.2017.03.008] [Citation(s) in RCA: 114] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Revised: 01/09/2017] [Accepted: 03/01/2017] [Indexed: 02/06/2023] Open
Abstract
The histone deacetylase SIRT6 promotes DNA repair, but its activity declines with age with a concomitant accumulation of DNA damage. Furthermore, SIRT6 knockout mice exhibit an accelerated aging phenotype and die prematurely. Here, we report that brain-specific SIRT6-deficient mice survive but present behavioral defects with major learning impairments by 4 months of age. Moreover, the brains of these mice show increased signs of DNA damage, cell death, and hyperphosphorylated Tau-a critical mark in several neurodegenerative diseases. Mechanistically, SIRT6 regulates Tau protein stability and phosphorylation through increased activation of the kinase GSK3α/β. Finally, SIRT6 mRNA and protein levels are reduced in patients with Alzheimer's disease. Taken together, our results suggest that SIRT6 is critical to maintain genomic stability in the brain and that its loss leads to toxic Tau stability and phosphorylation. Therefore, SIRT6 and its downstream signaling could be targeted in Alzheimer's disease and age-related neurodegeneration.
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Affiliation(s)
- Shai Kaluski
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - Miguel Portillo
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - Antoine Besnard
- The Massachusetts General Hospital Cancer Center and The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Daniel Stein
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - Monica Einav
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - Lei Zhong
- The Massachusetts General Hospital Cancer Center and The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Uwe Ueberham
- Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstrasse 19, 04103 Leipzig, Germany
| | - Thomas Arendt
- Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstrasse 19, 04103 Leipzig, Germany
| | - Raul Mostoslavsky
- The Massachusetts General Hospital Cancer Center and The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Amar Sahay
- The Massachusetts General Hospital Cancer Center and The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Debra Toiber
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
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