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1
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Yuan T, Kumar S, Skinner ME, Victor-Joseph R, Abuaita M, Keijer J, Zhang J, Kunkel TJ, Liu Y, Petrunak EM, Saunders TL, Lieberman AP, Stuckey JA, Neamati N, Al-Murshedi F, Alfadhel M, Spelbrink JN, Rodenburg R, de Boer VC, Lombard DB. Human SIRT5 variants with reduced stability and activity do not cause neuropathology in mice. iScience 2024; 27:109991. [PMID: 38846003 PMCID: PMC11154205 DOI: 10.1016/j.isci.2024.109991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 03/06/2024] [Accepted: 05/13/2024] [Indexed: 06/09/2024] Open
Abstract
SIRT5 is a sirtuin deacylase that removes negatively charged lysine modifications, in the mitochondrial matrix and elsewhere in the cell. In benign cells and mouse models, under basal conditions, the phenotypes of SIRT5 deficiency are quite subtle. Here, we identify two homozygous SIRT5 variants in patients suspected to have mitochondrial disease. Both variants, P114T and L128V, are associated with reduced SIRT5 protein stability and impaired biochemical activity, with no evidence of neomorphic or dominant negative properties. The crystal structure of the P114T enzyme was solved and shows only subtle deviations from wild-type. Via CRISPR-Cas9, we generated a mouse model that recapitulates the human P114T mutation; homozygotes show reduced SIRT5 levels and activity, but no obvious metabolic abnormalities, neuropathology, or other gross phenotypes. We conclude that these human SIRT5 variants most likely represent severe hypomorphs, but are likely not by themselves the primary pathogenic cause of the neuropathology observed in the patients.
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Affiliation(s)
- Taolin Yuan
- Human and Animal Physiology, Wageningen University, De Elst 1, Wageningen, the Netherlands
| | - Surinder Kumar
- Department of Pathology & Laboratory Medicine, Miller School of Medicine, and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Mary E. Skinner
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Ryan Victor-Joseph
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Majd Abuaita
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jaap Keijer
- Human and Animal Physiology, Wageningen University, De Elst 1, Wageningen, the Netherlands
| | - Jessica Zhang
- Department of Pathology & Laboratory Medicine, Miller School of Medicine, and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
| | - Thaddeus J. Kunkel
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yanghan Liu
- Department of Medicinal Chemistry, College of Pharmacy and Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Elyse M. Petrunak
- Life Sciences Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
| | - Thomas L. Saunders
- Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Jeanne A. Stuckey
- Life Sciences Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
| | - Nouri Neamati
- Department of Medicinal Chemistry, College of Pharmacy and Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Fathiya Al-Murshedi
- Genetic and Developmental Medicine Clinic, Department of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Oman
| | - Majid Alfadhel
- Medical Genomic Research Department, King Abdullah International Medical Research Center(KAIMRC), King Saud Bin Abdulaziz University for Health Sciences(KSAU-HS), Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia
- Genetics and Precision Medicine Department (GPM), King Abdullah Specialized Children’s Hospital (KASCH), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia
| | - Johannes N. Spelbrink
- Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Richard Rodenburg
- Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Vincent C.J. de Boer
- Human and Animal Physiology, Wageningen University, De Elst 1, Wageningen, the Netherlands
| | - David B. Lombard
- Department of Pathology & Laboratory Medicine, Miller School of Medicine, and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
- Miami VA Healthcare System, Miami, FL 33125, USA
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Liu S, Li R, Sun YW, Lin H, Li HF. Protein succinylation, hepatic metabolism, and liver diseases. World J Hepatol 2024; 16:344-352. [PMID: 38577527 PMCID: PMC10989315 DOI: 10.4254/wjh.v16.i3.344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/08/2024] [Accepted: 03/01/2024] [Indexed: 03/27/2024] Open
Abstract
Succinylation is a highly conserved post-translational modification that is processed via enzymatic and non-enzymatic mechanisms. Succinylation exhibits strong effects on protein stability, enzyme activity, and transcriptional regulation. Protein succinylation is extensively present in the liver, and increasing evidence has demonstrated that succinylation is closely related to hepatic metabolism. For instance, histone acetyltransferase 1 promotes liver glycolysis, and the sirtuin 5-induced desuccinylation is involved in the regulation of the hepatic urea cycle and lipid metabolism. Therefore, the effects of succinylation on hepatic glucose, amino acid, and lipid metabolism under the action of various enzymes will be discussed in this work. In addition, how succinylases regulate the progression of different liver diseases will be reviewed, including the desuccinylation activity of sirtuin 7, which is closely associated with fatty liver disease and hepatitis, and the actions of lysine acetyltransferase 2A and histone acetyltransferase 1 that act as succinyltransferases to regulate the succinylation of target genes that influence the development of hepatocellular carcinoma. In view of the diversity and significance of protein succinylation, targeting the succinylation pathway may serve as an attractive direction for the treatment of liver diseases.
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Affiliation(s)
- Shuang Liu
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an 271018, Shandong Province, China
| | - Rui Li
- College of Life Sciences, Shandong Agricultural University, Tai'an 271018, Shandong Province, China
| | - Ya-Wen Sun
- College of Life Sciences, Shandong Agricultural University, Tai'an 271018, Shandong Province, China
| | - Hai Lin
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an 271018, Shandong Province, China
| | - Hai-Fang Li
- College of Life Sciences, Shandong Agricultural University, Tai'an 271018, Shandong Province, China.
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Yuan T, Kumar S, Skinner M, Victor-Joseph R, Abuaita M, Keijer J, Zhang J, Kunkel TJ, Liu Y, Petrunak EM, Saunders TL, Lieberman AP, Stuckey JA, Neamati N, Al-Murshedi F, Alfadhel M, Spelbrink JN, Rodenburg R, de Boer VCJ, Lombard DB. SIRT5 variants from patients with mitochondrial disease are associated with reduced SIRT5 stability and activity, but not with neuropathology. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.06.570371. [PMID: 38105987 PMCID: PMC10723467 DOI: 10.1101/2023.12.06.570371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
SIRT5 is a sirtuin deacylase that represents the major activity responsible for removal of negatively-charged lysine modifications, in the mitochondrial matrix and elsewhere in the cell. In benign cells and mouse models, under basal non-stressed conditions, the phenotypes of SIRT5 deficiency are generally quite subtle. Here, we identify two homozygous SIRT5 variants in human patients suffering from severe mitochondrial disease. Both variants, P114T and L128V, are associated with reduced SIRT5 protein stability and impaired biochemical activity, with no evidence of neomorphic or dominant negative properties. The crystal structure of the P114T enzyme was solved and shows only subtle deviations from wild-type. Via CRISPR-Cas9, we generate a mouse model that recapitulates the human P114T mutation; homozygotes show reduced SIRT5 levels and activity, but no obvious metabolic abnormalities, neuropathology or other gross evidence of severe disease. We conclude that these human SIRT5 variants most likely represent severe hypomorphs, and are likely not the primary pathogenic cause of the neuropathology observed in the patients.
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Affiliation(s)
- Taolin Yuan
- Human and Animal Physiology, Wageningen University, De Elst 1, Wageningen, The Netherlands
| | - Surinder Kumar
- Department of Pathology & Laboratory Medicine, Miller School of Medicine, and Sylvester Comprehensive Cancer Center, University of Miami, Miami FL 33136
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109
| | - Mary Skinner
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109
| | | | - Majd Abuaita
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109
| | - Jaap Keijer
- Human and Animal Physiology, Wageningen University, De Elst 1, Wageningen, The Netherlands
| | - Jessica Zhang
- Department of Pathology & Laboratory Medicine, Miller School of Medicine, and Sylvester Comprehensive Cancer Center, University of Miami, Miami FL 33136
| | | | - Yanghan Liu
- Department of Medicinal Chemistry, College of Pharmacy and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109
| | - Elyse M. Petrunak
- Life Sciences Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Thomas L. Saunders
- Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
| | | | - Jeanne A. Stuckey
- Life Sciences Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Nouri Neamati
- Department of Medicinal Chemistry, College of Pharmacy and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109
| | - Fathiya Al-Murshedi
- Genetic and Developmental Medicine Clinic, Department of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Oman
| | - Majid Alfadhel
- Medical Genomic Research Department, King Abdullah International Medical Research Center(KAIMRC), King Saud Bin Abdulaziz University for Health Sciences(KSAU-HS), Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia
- Genetics and Precision Medicine department (GPM), King Abdullah Specialized Children’s Hospital (KASCH), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia
| | - Johannes N. Spelbrink
- Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Richard Rodenburg
- Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Vincent C. J. de Boer
- Human and Animal Physiology, Wageningen University, De Elst 1, Wageningen, The Netherlands
| | - David B. Lombard
- Department of Pathology & Laboratory Medicine, Miller School of Medicine, and Sylvester Comprehensive Cancer Center, University of Miami, Miami FL 33136
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109
- Miami VA Healthcare System, Miami FL 33125
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D'Amico CI, Polasky DA, Steyer DJ, Ruotolo BT, Kennedy RT. Ion Mobility-Mass Spectrometry Coupled to Droplet Microfluidics for Rapid Protein Structure Analysis and Drug Discovery. Anal Chem 2022; 94:13084-13091. [PMID: 36098981 DOI: 10.1021/acs.analchem.2c02307] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Native mass spectrometry coupled to ion mobility (IM-MS) has become an important tool for the investigation of protein structure and dynamics upon ligand binding. Additionally, collisional activation or collision induced unfolding (CIU) can further probe conformational changes induced by ligand binding; however, larger scale screens have not been implemented due to limitations associated with throughput and sample introduction. In this work we explore the high-throughput capabilities of CIU fingerprinting. Fingerprint collection times were reduced 10-fold over traditional data collections through the use of improved smoothing and interpolation algorithms. Fast-CIU was then coupled to a droplet sample introduction approach using 40 nL droplet sample volumes and 2 s dwell times at each collision voltage. This workflow, which increased throughput by ∼16-fold over conventional nanospray CIU methods, was applied to a 96-compound screen against Sirtuin-5, a protein target of clinical interest. Over 20 novel Sirtuin-5 binders were identified, and it was found that Sirtuin-5 inhibitors will stabilize specific Sirtuin-5 gas-phase conformations. This work demonstrates that droplet-CIU can be implemented as a high-throughput biophysical characterization approach. Future work will focus on improving the throughput of this workflow and on automating data acquisition and analysis.
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Affiliation(s)
- Cara I D'Amico
- Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Daniel A Polasky
- Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Daniel J Steyer
- Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Brandon T Ruotolo
- Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Robert T Kennedy
- Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.,Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
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Siculella L, Giannotti L, Di Chiara Stanca B, Calcagnile M, Rochira A, Stanca E, Alifano P, Damiano F. Evidence for a Negative Correlation between Human Reactive Enamine-Imine Intermediate Deaminase A (RIDA) Activity and Cell Proliferation Rate: Role of Lysine Succinylation of RIDA. Int J Mol Sci 2021; 22:ijms22083804. [PMID: 33916919 PMCID: PMC8067581 DOI: 10.3390/ijms22083804] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/29/2021] [Accepted: 04/02/2021] [Indexed: 01/17/2023] Open
Abstract
Reactive intermediate deaminase (Rid) proteins are enzymes conserved in all domains of life. UK114, a mammalian member of RidA subfamily, has been firstly identified as a component of liver perchloric acid-soluble proteins (L-PSP). Although still poorly defined, several functions have been attributed to the mammalian protein UK114/RIDA, including the reactive intermediate deamination activity. The expression of UK114/RIDA has been observed in some tumors, arousing interest in this protein as an evaluable tumor marker. However, other studies reported a negative correlation between UK114/RIDA expression, tumor differentiation degree and cell proliferation. This work addressed the question of UK114/RIDA expression in human non-tumor HEK293 cell lines and in some human tumor cell lines. Here we reported that human RIDA (hRIDA) was expressed in all the analyzed cell line and subjected to lysine (K-)succinylation. In HEK293, hRIDA K-succinylation was negatively correlated to the cell proliferation rate and was under the control of SIRT5. Moreover, K-succinylation clearly altered hRIDA quantification by immunoblotting, explaining, at least in part, some discrepancies about RIDA expression reported in previous studies. We found that hRIDA was able to deaminate reactive enamine-imine intermediates and that K-succinylation drastically reduced deaminase activity. As predicted by in silico analysis, the observed reduction of deaminase activity has been related to the drastic alterations of hRIDA structure inferred by K-succinylation. The role of hRIDA and the importance of its K-succinylation in cell metabolism, especially in cancer biology, have been discussed.
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Affiliation(s)
- Luisa Siculella
- Laboratory of Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy; (L.G.); (B.D.C.S.); (A.R.); (E.S.)
- Correspondence: (L.S.); (F.D.); Tel.: +39-0832-298-696 (L.S.); +39-0832-298-698 (F.D.)
| | - Laura Giannotti
- Laboratory of Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy; (L.G.); (B.D.C.S.); (A.R.); (E.S.)
| | - Benedetta Di Chiara Stanca
- Laboratory of Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy; (L.G.); (B.D.C.S.); (A.R.); (E.S.)
| | - Matteo Calcagnile
- Laboratory of Microbiology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy; (M.C.); (P.A.)
| | - Alessio Rochira
- Laboratory of Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy; (L.G.); (B.D.C.S.); (A.R.); (E.S.)
| | - Eleonora Stanca
- Laboratory of Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy; (L.G.); (B.D.C.S.); (A.R.); (E.S.)
| | - Pietro Alifano
- Laboratory of Microbiology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy; (M.C.); (P.A.)
| | - Fabrizio Damiano
- Laboratory of Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy; (L.G.); (B.D.C.S.); (A.R.); (E.S.)
- Correspondence: (L.S.); (F.D.); Tel.: +39-0832-298-696 (L.S.); +39-0832-298-698 (F.D.)
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Yuan T, Keijer J, Guo AH, Lombard DB, de Boer VCJ. An optimized desuccinylase activity assay reveals a difference in desuccinylation activity between proliferative and differentiated cells. Sci Rep 2020; 10:17030. [PMID: 33046741 PMCID: PMC7552388 DOI: 10.1038/s41598-020-72833-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 09/03/2020] [Indexed: 12/21/2022] Open
Abstract
Succinylation is a novel post-translational modification identified on many proteins and is involved in multiple biological processes. Succinylation levels are dynamically regulated, balanced by succinylation and desuccinylation processes, and are closely connected to metabolic state in vivo. Sirtuins have been shown to possess NAD+-dependent desuccinylation activity in vitro and in vivo, among which the desuccinylation activity of SIRT5 is most extensively studied. Our understanding of the response of succinylation levels to different metabolic conditions, is hampered by the lack of a fast NAD+-dependent desuccinylation assay in a physiological context. In the present study, we therefore optimized and validated a fluorescence-based assay for measuring NAD+-dependent desuccinylation activity in cell lysates. Our results demonstrated that shorter and stricter reaction time was critical to approach the initial rate of NAD+-dependent desuccinylation activity in crude cell lysate systems, as compared to the desuccinylation reaction of purified His-SIRT5. Analysis of desuccinylation activity in SIRT5 knockout HEK293T cells confirmed the relevance of SIRT5 in cellular desuccinylation activity, as well as the presence of other NAD+-dependent desuccinylase activities. In addition, we were able to analyse desuccinylation and deacetylation activity in multiple cell lines using this assay. We showed a remarkably higher desuccinylase activity, but not deacetylase activity, in proliferative cultured muscle and adipose cells in comparison with their differentiated counterparts. Our results reveal an alteration in NAD+-dependent desuccinylation activity under different metabolic states.
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Affiliation(s)
- Taolin Yuan
- Human and Animal Physiology, Wageningen University & Research, Wageningen, 6708 WD, The Netherlands
| | - Jaap Keijer
- Human and Animal Physiology, Wageningen University & Research, Wageningen, 6708 WD, The Netherlands
| | - Angela H Guo
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - David B Lombard
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Vincent C J de Boer
- Human and Animal Physiology, Wageningen University & Research, Wageningen, 6708 WD, The Netherlands.
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Zou R, Shi W, Tao J, Li H, Lin X, Yang S, Hua P. SIRT5 and post-translational protein modifications: A potential therapeutic target for myocardial ischemia-reperfusion injury with regard to mitochondrial dynamics and oxidative metabolism. Eur J Pharmacol 2018; 818:410-418. [DOI: 10.1016/j.ejphar.2017.11.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 10/23/2017] [Accepted: 11/01/2017] [Indexed: 11/27/2022]
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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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