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Zhang Y, Yang J, Min J, Huang S, Li Y, Liu S. The emerging role of E3 ubiquitin ligases and deubiquitinases in metabolic dysfunction-associated steatotic liver disease. J Transl Med 2025; 23:368. [PMID: 40133964 PMCID: PMC11938720 DOI: 10.1186/s12967-025-06255-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 02/17/2025] [Indexed: 03/27/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, with a prevalence as high as 32.4%. MASLD encompasses a spectrum of liver pathologies, ranging from steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and, in some cases, progression to end-stage liver disease (cirrhosis and hepatocellular carcinoma). A comprehensive understanding of the pathogenesis of this highly prevalent liver disease may facilitate the identification of novel targets for the development of improved therapies. E3 ubiquitin ligases and deubiquitinases (DUBs) are key regulatory components of the ubiquitin‒proteasome system (UPS), which plays a pivotal role in maintaining intracellular protein homeostasis. Emerging evidence implicates that aberrant expression of E3 ligases and DUBs is involved in the progression of MASLD. Here, we review abnormalities in E3 ligases and DUBs by (1) discussing their targets, mechanisms, and functions in MASLD; (2) summarizing pharmacological interventions targeting these enzymes in preclinical and clinical studies; and (3) addressing challenges and future therapeutic strategies. This review synthesizes current evidence to highlight the development of novel therapeutic strategies based on the UPS for MASLD and progressive liver disease.
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Affiliation(s)
- Yu Zhang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, CSU-Sinocare Research Center for Nutrition and Metabolic Health, Furong Laboratory, Changsha, Hunan, 410011, China
| | - Jiahui Yang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, CSU-Sinocare Research Center for Nutrition and Metabolic Health, Furong Laboratory, Changsha, Hunan, 410011, China
| | - Jiali Min
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, CSU-Sinocare Research Center for Nutrition and Metabolic Health, Furong Laboratory, Changsha, Hunan, 410011, China
| | - Shan Huang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, CSU-Sinocare Research Center for Nutrition and Metabolic Health, Furong Laboratory, Changsha, Hunan, 410011, China
| | - Yuchen Li
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, CSU-Sinocare Research Center for Nutrition and Metabolic Health, Furong Laboratory, Changsha, Hunan, 410011, China
| | - Shanshan Liu
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, CSU-Sinocare Research Center for Nutrition and Metabolic Health, Furong Laboratory, Changsha, Hunan, 410011, China.
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Fan S, Chen W, Li Y, Guo K, Tang H, Ye J, Zhou Z, Tan M, Wei H, Huang X, Huang K, Ke X. Qige Decoction attenuated non-alcoholic fatty liver disease through regulating SIRT6-PPARα-mediated fatty acid oxidation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 138:156395. [PMID: 39855055 DOI: 10.1016/j.phymed.2025.156395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 11/24/2024] [Accepted: 01/12/2025] [Indexed: 01/27/2025]
Abstract
BACKGROUND Sirtuin 6 (SIRT6), a potential therapeutic target for non-alcoholic fatty liver disease (NAFLD), has been shown to regulate fatty acid oxidation (FAO) by interacting with peroxisome proliferator-activated receptor α (PPARα). However, the impact of SIRT6-PPARα pathway on NAFLD phenotype has not yet been reported. Qige decoction (QG), a traditional Chinese medicine (TCM) formula, is widely applied to treat disorders of glycolipid metabolism. Our previous experiments showed that QG reduced hepatic steatosis and provided preliminary evidence that QG may promote FAO. However, a thorough understanding of molecular mechanisms by which QG regulates FAO requires further investigation. PURPOSE To investigate the role of SIRT6-PPARα signalling pathway on NAFLD phenotype and explore the mechanism by which QG improves NAFLD and its relationship with FAO regulated by SIRT6-PPARα signalling pathway. METHODS In vivo study, NAFLD mice induced by high fat diet (HFD) were divided into two parts. The first part involved four groups: control (CON), model (MOD), PPARα agonist (WY-14,643, WY), and SIRT6 inhibitor (OSS-128,167, OS) groups. The second part involved five groups: CON group, MOD group, positive drug (POS) group, low dose QG (QGL) group, and high dose QG (QGH) group. Widely-targeted lipidomic were performed by UHPLC-QTOF/MS to analyse differential lipids (DELs) in the liver, while differentially expressed genes (DEGs) were analysed by transcriptome analysis on the Illumina sequencing platform. In vitro study, co-immunoprecipitation and dual luciferase assay were employed to further identify the molecular mechanisms of SIRT6-PPARα interaction. The lentiviral vector, TG assay, and acetyl-CoA assay were used to clarify the indispensable role of the SIRT6-PPARα signalling pathway on QG amelioration of lipid accumulation in vitro. RESULTS Down-regulation of SIRT6 inhibited PPARα-mediated FAO and aggravated lipid accumulation in hepatocytes both in vivo and in vitro. SIRT6 bound to PPARα in HepG2 cells; however, SIRT6 activation of the PPARα promoter was not detected. Along with QG reduced hepatocyte lipid accumulation, SIRT6-PPARα signalling pathway was upregulated in vivo and in vitro. However, the alleviating effect of QG on lipid accumulation was blocked by SIRT6 silencing in vitro. CONCLUSION This study verified that SIRT6-PPARα signalling pathway inhibition exacerbated NAFLD dyslipidaemia and hepatic steatosis. In addition, this study provided the first in-depth analysis of the molecular mechanisms by which QG ameliorates NFALD, involving promotion of FAO through activation of the SIRT6-PPARα signalling pathway. Our study offers significant insights for the clinical application of QG.
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Affiliation(s)
- Simin Fan
- Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 51000 Guangdong, PR China; First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou 510410 Guangdong, PR China; The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405 Guangdong, PR China
| | - Wei Chen
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405 Guangdong, PR China
| | - Yanfang Li
- First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou 510410 Guangdong, PR China
| | - Kaixin Guo
- First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou 510410 Guangdong, PR China
| | - Hui Tang
- First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou 510410 Guangdong, PR China
| | - Jintong Ye
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405 Guangdong, PR China
| | - Zunming Zhou
- First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou 510410 Guangdong, PR China
| | - Meiao Tan
- First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou 510410 Guangdong, PR China
| | - Haoyang Wei
- First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou 510410 Guangdong, PR China
| | - Xiwen Huang
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405 Guangdong, PR China
| | - Keer Huang
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405 Guangdong, PR China.
| | - Xuehong Ke
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405 Guangdong, PR China.
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Kielbowski K, Bratborska AW, Bakinowska E, Pawlik A. Sirtuins as therapeutic targets in diabetes. Expert Opin Ther Targets 2025; 29:117-135. [PMID: 40116767 DOI: 10.1080/14728222.2025.2482563] [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: 08/28/2024] [Revised: 03/01/2025] [Accepted: 03/18/2025] [Indexed: 03/23/2025]
Abstract
INTRODUCTION Sirtuins (SIRTs) are NAD+-dependent deacetylases that mediate post-translational modifications of proteins. Seven members of the SIRT family have been identified in mammals. Importantly, SIRTs interact with numerous metabolic and inflammatory pathways. Thus, researchers have investigated their role in metabolic and inflammatory disorders. AREAS COVERED In this review, we comprehensively discuss the involvement of SIRTs in the processes of pancreatic β-cell dysfunction, glucose tolerance, insulin secretion, lipid metabolism, and adipocyte functions. In addition, we describe the current evidence regarding modulation of the expression and activity of SIRTs in diabetes, diabetic complications, and obesity. EXPERT OPINION The development of specific SIRT activators and inhibitors that exhibit high selectivity toward specific SIRT isoforms remains a major challenge. This involves the need to elucidate the physiological pathways involving SIRTs, as well as their important role in the development of metabolic disorders. Molecular modeling techniques will be helpful to develop new compounds that modulate the activity of SIRTs, which may contribute to the preparation of new drugs that selectively target specific SIRTs. SIRTs hold promise as potential targets in metabolic disease, but there is much to learn about specific modulators and the final answers will await clinical trials.
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Affiliation(s)
- Kajetan Kielbowski
- Department of Physiology, Pomeranian Medical University, Szczecin, Poland
| | | | - Estera Bakinowska
- Department of Physiology, Pomeranian Medical University, Szczecin, Poland
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, Szczecin, Poland
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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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Ezz-Eldin YM, El-Din Ewees MG, Khalaf MM, Azouz AA. Modulation of SIRT6 related signaling pathways of p-AKT/mTOR and NRF2/HO-1 by memantine contributes to curbing the progression of tamoxifen/HFD-induced MASH in rats. Eur J Pharmacol 2024; 984:177069. [PMID: 39442744 DOI: 10.1016/j.ejphar.2024.177069] [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: 07/08/2024] [Revised: 10/02/2024] [Accepted: 10/20/2024] [Indexed: 10/25/2024]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disorder marked by hepatic fat accumulation and inflammatory infiltrates which may evolve to cirrhosis. Clinical studies have demonstrated the higher risk of MASH development after tamoxifen (TAM) therapy, especially in obese patients. Therefore, we aimed to evaluate MASH induction by TAM combined with high fat diet (HFD) and the potential interference of memantine (MEMA) with MASH progression via modulation of SIRT6 and its related signaling pathways. MASH was induced in female Wistar rats by co-administration of TAM (25 mg/kg/day, p.o.) and HFD for 5 weeks. Liver function biomarkers, tissue triglyceride and cholesterol, MASH scoring, SIRT6 with its related signals, and lipid synthesis/oxidation markers were estimated. By comparison to MASH group, MEMA improved liver function indices (ALT, AST, ALP, albumin) and reduced the progression of MASH, evidenced by decreased accumulation of lipids in hepatic tissue, improved histological features, and reduced MASH scoring. MEMA enhanced hepatic SIRT6 and downregulated p-AKT/mTOR signaling, that subsequently reduced expressions of the lipid synthesis biomarkers (SREBP1c, SCD), while elevating the lipid oxidation markers (PPAR-α, CPT1). Moreover, MEMA enhanced NRF2/HO-1 signaling, with subsequently improved antioxidant defense and pro-inflammatory/anti-inflammatory cytokines balance. Analysis of SIRT6 correlations with p-AKT/mTOR, NRF2/HO-1, SREBP1c, and PPAR-α further confirmed our results. Consequently, we conclude that MEMA could interfere with MASH progression, at least in part, via enhanced SIRT6 expression and modulation of its related p-AKT/mTOR and NRF2/HO-1 signaling pathways, eventually reducing liver steatosis and inflammation. That could be a promising therapeutic modality for curbing MASH progression.
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Affiliation(s)
- Yousra M Ezz-Eldin
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt
| | | | - Marwa M Khalaf
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt
| | - Amany A Azouz
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
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Zhao J, Zhang H, Pan C, He Q, Zheng K, Tang Y. Advances in research on the relationship between the LMNA gene and human diseases (Review). Mol Med Rep 2024; 30:236. [PMID: 39422026 PMCID: PMC11529173 DOI: 10.3892/mmr.2024.13358] [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: 06/18/2024] [Accepted: 08/29/2024] [Indexed: 10/19/2024] Open
Abstract
The LMNA gene, which is responsible for encoding lamin A/C proteins, is recognized as a primary constituent of the nuclear lamina. This protein serves crucial roles in various cellular physiological activities, including the maintenance of cellular structural stability, regulation of gene expression, mechanosensing and cellular motility. A significant association has been established between the LMNA gene and several major human diseases. Mutations, dysregulated expression of the LMNA gene, and improper processing of its encoded protein can result in a spectrum of pathological conditions. These diseases, collectively termed laminopathies, are directly attributed to LMNA gene dysfunction. The present review examines the recent advancements in research concerning the LMNA gene and its association with human diseases, while exploring its pathological roles. Particular emphasis is placed on the current status of LMNA gene research in the context of tumors. This includes an analysis of the abundance of LMNA alterations in cancer and its interplay with various signaling pathways. The aim of the present review was to provide novel perspectives for studying the development of LMNA‑related diseases and additional theoretical insights for basic and clinical translational research in this field.
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Affiliation(s)
- Jiumei Zhao
- Department of Laboratory, Chongqing Nanchuan District People's Hospital, Chongqing Medical University, Chongqing 408400, P.R. China
| | - Huijuan Zhang
- Forensic Science Centre, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Chenglong Pan
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Qian He
- School of Biomedical Engineering, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Kepu Zheng
- Forensic Science Centre, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Yu Tang
- Department of Pathology, The Third Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
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Baeken MW. Sirtuins and their influence on autophagy. J Cell Biochem 2024; 125:e30377. [PMID: 36745668 DOI: 10.1002/jcb.30377] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/02/2023] [Accepted: 01/19/2023] [Indexed: 02/07/2023]
Abstract
Sirtuins and autophagy are well-characterized agents that can promote longevity and protect individual organisms from age-associated diseases like neurodegenerative disorders. In recent years, more and more data has been obtained that discerned potential overlaps and crosstalk between Sirtuin proteins and autophagic activity. This review aims to summarize the advances within the field for each individual Sirtuin in mammalian systems. In brief, most Sirtuins have been implicated in promoting autophagy, with Sirtuin 1 and Sirtuin 6 showing the highest immediate involvement, while Sirtuin 4 and Sirtuin 5 only demonstrate occasional influence. The way Sirtuins regulate autophagy, however, is very diverse, as they have been shown to regulate gene expression of autophagy-associated genes and posttranslational modifications of proteins, with consequences for the activity and cellular localization of these proteins. They have also been shown to determine specific proteins for autophagic degradation. Overall, much data has been accumulated over recent years, yet many open questions remain. Especially although the dynamic between Sirtuin proteins and the immediate regulation of autophagic players like Light Chain 3B has been confirmed, many of these proteins have various orthologues in mammalian systems, and research so far has not exceeded the bona fide components of autophagy.
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Affiliation(s)
- Marius W Baeken
- Nucleic Acid Chemistry and Engineering Unit, Okinawa Institute of Science and Technology Graduate University, Onna-son, Okinawa, Japan
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Nguyen LH, Cho YE, Kim S, Kim Y, Kwak J, Suh JS, Lee J, Son K, Kim M, Jang ES, Song N, Choi B, Kim J, Tak Y, Hwang T, Jo J, Lee EW, Kim SB, Kim S, Kwon OB, Kim S, Lee SR, Lee H, Kim TJ, Hwang S, Yun H. Discovery of N-Aryl- N'-[4-(aryloxy)cyclohexyl]squaramide-Based Inhibitors of LXR/SREBP-1c Signaling Pathway Ameliorating Steatotic Liver Disease: Navigating the Role of SIRT6 Activation. J Med Chem 2024; 67:17608-17628. [PMID: 39259827 DOI: 10.1021/acs.jmedchem.4c01597] [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: 09/13/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily attributed to the abnormal upregulation of hepatic lipogenesis, which is especially caused by the overactivation of the liver X receptor/sterol regulatory element-binding protein-1c (LXR/SREBP-1c) pathway in hepatocytes. In this study, we report the rational design and synthesis of a novel series of squaramides via bioisosteric replacement, which was evaluated for its inhibitory activity on the LXR/SREBP-1c pathway using dual cell-based assays. Compound 31 was found to significantly downregulate LXR, SREBP-1c, and their target genes associated with lipogenesis. Further investigation revealed that compound 31 may indirectly inhibit the LXR/SREBP-1c pathway by activating the upstream regulator sirtuin 6 (SIRT6). Encouragingly, compound 31 substantially attenuated lipid accumulation in HepG2 cells and in the liver of high-fat-diet-fed mice. These findings suggest that compound 31 holds promise as a candidate for the development of treatments for MASLD and other lipid metabolism-related diseases.
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Affiliation(s)
- Long Huu Nguyen
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Ye Eun Cho
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Soyeong Kim
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea
| | - Yeonsoo Kim
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Jinsook Kwak
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Jung-Soo Suh
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Republic of Korea
| | - Jinyoung Lee
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Kyuwon Son
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Minseong Kim
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Eun Seo Jang
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Naghyun Song
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - BuChul Choi
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Jiah Kim
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Yealin Tak
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Taeyeon Hwang
- Korea Bioinformation Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon 34141, Republic of Korea
| | - Jeyun Jo
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Eun-Woo Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
| | - Sang-Bum Kim
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea
| | - Sanghyun Kim
- Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea
| | - Oh-Bin Kwon
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea
| | - Sangok Kim
- Korea Bioinformation Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon 34141, Republic of Korea
| | - Seoung Rak Lee
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
- Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
| | - Haeseung Lee
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
- Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
| | - Tae-Jin Kim
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Republic of Korea
| | - Seonghwan Hwang
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
- Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
| | - Hwayoung Yun
- College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
- Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
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Liu C, Pan X, Hao Z, Wang X, Wang C, Song G. Resveratrol suppresses hepatic fatty acid synthesis and increases fatty acid β-oxidation via the microRNA-33/SIRT6 signaling pathway. Exp Ther Med 2024; 28:326. [PMID: 38979023 PMCID: PMC11229395 DOI: 10.3892/etm.2024.12615] [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: 09/26/2023] [Accepted: 02/23/2024] [Indexed: 07/10/2024] Open
Abstract
Hyperlipidemia is a strong risk factor for numerous diseases. Resveratrol (Res) is a non-flavonoid polyphenol organic compound with multiple biological functions. However, the specific molecular mechanism and its role in hepatic lipid metabolism remain unclear. Therefore, the aim of the present study was to elucidate the mechanism underlying how Res improves hepatic lipid metabolism by decreasing microRNA-33 (miR-33) levels. First, blood miR-33 expression in participants with hyperlipidemia was detected by reverse transcription-quantitative PCR, and the results revealed significant upregulation of miR-33 expression in hyperlipidemia. Additionally, after transfection of HepG2 cells with miR-33 mimics or inhibitor, western blot analysis indicated downregulation and upregulation, respectively, of the mRNA and protein expression levels of sirtuin 6 (SIRT6). Luciferase reporter analysis provided further evidence for binding of miR-33 with the SIRT6 3'-untranslated region. Furthermore, the levels of peroxisome proliferator-activated receptor-γ (PPARγ), PPARγ-coactivator 1α and carnitine palmitoyl transferase 1 were increased, while the concentration levels of acetyl-CoA carboxylase, fatty acid synthase and sterol regulatory element-binding protein 1 were decreased when SIRT6 was overexpressed. Notably, Res improved the basic metabolic parameters of mice fed a high-fat diet by regulating the miR-33/SIRT6 signaling pathway. Thus, it was demonstrated that the dysregulation of miR-33 could lead to lipid metabolism disorders, while Res improved lipid metabolism by regulating the expression of miR-33 and its target gene, SIRT6. Thus, Res can be used to prevent or treat hyperlipidemia and associated diseases clinically by suppressing hepatic fatty acid synthesis and increasing fatty acid β-oxidation.
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Affiliation(s)
- Chunqiao Liu
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
- Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Xinyan Pan
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
- Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Zhihua Hao
- Department of Health Care, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Xing Wang
- Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Chao Wang
- Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Guangyao Song
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
- Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
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Wei Y, Shao J, Pang Y, Wen C, Wei K, Peng L, Wang Y, Wei X. Antidiabetic Potential of Tea and Its Active Compounds: From Molecular Mechanism to Clinical Evidence. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:11837-11853. [PMID: 38743877 DOI: 10.1021/acs.jafc.3c08492] [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: 05/16/2024]
Abstract
Diabetes mellitus (DM) is a chronic endocrine disorder that poses a long-term risk to human health accompanied by serious complications. Common antidiabetic drugs are usually accompanied by side effects such as hepatotoxicity and nephrotoxicity. There is an urgent need for natural dietary alternatives for diabetic treatment. Tea (Camellia sinensis) consumption has been widely investigated to lower the risk of diabetes and its complications through restoring glucose metabolism homeostasis, safeguarding pancreatic β-cells, ameliorating insulin resistance, ameliorating oxidative stresses, inhibiting inflammatory response, and regulating intestinal microbiota. It is indispensable to develop effective strategies to improve the absorption of tea active compounds and exert combinational effects with other natural compounds to broaden its hypoglycemic potential. The advances in clinical trials and population-based investigations are also discussed. This review primarily delves into the antidiabetic potential and underlying mechanisms of tea active compounds, providing a theoretical basis for the practical application of tea and its active compounds against diabetes.
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Affiliation(s)
- Yang Wei
- Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P.R. China
| | - Jie Shao
- Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P.R. China
| | - Yuxuan Pang
- Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P.R. China
| | - Caican Wen
- Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P.R. China
| | - Kang Wei
- Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P.R. China
| | - Lanlan Peng
- Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P.R. China
| | - Yuanfeng Wang
- College of Life Sciences, Shanghai Normal University, 100 Guilin Road, Shanghai 200234, P.R. China
| | - Xinlin Wei
- Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P.R. China
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11
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Ungurianu A, Zanfirescu A, Margină D. Exploring the therapeutic potential of quercetin: A focus on its sirtuin-mediated benefits. Phytother Res 2024; 38:2361-2387. [PMID: 38429891 DOI: 10.1002/ptr.8168] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/12/2023] [Accepted: 11/20/2023] [Indexed: 03/03/2024]
Abstract
As the global population ages, preventing lifestyle- and aging-related diseases is increasing, necessitating the search for safe and affordable therapeutic interventions. Among nutraceuticals, quercetin, a flavonoid ubiquitously present in various plants, has garnered considerable interest. This review aimed to collate and analyze existing literature on the therapeutic potentials of quercetin, especially its interactions with SIRTs and its clinical applicability based on its bioavailability and safety. This narrative review was based on a literature survey spanning from 2015 to 2023 using PUBMED. The keywords and MeSH terms used were: "quercetin" AND "bioavailability" OR "metabolism" OR "metabolites" as well as "quercetin" AND "SIRTuin" OR "SIRT*" AND "cellular effects" OR "pathway" OR "signaling" OR "neuroprotective" OR "cardioprotective" OR "nephroprotective" OR "antiatherosclerosis" OR "diabetes" OR "antidiabetic" OR "dyslipidemia" AND "mice" OR "rats". Quercetin demonstrates multiple therapeutic activities, including neuroprotective, cardioprotective, and anti-atherosclerotic effects. Its antioxidant, anti-inflammatory, antiviral, and immunomodulatory properties are well-established. At a molecular level, it majorly interacts with SIRTs, particularly SIRT1 and SIRT6, and modulates numerous signaling pathways, contributing to its therapeutic effects. These pathways play roles in reducing oxidative stress, inflammation, autophagy regulation, mitochondrial biogenesis, glucose utilization, fatty acid oxidation, and genome stability. However, clinical trials on quercetin's effectiveness in humans are scarce. Quercetin exhibits a wide range of SIRT-mediated therapeutic effects. Despite the compelling preclinical data, more standardized clinical trials are needed to fully understand its therapeutic potential. Future research should focus on addressing its bioavailability and safety concerns.
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Affiliation(s)
- Anca Ungurianu
- Carol Davila University of Medicine and Pharmacy, Faculty of Pharmacy, Department of Biochemistry, Bucharest, Romania
| | - Anca Zanfirescu
- Faculty of Pharmacy, Department of Pharmacology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Denisa Margină
- Carol Davila University of Medicine and Pharmacy, Faculty of Pharmacy, Department of Biochemistry, Bucharest, Romania
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12
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Yang S, Liu C, Jiang M, Liu X, Geng L, Zhang Y, Sun S, Wang K, Yin J, Ma S, Wang S, Belmonte JCI, Zhang W, Qu J, Liu GH. A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes. Protein Cell 2024; 15:98-120. [PMID: 37378670 PMCID: PMC10833472 DOI: 10.1093/procel/pwad039] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 05/19/2023] [Indexed: 06/29/2023] Open
Abstract
Aging increases the risk of liver diseases and systemic susceptibility to aging-related diseases. However, cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely characterized. Here, we constructed the first single-nucleus transcriptomic landscape of primate liver aging, in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell-cell interactions between hepatocytes and niche cells. Upon in-depth dissection of this rich dataset, we identified impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during aging. In particular, hyperactivated sterol regulatory element-binding protein (SREBP) signaling was a hallmark of the aged liver, and consequently, forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes, manifesting as impaired detoxification and accelerated cellular senescence. This study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.
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Affiliation(s)
- Shanshan Yang
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Xuanwu Hospital Capital Medical University, Beijing 100053, China
| | - Chengyu Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Mengmeng Jiang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Xiaoqian Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Lingling Geng
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Yiyuan Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Shuhui Sun
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Kang Wang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jian Yin
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shuai Ma
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Si Wang
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | | | - Weiqi Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Aging Biomarker Consortium, Beijing 100101, China
| | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Aging Biomarker Consortium, Beijing 100101, China
| | - Guang-Hui Liu
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
- Xuanwu Hospital Capital Medical University, Beijing 100053, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Aging Biomarker Consortium, Beijing 100101, China
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Wang Q, Liu J, Chen Z, Zheng J, Wang Y, Dong J. Targeting metabolic reprogramming in hepatocellular carcinoma to overcome therapeutic resistance: A comprehensive review. Biomed Pharmacother 2024; 170:116021. [PMID: 38128187 DOI: 10.1016/j.biopha.2023.116021] [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: 09/18/2023] [Revised: 11/23/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023] Open
Abstract
Hepatocellular carcinoma (HCC) poses a heavy burden on human health with high morbidity and mortality rates. Systematic therapy is crucial for advanced and mid-term HCC, but faces a significant challenge from therapeutic resistance, weakening drug effectiveness. Metabolic reprogramming has gained attention as a key contributor to therapeutic resistance. Cells change their metabolism to meet energy demands, adapt to growth needs, or resist environmental pressures. Understanding key enzyme expression patterns and metabolic pathway interactions is vital to comprehend HCC occurrence, development, and treatment resistance. Exploring metabolic enzyme reprogramming and pathways is essential to identify breakthrough points for HCC treatment. Targeting metabolic enzymes with inhibitors is key to addressing these points. Inhibitors, combined with systemic therapeutic drugs, can alleviate resistance, prolong overall survival for advanced HCC, and offer mid-term HCC patients a chance for radical resection. Advances in metabolic research methods, from genomics to metabolomics and cells to organoids, help build the HCC metabolic reprogramming network. Recent progress in biomaterials and nanotechnology impacts drug targeting and effectiveness, providing new solutions for systemic therapeutic drug resistance. This review focuses on metabolic enzyme changes, pathway interactions, enzyme inhibitors, research methods, and drug delivery targeting metabolic reprogramming, offering valuable references for metabolic approaches to HCC treatment.
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Affiliation(s)
- Qi Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun 130021, China
| | - Juan Liu
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing 100021, China; Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China; Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing 102218, China; Key Laboratory of Digital Intelligence Hepatology (Ministry of Education/Beijing), School of Clinical Medicine, Tsinghua University, Beijing, China.
| | - Ziye Chen
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China
| | - Jingjing Zheng
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Yunfang Wang
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing 100021, China; Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China; Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing 102218, China; Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China; Key Laboratory of Digital Intelligence Hepatology (Ministry of Education/Beijing), School of Clinical Medicine, Tsinghua University, Beijing, China.
| | - Jiahong Dong
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun 130021, China; Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing 100021, China; Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China; Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing 102218, China; Key Laboratory of Digital Intelligence Hepatology (Ministry of Education/Beijing), School of Clinical Medicine, Tsinghua University, Beijing, China.
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Xu M, Zhang P, Lv W, Chen Y, Chen M, Leng Y, Hu T, Wang K, Zhao Y, Shen J, You X, Gu D, Zhao W, Tan S. A bifunctional anti-PCSK9 scFv/Exendin-4 fusion protein exhibits enhanced lipid-lowering effects via targeting multiple signaling pathways in HFD-fed mice. Int J Biol Macromol 2023; 253:127003. [PMID: 37739280 DOI: 10.1016/j.ijbiomac.2023.127003] [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: 10/21/2022] [Revised: 05/14/2023] [Accepted: 09/17/2023] [Indexed: 09/24/2023]
Abstract
Fusion protein which encompasses more than one functional component, has become one of the most important representatives of macromolecular drugs for disease treatment since that monotherapy itself might not be effective enough to eradicate the disease. In this study, we sought to construct a bifunctional antibody fusion protein by fusing anti-PCSK9 scFv with Exendin-4 for simultaneously lowering both LDL-C and TG. Firstly, three Ex4-anti-PCSK9 scFv fusion proteins were constructed by genetically connecting the C-terminal of Exendin-4 to the N-terminal of anti-PCSK9 scFv through various flexible linker peptides (G4S)n (n = 2, 3, 4). After soluble expression in E. coli, the most potent Ex4-(G4S)4-anti-PCSK9 scFv fusion protein was selected based on in vitro activity assays. Then, we investigated the in vivo therapeutic effects of Ex4-(G4S)4-anti-PCSK9 scFv on the serum lipid profile and bodyweight changes as well as underlying molecular mechanism in HFD-fed C57BL/6 mice. The data showed that Ex4-(G4S)4-anti-PCSK9 scFv exhibits enhanced effects of lowering both LDL-C and TG in serum, reducing food intake and body weight via blocking PCSK9/LDLR, activating AMPK/SREBP-1 pathways, and up-regulating sirt6. Conclusively, Ex4-(G4S)4-anti-PCSK9 has the potential to serve as a promising therapeutic agent for effectively treating dyslipidemia with high levels of both LDL-C and TG.
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Affiliation(s)
- Menglong Xu
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Panpan Zhang
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Wenxiu Lv
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Yuting Chen
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Manman Chen
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Yeqing Leng
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Tuo Hu
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Ke Wang
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Yaqiang Zhao
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Jiaqi Shen
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Xiangyan You
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Dian Gu
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Wenfeng Zhao
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Shuhua Tan
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China.
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Yamagata K, Mizumoto T, Yoshizawa T. The Emerging Role of SIRT7 in Glucose and Lipid Metabolism. Cells 2023; 13:48. [PMID: 38201252 PMCID: PMC10778536 DOI: 10.3390/cells13010048] [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: 11/21/2023] [Revised: 12/13/2023] [Accepted: 12/24/2023] [Indexed: 01/12/2024] Open
Abstract
Sirtuins (SIRT1-7 in mammals) are a family of NAD+-dependent lysine deacetylases and deacylases that regulate diverse biological processes, including metabolism, stress responses, and aging. SIRT7 is the least well-studied member of the sirtuins, but accumulating evidence has shown that SIRT7 plays critical roles in the regulation of glucose and lipid metabolism by modulating many target proteins in white adipose tissue, brown adipose tissue, and liver tissue. This review focuses on the emerging roles of SIRT7 in glucose and lipid metabolism in comparison with SIRT1 and SIRT6. We also discuss the possible implications of SIRT7 inhibition in the treatment of metabolic diseases such as type 2 diabetes and obesity.
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Affiliation(s)
- Kazuya Yamagata
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (T.M.); (T.Y.)
- Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Tomoya Mizumoto
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (T.M.); (T.Y.)
| | - Tatsuya Yoshizawa
- Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (T.M.); (T.Y.)
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Wang Y, Liu T, Cai Y, Liu W, Guo J. SIRT6's function in controlling the metabolism of lipids and glucose in diabetic nephropathy. Front Endocrinol (Lausanne) 2023; 14:1244705. [PMID: 37876546 PMCID: PMC10591331 DOI: 10.3389/fendo.2023.1244705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 09/21/2023] [Indexed: 10/26/2023] Open
Abstract
Diabetic nephropathy (DN) is a complication of diabetes mellitus (DM) and the main cause of excess mortality in patients with type 2 DM. The pathogenesis and progression of DN are closely associated with disorders of glucose and lipid metabolism. As a member of the sirtuin family, SIRT6 has deacetylation, defatty-acylation, and adenosine diphosphate-ribosylation enzyme activities as well as anti-aging and anticancer activities. SIRT6 plays an important role in glucose and lipid metabolism and signaling, especially in DN. SIRT6 improves glucose and lipid metabolism by controlling glycolysis and gluconeogenesis, affecting insulin secretion and transmission and regulating lipid decomposition, transport, and synthesis. Targeting SIRT6 may provide a new therapeutic strategy for DN by improving glucose and lipid metabolism. This review elaborates on the important role of SIRT6 in glucose and lipid metabolism, discusses the potential of SIRT6 as a therapeutic target to improve glucose and lipid metabolism and alleviate DN occurrence and progression of DN, and describes the prospects for future research.
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Affiliation(s)
- Ying Wang
- Country Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Tongtong Liu
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuzi Cai
- Country Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Weijing Liu
- Country Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Jing Guo
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
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Abbotto E, Miro C, Piacente F, Salis A, Murolo M, Nappi A, Millo E, Russo E, Cichero E, Sturla L, Del Rio A, De Flora A, Nencioni A, Dentice M, Bruzzone S. SIRT6 pharmacological inhibition delays skin cancer progression in the squamous cell carcinoma. Biomed Pharmacother 2023; 166:115326. [PMID: 37611438 DOI: 10.1016/j.biopha.2023.115326] [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: 06/27/2023] [Revised: 08/08/2023] [Accepted: 08/12/2023] [Indexed: 08/25/2023] Open
Abstract
Sirtuin 6 (SIRT6) has a critical role in cutaneous Squamous Cell Carcinoma (cSCC): SIRT6 silencing in skin SCC cells has pro-differentiating effects and SIRT6 deletion abrogated DMBA-TPA-induced skin tumorigenesis in mice. On the other hand, SIRT6 acts as tumor suppressor in SCC by enhancing glycolysis in tumor propagating cells. Herein, pharmacological modulation of SIRT6 deacetylase activity was investigated in cSCC, with S6 (inhibitor) or MDL-800 (activator). In cSCC cells, S6 recreated the pro-differentiating effects of SIRT6 silencing, as the levels of Keratin 1, Keratin 10 and Loricrin were upregulated compared to controls. Next, the effects of SIRT6 pharmacological modulation were evaluated in a DMBA-TPA-induced skin cancer mouse model. Mice treated with the inhibitor S6 in a preventive approach, i.e. at the beginning of the promotion stage, presented reduced number and size of papillomas, compared to the controls. The epidermal hyperproliferation marker Keratin 6 and the cSCC marker Keratin 8 were less abundant when SIRT6 was inhibited. In S6-treated lesions, the Epithelial-Mesenchymal Transition (EMT) markers Zeb1 and Vimentin were less expressed compared to untreated lesions. In a therapeutic approach, i.e. treatment starting after papilloma appearance, the S6 group presented reduced papillomas (number and size), whereas MDL-800-treated mice displayed an opposite trend. In S6-treated lesions, Keratin 6 and Keratin 8 were less expressed, EMT was less advanced, with a higher E-cadherin/Vimentin ratio, indicating a delayed carcinogenesis when SIRT6 was inhibited. Our results confirm that SIRT6 plays a role in skin carcinogenesis and suggest SIRT6 pharmacological inhibition as a promising strategy in cSCC.
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Affiliation(s)
- Elena Abbotto
- DIMES, Section of Biochemistry, University of Genova, Viale Benedetto XV, 1, 16132 Genova, Italy
| | - Caterina Miro
- Department of Clinical Medicine and Surgery, University of Napoli Federico II, Via Pansini, 5, 80131 Napoli, Italy
| | - Francesco Piacente
- DIMES, Section of Biochemistry, University of Genova, Viale Benedetto XV, 1, 16132 Genova, Italy
| | - Annalisa Salis
- DIMES, Section of Biochemistry, University of Genova, Viale Benedetto XV, 1, 16132 Genova, Italy
| | - Melania Murolo
- Department of Clinical Medicine and Surgery, University of Napoli Federico II, Via Pansini, 5, 80131 Napoli, Italy
| | - Annarita Nappi
- Department of Clinical Medicine and Surgery, University of Napoli Federico II, Via Pansini, 5, 80131 Napoli, Italy
| | - Enrico Millo
- DIMES, Section of Biochemistry, University of Genova, Viale Benedetto XV, 1, 16132 Genova, Italy
| | - Eleonora Russo
- Department of Pharmacy, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy
| | - Elena Cichero
- Department of Pharmacy, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy
| | - Laura Sturla
- DIMES, Section of Biochemistry, University of Genova, Viale Benedetto XV, 1, 16132 Genova, Italy
| | - Alberto Del Rio
- Innovamol Consulting Srl, Strada San Faustino 167, 41126 Modena, Italy; Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council of Italy (CNR), Via P. Gobetti 101, I-40129 Bologna, Italy
| | - Antonio De Flora
- DIMES, Section of Biochemistry, University of Genova, Viale Benedetto XV, 1, 16132 Genova, Italy
| | - Alessio Nencioni
- Department of Internal Medicine, University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy; IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy.
| | - Monica Dentice
- Department of Clinical Medicine and Surgery, University of Napoli Federico II, Via Pansini, 5, 80131 Napoli, Italy
| | - Santina Bruzzone
- DIMES, Section of Biochemistry, University of Genova, Viale Benedetto XV, 1, 16132 Genova, Italy; IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy.
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Prakhar P, Bhatt B, Lohia GK, Shah A, Mukherjee T, Kolthur-Seetharam U, Sundaresan NR, Rajmani RS, Balaji KN. G9a and Sirtuin6 epigenetically modulate host cholesterol accumulation to facilitate mycobacterial survival. PLoS Pathog 2023; 19:e1011731. [PMID: 37871034 PMCID: PMC10621959 DOI: 10.1371/journal.ppat.1011731] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 11/02/2023] [Accepted: 10/02/2023] [Indexed: 10/25/2023] Open
Abstract
Cholesterol derived from the host milieu forms a critical factor for mycobacterial pathogenesis. However, the molecular circuitry co-opted by Mycobacterium tuberculosis (Mtb) to accumulate cholesterol in host cells remains obscure. Here, we report that the coordinated action of WNT-responsive histone modifiers G9a (H3K9 methyltransferase) and SIRT6 (H3K9 deacetylase) orchestrate cholesterol build-up in in vitro and in vivo mouse models of Mtb infection. Mechanistically, G9a, along with SREBP2, drives the expression of cholesterol biosynthesis and uptake genes; while SIRT6 along with G9a represses the genes involved in cholesterol efflux. The accumulated cholesterol in Mtb infected macrophages promotes the expression of antioxidant genes leading to reduced oxidative stress, thereby supporting Mtb survival. In corroboration, loss-of-function of G9a in vitro and pharmacological inhibition in vivo; or utilization of BMDMs derived from Sirt6-/- mice or in vivo infection in haplo-insufficient Sirt6-/+ mice; hampered host cholesterol accumulation and restricted Mtb burden. These findings shed light on the novel roles of G9a and SIRT6 during Mtb infection and highlight the previously unknown contribution of host cholesterol in potentiating anti-oxidative responses for aiding Mtb survival.
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Affiliation(s)
- Praveen Prakhar
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India
| | - Bharat Bhatt
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India
| | - Gaurav Kumar Lohia
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India
| | - Awantika Shah
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India
| | - Tanushree Mukherjee
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India
| | - Ullas Kolthur-Seetharam
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Nagalingam R. Sundaresan
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India
| | - Raju S. Rajmani
- Centre for Infectious Disease Research, Indian Institute of Science, Bangalore–, Karnataka, India
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19
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You Y, Liang W. SIRT1 and SIRT6: The role in aging-related diseases. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166815. [PMID: 37499928 DOI: 10.1016/j.bbadis.2023.166815] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 06/26/2023] [Accepted: 07/19/2023] [Indexed: 07/29/2023]
Abstract
Aging is characterized by progressive functional deterioration with increased risk of mortality. It is a complex biological process driven by a multitude of intertwined mechanisms such as increased DNA damage, chronic inflammation, and metabolic dysfunction. Sirtuins (SIRTs) are a family of NAD+-dependent enzymes that regulate fundamental biological functions from genomic stability and lifespan to energy metabolism and tumorigenesis. Of the seven mammalian SIRT isotypes (SIRT1-7), SIRT1 and SIRT6 are well-recognized for regulating signaling pathways related to aging. Herein, we review the protective role of SIRT1 and SIRT6 in aging-related diseases at molecular, cellular, tissue, and whole-organism levels. We also discuss the therapeutic potential of SIRT1 and SIRT6 modulators in the treatment of these diseases and challenges thereof.
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Affiliation(s)
- Yuzi You
- Department of General Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Wei Liang
- Department of Geriatrics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
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20
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Duan J, Huang Z, Nice EC, Xie N, Chen M, Huang C. Current advancements and future perspectives of long noncoding RNAs in lipid metabolism and signaling. J Adv Res 2023; 48:105-123. [PMID: 35973552 PMCID: PMC10248733 DOI: 10.1016/j.jare.2022.08.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 08/04/2022] [Accepted: 08/10/2022] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The investigation of lncRNAs has provided a novel perspective for elucidating mechanisms underlying diverse physiological and pathological processes. Compelling evidence has revealed an intrinsic link between lncRNAs and lipid metabolism, demonstrating that lncRNAs-induced disruption of lipid metabolism and signaling contribute to the development of multiple cancers and some other diseases, including obesity, fatty liver disease, and cardiovascular disease. AIMOF REVIEW The current review summarizes the recent advances in basic research about lipid metabolism and lipid signaling-related lncRNAs. Meanwhile, the potential and challenges of targeting lncRNA for the therapy of cancers and other lipid metabolism-related diseases are also discussed. KEY SCIENTIFIC CONCEPT OF REVIEW Compared with the substantial number of lncRNA loci, we still know little about the role of lncRNAs in metabolism. A more comprehensive understanding of the function and mechanism of lncRNAs may provide a new standpoint for the study of lipid metabolism and signaling. Developing lncRNA-based therapeutic approaches is an effective strategy for lipid metabolism-related diseases.
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Affiliation(s)
- Jiufei Duan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041 Chengdu, China
| | - Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041 Chengdu, China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Na Xie
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041 Chengdu, China.
| | - Mingqing Chen
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, 430079 Wuhan, China.
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041 Chengdu, China.
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21
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Sun Y, Zheng C, Li T, He X, Yang F, Guo W, Song J, Gao Y, Deng C, Huang X. GB1a Activates SIRT6 to Regulate Lipid Metabolism in Mouse Primary Hepatocytes. Int J Mol Sci 2023; 24:ijms24119540. [PMID: 37298491 DOI: 10.3390/ijms24119540] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/18/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Lipid accumulation, oxidative stress, and inflammation in hepatocytes are features of nonalcoholic fatty liver disease (NAFLD). Garcinia biflavonoid 1a (GB1a) is a natural product capable of hepatic protection. In this study, the effect of GB1a on anti-inflammatory, antioxidant, and regulation of the accumulation in HepG2 cells and mouse primary hepatocytes (MPHs) was investigated, and its regulatory mechanism was further explored. The result showed that GB1a reduced triglyceride (TG) content and lipid accumulation by regulating the expression of SREBP-1c and PPARα; GB1a reduced reactive oxygen species (ROS) and improved cellular oxidative stress to protect mitochondrial morphology by regulating genes Nrf2, HO-1, NQO1, and Keap1; and GB1a reduced the damage of hepatocytes by inhibiting the expression of inflammatory cytokines interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa B (NF-κB) p65. The activities of GB1a were lost in liver SIRT6-specific knockout mouse primary hepatocytes (SIRT6-LKO MPHs). This indicated that activating SIRT6 was critical for GB1a to perform its activity, and GB1a acted as an agonist of SIRT6. It was speculated that GB1a may be a potential drug for NAFLD treatment.
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Affiliation(s)
- Yongzhi Sun
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Congmin Zheng
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Ting Li
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Xinqian He
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Fan Yang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Wenfeng Guo
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- Institute of Science and Technology Park, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Jianping Song
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- Institute of Science and Technology Park, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Yong Gao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Changsheng Deng
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- Institute of Science and Technology Park, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Xinan Huang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- Institute of Science and Technology Park, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
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22
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Liu YP, Wen R, Liu CF, Zhang TN, Yang N. Cellular and molecular biology of sirtuins in cardiovascular disease. Biomed Pharmacother 2023; 164:114931. [PMID: 37263163 DOI: 10.1016/j.biopha.2023.114931] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 05/15/2023] [Accepted: 05/22/2023] [Indexed: 06/03/2023] Open
Abstract
Sirtuins (SIRTs) are a nicotinic adenine dinucleotide (+) -dependent histone deacetylase that regulates critical signaling pathways in prokaryotes and eukaryotes. Studies have identified seven mammalian homologs of the yeast SIRT silencing message regulator 2, namely, SIRT1-SIRT7. Recent in vivo and in vitro studies have successfully demonstrated the involvement of SIRTs in key pathways for cell biological function in physiological and pathological processes of the cardiovascular system, including processes including cellular senescence, oxidative stress, apoptosis, DNA damage, and cellular metabolism. Emerging evidence has stimulated a significant evolution in preventing and treating cardiovascular disease (CVD). Here, we review the important roles of SIRTs for the regulatory pathways involved in the pathogenesis of cardiovascular diseases and their molecular targets, including novel protein post-translational modifications of succinylation. In addition, we summarize the agonists and inhibitors currently identified to target novel specific small molecules of SIRTs. A better understanding of the role of SIRTs in the biology of CVD opens new avenues for therapeutic intervention with great potential for preventing and treating CVD.
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Affiliation(s)
- Yong-Ping Liu
- Department of Pediatric, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China
| | - Ri Wen
- Department of Pediatric, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China
| | - Chun-Feng Liu
- Department of Pediatric, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China
| | - Tie-Ning Zhang
- Department of Pediatric, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
| | - Ni Yang
- Department of Pediatric, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
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23
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Dong XC. Sirtuin 6-A Key Regulator of Hepatic Lipid Metabolism and Liver Health. Cells 2023; 12:cells12040663. [PMID: 36831330 PMCID: PMC9954390 DOI: 10.3390/cells12040663] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/14/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Sirtuin 6 (SIRT6) is an NAD-dependent deacetylase/deacylase/mono-ADP ribosyltransferase, a member of the sirtuin protein family. SIRT6 has been implicated in hepatic lipid homeostasis and liver health. Hepatic lipogenesis is driven by several master regulators including liver X receptor (LXR), carbohydrate response element binding protein (ChREBP), and sterol regulatory element binding protein 1 (SREBP1). Interestingly, these three transcription factors can be negatively regulated by SIRT6 through direct deacetylation. Fatty acid oxidation is regulated by peroxisome proliferator activated receptor alpha (PPARα) in the liver. SIRT6 can promote fatty acid oxidation by the activation of PPARα or the suppression of miR-122. SIRT6 can also directly modulate acyl-CoA synthetase long chain family member 5 (ACSL5) activity for fatty acid oxidation. SIRT6 also plays a critical role in the regulation of total cholesterol and low-density lipoprotein (LDL)-cholesterol through the regulation of SREBP2 and proprotein convertase subtilisin/kexin type 9 (PCSK9), respectively. Hepatic deficiency of Sirt6 in mice has been shown to cause hepatic steatosis, inflammation, and fibrosis, hallmarks of alcoholic and nonalcoholic steatohepatitis. SIRT6 can dampen hepatic inflammation through the modulation of macrophage polarization from M1 to M2 type. Hepatic stellate cells are a key cell type in hepatic fibrogenesis. SIRT6 plays a strong anti-fibrosis role by the suppression of multiple fibrogenic pathways including the transforming growth factor beta (TGFβ)-SMAD family proteins and Hippo pathways. The role of SIRT6 in liver cancer is quite complicated, as both tumor-suppressive and tumor-promoting activities have been documented in the literature. Overall, SIRT6 has multiple salutary effects on metabolic homeostasis and liver health, and it may serve as a therapeutic target for hepatic metabolic diseases. To date, numerous activators and inhibitors of SIRT6 have been developed for translational research.
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Affiliation(s)
- X. Charlie Dong
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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24
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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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25
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Hou T, Tian Y, Cao Z, Zhang J, Feng T, Tao W, Sun H, Wen H, Lu X, Zhu Q, Li M, Lu X, Liu B, Zhao Y, Yang Y, Zhu WG. Cytoplasmic SIRT6-mediated ACSL5 deacetylation impedes nonalcoholic fatty liver disease by facilitating hepatic fatty acid oxidation. Mol Cell 2022; 82:4099-4115.e9. [PMID: 36208627 DOI: 10.1016/j.molcel.2022.09.018] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 08/08/2022] [Accepted: 09/16/2022] [Indexed: 11/05/2022]
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26
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Wang D, Wang X. Diosgenin and Its Analogs: Potential Protective Agents Against Atherosclerosis. Drug Des Devel Ther 2022; 16:2305-2323. [PMID: 35875677 PMCID: PMC9304635 DOI: 10.2147/dddt.s368836] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 07/09/2022] [Indexed: 11/23/2022] Open
Abstract
Atherosclerosis is a chronic inflammatory disease of the artery wall associated with lipid metabolism imbalance and maladaptive immune response, which mediates most cardiovascular events. First-line drugs such as statins and antiplatelet drug aspirin have shown good effects against atherosclerosis but may lead to certain side effects. Thus, the development of new, safer, and less toxic agents for atherosclerosis is urgently needed. Diosgenin and its analogs have gained importance for their efficacy against life-threatening diseases, including cardiovascular, endocrine, nervous system diseases, and cancer. Diosgenin and its analogs are widely found in the rhizomes of Dioscore, Solanum, and other species and share similar chemical structures and pharmacological effects. Recent data suggested diosgenin plays an anti-atherosclerosis role through its anti-inflammatory, antioxidant, plasma cholesterol-lowering, anti-proliferation, and anti-thrombotic effects. However, a review of the effects of diosgenin and its natural structure analogs on AS is still lacking. This review summarizes the effects of diosgenin and its analogs on vascular endothelial dysfunction, vascular smooth muscle cell (VSMC) proliferation, migration and calcification, lipid metabolism, and inflammation, and provides a new overview of its anti-atherosclerosis mechanism. Besides, the structures, sources, safety, pharmacokinetic characteristics, and biological availability are introduced to reveal the limitations and challenges of current studies, hoping to provide a theoretical basis for the clinical application of diosgenin and its analogs and provide a new idea for developing new agents for atherosclerosis.
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Affiliation(s)
- Dan Wang
- Cardiovascular Research Institute of Traditional Chinese Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
- Cardiovascular Department of Traditional Chinese Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Branch of National Clinical Research Center for Chinese Medicine Cardiology, Shanghai, People’s Republic of China
| | - Xiaolong Wang
- Cardiovascular Research Institute of Traditional Chinese Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
- Cardiovascular Department of Traditional Chinese Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Branch of National Clinical Research Center for Chinese Medicine Cardiology, Shanghai, People’s Republic of China
- Correspondence: Xiaolong Wang, Tel +86 13501991450, Fax +86 21 51322445, Email
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27
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Liu T, Yu J, Ge C, Zhao F, Chen J, Miao C, Jin W, Zhou Q, Geng Q, Lin H, Tian H, Chen T, Xie H, Cui Y, Yao M, Xiao X, Li J, Li H. Sperm associated antigen 4 promotes SREBP1-mediated de novo lipogenesis via interaction with lamin A/C and contributes to tumor progression in hepatocellular carcinoma. Cancer Lett 2022; 536:215642. [PMID: 35307486 DOI: 10.1016/j.canlet.2022.215642] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/22/2022] [Accepted: 03/10/2022] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is a highly malignant tumor and its progression is associated with altered lipid metabolism in precancerous lesions, such as non-alcoholic fatty liver disease. Here, we identified sperm associated antigen 4 (SPAG4), and explored its oncogenic role in HCC progression. Database analysis and immunohistochemistry indicated increased level of SPAG4 in HCC tissues which was of prognostic value. Gain/loss-of-function experiments showed that SPAG4 exerted oncogenic roles in HCC growth both in vitro and in vivo. RNA sequencing revealed activation of a lipogenic state and SREBP1-mediated pathway following SPAG4 overexpression. Mechanistically, the N-terminal region of SPAG4 bound to lamin A/C, which increased SREBP1 expression, nuclear translocation, and transcriptional activity. Treatment with orlistat, a lipid synthesis inhibitor, reversed SPAG4-mediated oncogenic effects, and its efficacy varied with SPAG4 level. The effect of orlistat was further amplified when combined with sorafenib in tumor xenograft mouse models. Our study provides evidence that SPAG4 mediates HCC progression by affecting lipid metabolism. Administration of orlistat combined with sorafenib reverses SPAG4-mediated oncogenesis in HCC cells and ectopic xenograft tumors in mice, suggesting that this pathway represents a potential target for HCC treatment.
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Affiliation(s)
- Tengfei Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China; Department of Oncology, Ren ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Junming Yu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Chao Ge
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Fangyu Zhao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Jing Chen
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Chunxiao Miao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Wenjiao Jin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Qingqing Zhou
- Department of Oncology, Rui jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200020, China
| | - Qin Geng
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Hechun Lin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Hua Tian
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Taoyang Chen
- Qi Dong Liver Cancer Institute, Qi Dong, 226200, China
| | - Haiyang Xie
- Department of General Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China
| | - Ying Cui
- Cancer Institute of Guangxi, Nanning, 530027, China
| | - Ming Yao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Xiuying Xiao
- Department of Oncology, Ren ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Jinjun Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Hong Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China.
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28
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McGinnis CD, Jennings EQ, Harris PS, Galligan JJ, Fritz KS. Biochemical Mechanisms of Sirtuin-Directed Protein Acylation in Hepatic Pathologies of Mitochondrial Dysfunction. Cells 2022; 11:cells11132045. [PMID: 35805129 PMCID: PMC9266223 DOI: 10.3390/cells11132045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/06/2022] [Accepted: 06/10/2022] [Indexed: 12/12/2022] Open
Abstract
Mitochondrial protein acetylation is associated with a host of diseases including cancer, Alzheimer’s, and metabolic syndrome. Deciphering the mechanisms regarding how protein acetylation contributes to disease pathologies remains difficult due to the complex diversity of pathways targeted by lysine acetylation. Specifically, protein acetylation is thought to direct feedback from metabolism, whereby nutritional status influences mitochondrial pathways including beta-oxidation, the citric acid cycle, and the electron transport chain. Acetylation provides a crucial connection between hepatic metabolism and mitochondrial function. Dysregulation of protein acetylation throughout the cell can alter mitochondrial function and is associated with numerous liver diseases, including non-alcoholic and alcoholic fatty liver disease, steatohepatitis, and hepatocellular carcinoma. This review introduces biochemical mechanisms of protein acetylation in the regulation of mitochondrial function and hepatic diseases and offers a viewpoint on the potential for targeted therapies.
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Affiliation(s)
- Courtney D. McGinnis
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (C.D.M.); (P.S.H.)
| | - Erin Q. Jennings
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA; (E.Q.J.); (J.J.G.)
| | - Peter S. Harris
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (C.D.M.); (P.S.H.)
| | - James J. Galligan
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA; (E.Q.J.); (J.J.G.)
| | - Kristofer S. Fritz
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (C.D.M.); (P.S.H.)
- Correspondence:
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29
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Xiang X, Ohshiro K, Zaidi S, Yang X, Bhowmick K, Vegesna AK, Bernstein D, Crawford JM, Mishra B, Latham PS, Gough NR, Rao S, Mishra L. Impaired reciprocal regulation between SIRT6 and TGF-β signaling in fatty liver. FASEB J 2022; 36:e22335. [PMID: 35506565 PMCID: PMC11288617 DOI: 10.1096/fj.202101518r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 03/14/2022] [Accepted: 04/21/2022] [Indexed: 11/11/2022]
Abstract
Dysregulated transforming growth factor-beta (TGF-β) signaling contributes to fibrotic liver disease and hepatocellular cancer (HCC), both of which are associated with fatty liver disease. SIRT6 limits fibrosis by inhibiting TGF-β signaling through deacetylating SMAD2 and SMAD3 and limits lipogenesis by inhibiting SREBP1 and SREBP2 activity. Here, we showed that, compared to wild-type mice, high-fat diet-induced fatty liver is worse in TGF-β signaling-deficient mice (SPTBN1+/- ) and the mutant mice had reduced SIRT6 abundance in the liver. Therefore, we hypothesized that altered reciprocal regulation between TGF-β signaling and SIRT6 contributes to these liver pathologies. We found that deficiency in SMAD3 or SPTBN1 reduced SIRT6 mRNA and protein abundance and impaired TGF-β induction of SIRT6 transcripts, and that SMAD3 bound to the SIRT6 promoter, suggesting that an SMAD3-SPTBN1 pathway mediated the induction of SIRT6 in response to TGF-β. Overexpression of SIRT6 in HCC cells reduced the expression of TGF-β-induced genes, consistent with the suppressive role of SIRT6 on TGF-β signaling. Manipulation of SIRT6 abundance in HCC cells altered sterol regulatory element-binding protein (SREBP) activity and overexpression of SIRT6 reduced the amount of acetylated SPTBN1 and the abundance of both SMAD3 and SPTBN1. Furthermore, induction of SREBP target genes in response to SIRT6 overexpression was impaired in SPTBN1 heterozygous cells. Thus, we identified a regulatory loop between SIRT6 and SPTBN1 that represents a potential mechanism for susceptibility to fatty liver in the presence of dysfunctional TGF-β signaling.
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Affiliation(s)
- Xiyan Xiang
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, 11724, USA
| | - Kazufumi Ohshiro
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
| | - Sobia Zaidi
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, 11724, USA
| | - Xiaochun Yang
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, 11724, USA
| | - Krishanu Bhowmick
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, 11724, USA
| | - Anil K. Vegesna
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
| | - David Bernstein
- Division of Hepatology, Northwell Health and Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
| | - James M Crawford
- Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
| | - Bibhuti Mishra
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Department of Neurology, Northwell Health, Manhasset, NY, 11030, USA
| | - Patricia S. Latham
- Department of Pathology, George Washington University, Washington, DC, 20037, USA
| | - Nancy R. Gough
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
| | - Shuyun Rao
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
| | - Lopa Mishra
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, 11724, USA
- Division of Gastroenterology, Department of Medicine, Northwell Health, NY, 11030, USA
- Department of Surgery, The George Washington University, Washington, DC, 20037, USA
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Wu S, Liu H. Sirtuins-Novel Regulators of Epigenetic Alterations in Airway Inflammation. Front Genet 2022; 13:862577. [PMID: 35620467 PMCID: PMC9127257 DOI: 10.3389/fgene.2022.862577] [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: 01/26/2022] [Accepted: 03/31/2022] [Indexed: 11/13/2022] Open
Abstract
Histone modification is an important epigenetic alteration, and histone deacetylases are involved in the occurrence and development of various respiratory diseases. Sirtuins (SIRTs) have been demonstrated to play an important role in the formation and progression of chronic inflammatory diseases of the respiratory tract. SIRTs participate in the regulation of oxidative stress and inflammation and are related to cell structure and cellular localization. This paper summarizes the roles and mechanisms of SIRTs in airway inflammation and describes the latest research on SIRT modulators, aiming to provide a theoretical basis for the study of potential epigenetic alteration-inducing drug targets.
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Affiliation(s)
- Shunyu Wu
- Department of Otolaryngological, the Second Affiliated Hospital of the Naval Military Medical University (Shanghai Changzheng Hospital), Shanghai, China
| | - Huanhai Liu
- Department of Otolaryngological, the Second Affiliated Hospital of the Naval Military Medical University (Shanghai Changzheng Hospital), Shanghai, China
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Yang Y, Zhu M, Liang J, Wang H, Sun D, Li H, Chen L. SIRT6 mediates multidimensional modulation to maintain organism homeostasis. J Cell Physiol 2022; 237:3205-3221. [PMID: 35621134 DOI: 10.1002/jcp.30791] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 05/05/2022] [Accepted: 05/16/2022] [Indexed: 12/20/2022]
Abstract
As a member of the silent information regulators (sirtuins) family, SIRT6 can regulate a variety of biological processes, including DNA repair, glucose and lipid metabolism, oxidative stress and lifespan, and so forth. SIRT6 maintains organism homeostasis in a variety of phenotypes by mediating epigenetic regulation and posttranslational modification of functional proteins. In this review, we outline the structural basis of SIRT6 enzyme activity and its mechanism of maintaining organism homeostasis in a variety of phenotypes, with an emphasis on the upstream that regulates SIRT6 expression and the downstream substrates. And how SIRT6 achieves multidimensional coordination to maintain organism homeostasis and even extend lifespan. We try to understand the regulatory mechanism of SIRT6 in different phenotypes from the perspective of protein interaction.
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Affiliation(s)
- Yueying Yang
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Man Zhu
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Jing Liang
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Hui Wang
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Dejuan Sun
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Hua Li
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.,School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lixia Chen
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
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Hepatic SIRT6 Modulates Transcriptional Activities of FXR to Alleviate Acetaminophen-induced Hepatotoxicity. Cell Mol Gastroenterol Hepatol 2022; 14:271-293. [PMID: 35526796 PMCID: PMC9218579 DOI: 10.1016/j.jcmgh.2022.04.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 04/21/2022] [Accepted: 04/26/2022] [Indexed: 01/06/2023]
Abstract
BACKGROUND & AIMS Excessive acetaminophen (APAP) intake causes oxidative stress and inflammation, leading to fatal hepatotoxicity; however, the mechanism remains unclear. This study aims to explore the protective effects and detailed mechanisms of sirtuin 6 (SIRT6) in the defense against APAP-induced hepatotoxicity. METHODS Hepatocyte-specific SIRT6 knockout mice, farnesoid X receptor (FXR) knockout mice, and mice with genetic or pharmacological activation of SIRT6 were subjected to APAP to evaluate the critical role of SIRT6 in the pathogenesis of acute liver injury. RNA sequences were used to investigate molecular mechanisms underlying this process. RESULTS Hepatic SIRT6 expression was substantially reduced in the patients and mice with acute liver injury. The deletion of SIRT6 in mice and mice primary hepatocytes led to high N-acetyl-p-benzo-quinoneimine and low glutathione levels in the liver, thereby enhancing APAP overdose-induced liver injury, manifested as increased hepatic centrilobular necrosis, oxidative stress, and inflammation. Conversely, overexpression or pharmacological activation of SIRT6 enhanced glutathione and decreased N-acetyl-p-benzo-quinoneimine, thus alleviating APAP-induced hepatotoxicity via normalization of liver damage, inflammatory infiltration, and oxidative stress. Our molecular analysis revealed that FXR is regulated by SIRT6, which is associated with the pathological progression of ALI. Mechanistically, SIRT6 deacetylates FXR and elevates FXR transcriptional activity. FXR ablation in mice and mice primary hepatocytes prominently blunted SIRT6 overexpression and activation-mediated ameliorative effects. Conversely, pharmacological activation of FXR mitigated APAP-induced hepatotoxicity in SIRT6 knockout mice. CONCLUSIONS Our current study suggests that SIRT6 plays a crucial role in APAP-induced hepatotoxicity, and pharmacological activation of SIRT6 may represent a novel therapeutic strategy for APAP overdose-induced liver injury.
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Bian C, Zhang H, Gao J, Wang Y, Li J, Guo D, Wang W, Song Y, Weng Y, Ren H. SIRT6 regulates SREBP1c-induced glucolipid metabolism in liver and pancreas via the AMPKα-mTORC1 pathway. J Transl Med 2022; 102:474-484. [PMID: 34923569 DOI: 10.1038/s41374-021-00715-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 11/11/2021] [Accepted: 11/12/2021] [Indexed: 11/09/2022] Open
Abstract
The aim of this study was to determine the mechanism by which SIRT6 regulates glucolipid metabolism disorders. We detected histological and molecular changes in Sprague-Dawley rats as well as in BRL 3A and INS-1 cell lines subjected to overnutrition and starvation. SIRT6, SREBP1c, and glucolipid metabolism biomarkers were identified by fluorescence co-localization, real-time PCR, and western blotting. Gene silencing studies were performed. Recombinant SIRT6, AMPK agonist (AICAR), mTOR inhibitor (rapamycin), and liver X receptor (LXR) agonist (T0901317) were used to pre-treated in BRL 3A and INS-1 cells. Real-time PCR and western blotting were used to detect related proteins, and cell counting was utilized to detect proliferation. We obtained conflicting results; SIRT6 and SREBP1c appeared in both the liver and pancreas of high-fat and hungry rats. Recombinant SIRT6 alleviated the decrease in AMPKα and increase in mTORC1 (complex of mTOR, Raptor, and Rheb) caused by overnutrition. SIRT6 siRNA reversed the glucolipid metabolic disorders caused by the AMPK agonist and mTOR inhibitor but not by the LXR agonist. Taken together, our results demonstrate that SIRT6 regulates glycolipid metabolism through AMPKα-mTORC1 regulating SREBP1c in the liver and pancreas induced by overnutrition and starvation, independent of LXR.
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Affiliation(s)
- Che Bian
- Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Haibo Zhang
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Jing Gao
- Department of Gerontology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yuxia Wang
- Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Jia Li
- Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Dan Guo
- Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Wei Wang
- Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Yuling Song
- Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Yang Weng
- Department of Gastroenterology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Huiwen Ren
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, China.
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Avilkina V, Chauveau C, Ghali Mhenni O. Sirtuin function and metabolism: Role in pancreas, liver, and adipose tissue and their crosstalk impacting bone homeostasis. Bone 2022; 154:116232. [PMID: 34678494 DOI: 10.1016/j.bone.2021.116232] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 10/07/2021] [Accepted: 10/08/2021] [Indexed: 12/12/2022]
Abstract
Mammalian sirtuins (SIRT1-7) are members of the nicotine adenine dinucleotide (NAD+)-dependent family of enzymes critical for histone deacetylation and posttranslational modification of proteins. Sirtuin family members regulate a wide spectrum of biological processes and are best known for maintaining longevity. Sirtuins are well characterized in metabolic tissues such as the pancreas, liver and adipose tissue (AT). They are regulated by a diverse range of stimuli, including nutrients and metabolic changes within the organism. Indeed, nutrient-associated conditions, such as obesity and anorexia nervosa (AN), were found to be associated with bone fragility development in osteoporosis. Interestingly, it has also been demonstrated that sirtuins, more specifically SIRT1, can regulate bone activity. Various studies have demonstrated the importance of sirtuins in bone in the regulation of bone homeostasis and maintenance of the balance between bone resorption and bone formation. However, to understand the molecular mechanisms involved in the negative regulation of bone homeostasis during overnutrition (obesity) or undernutrition, it is crucial to examine a wider picture and to determine the pancreatic, liver and adipose tissue pathway crosstalk responsible for bone loss. Particularly, under AN conditions, sirtuin family members are highly expressed in metabolic tissue, but this phenomenon is reversed in bone, and severe bone loss has been observed in human subjects. AN-associated bone loss may be connected to SIRT1 deficiency; however, additional factors may interfere with bone homeostasis. Thus, in this review, we focus on sirtuin activity in the pancreas, liver and AT in cases of over- and undernutrition, especially the regulation of their secretome by sirtuins. Furthermore, we examine how the secretome of the pancreas, liver and AT affects bone homeostasis, focusing on undernutrition. This review aims to lead to a better understanding of the crosstalk between sirtuins, metabolic organs and bone. In long term prospective it should contribute to promote improvement of therapeutic strategies for the prevention of metabolic diseases and the development of osteoporosis.
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Affiliation(s)
- Viktorija Avilkina
- Marrow Adiposity and Bone Lab (MABLab) ULR4490, Univ. Littoral Côte d'Opale, F-62200, Boulogne-sur-Mer, Univ. Lille F-59000 Lille, CHU Lille, F-59000 Lille, France
| | - Christophe Chauveau
- Marrow Adiposity and Bone Lab (MABLab) ULR4490, Univ. Littoral Côte d'Opale, F-62200, Boulogne-sur-Mer, Univ. Lille F-59000 Lille, CHU Lille, F-59000 Lille, France
| | - Olfa Ghali Mhenni
- Marrow Adiposity and Bone Lab (MABLab) ULR4490, Univ. Littoral Côte d'Opale, F-62200, Boulogne-sur-Mer, Univ. Lille F-59000 Lille, CHU Lille, F-59000 Lille, France.
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Raghu S, Prabhashankar AB, Shivanaiah B, Tripathi E, Sundaresan NR. Sirtuin 6 Is a Critical Epigenetic Regulator of Cancer. Subcell Biochem 2022; 100:337-360. [PMID: 36301499 DOI: 10.1007/978-3-031-07634-3_10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Sirtuin 6 (SIRT6) is a member of the mammalian sirtuin family with deacetylase, deacylase, and mono-ADP-ribosyl-transferase activities. It is a multitasking chromatin-associated protein regulating different cellular and physiological functions in cells. Specifically, SIRT6 dysfunction is implicated in several aging-related human diseases, including cancer. Studies indicate that SIRT6 has a tumor-specific role, and it is considered a tumor suppressor as well as a tumor growth inducer, depending on the type of cancer. In this chapter, we review the role of SIRT6 in metabolism, genomic stability, and cancer. Further, we provide an insight into the interplay of the tumor-suppressing and oncogenic roles of SIRT6 in cancer. Additionally, we discuss the use of small-molecule SIRT6 modulators as potential therapeutics.
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Affiliation(s)
- Sukanya Raghu
- Department of Microbiology and Cell Biology, Division of Biological Sciences, Indian Institute of Science (IISc), Bengaluru, Karnataka, India
| | - Arathi Bangalore Prabhashankar
- Department of Microbiology and Cell Biology, Division of Biological Sciences, Indian Institute of Science (IISc), Bengaluru, Karnataka, India
| | - Bhoomika Shivanaiah
- Department of Microbiology and Cell Biology, Division of Biological Sciences, Indian Institute of Science (IISc), Bengaluru, Karnataka, India
| | - Ekta Tripathi
- Department of Biotechnology, Faculty of Life and Allied Health Sciences, Ramaiah University of Applied Sciences, Bengaluru, India.
- Department of Microbiology and Cell Biology, Division of Biological Sciences, Indian Institute of Science (IISc), Bengaluru, Karnataka, India.
| | - Nagalingam Ravi Sundaresan
- Department of Microbiology and Cell Biology, Division of Biological Sciences, Indian Institute of Science (IISc), Bengaluru, Karnataka, India.
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Yang X, Feng J, Liang W, Zhu Z, Chen Z, Hu J, Yang D, Ding G. Roles of SIRT6 in kidney disease: a novel therapeutic target. Cell Mol Life Sci 2021; 79:53. [PMID: 34950960 PMCID: PMC11072764 DOI: 10.1007/s00018-021-04061-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 11/24/2021] [Accepted: 11/25/2021] [Indexed: 12/13/2022]
Abstract
SIRT6 is an NAD+ dependent deacetylase that belongs to the mammalian sirtuin family. SIRT6 is mainly located in the nucleus and regulates chromatin remodeling, genome stability, and gene transcription. SIRT6 extensively participates in various physiological activities such as DNA repair, energy metabolism, oxidative stress, inflammation, and fibrosis. In recent years, the role of epigenetics such as acetylation modification in renal disease has gradually received widespread attention. SIRT6 reduces oxidative stress, inflammation, and renal fibrosis, which is of great importance in maintaining cellular homeostasis and delaying the chronic progression of kidney disease. Here, we review the structure and biological function of SIRT6 and summarize the regulatory mechanisms of SIRT6 in kidney disease. Moreover, the role of SIRT6 as a potential therapeutic target for the progression of kidney disease will be discussed. SIRT6 plays an important role in kidney disease. SIRT6 regulates mitochondrial dynamics and mitochondrial biogenesis, induces G2/M cycle arrest, and plays an antioxidant role in nephrotoxicity, IR, obstructive nephropathy, and sepsis-induced AKI. SIRT6 prevents and delays progressive CKD induced by hyperglycemia, kidney senescence, hypertension, and lipid accumulation by regulating mitochondrial biogenesis, and has antioxidant, anti-inflammatory, and antifibrosis effects. Additionally, hypoxia, inflammation, and fibrosis are the main mechanisms of the AKI-to-CKD transition. SIRT6 plays a critical role in the AKI-to-CKD transition and kidney repair through anti-inflammatory, antifibrotic, and mitochondrial quality control mechanisms. AKI Acute kidney injury, CKD Chronic kidney disease.
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Affiliation(s)
- Xueyan Yang
- Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Nephrology and Urology Research Institute of Wuhan University, Wuhan, Hubei, China
| | - Jun Feng
- Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Nephrology and Urology Research Institute of Wuhan University, Wuhan, Hubei, China
| | - Wei Liang
- Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Nephrology and Urology Research Institute of Wuhan University, Wuhan, Hubei, China
| | - Zijing Zhu
- Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Nephrology and Urology Research Institute of Wuhan University, Wuhan, Hubei, China
| | - Zhaowei Chen
- Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Nephrology and Urology Research Institute of Wuhan University, Wuhan, Hubei, China
| | - Jijia Hu
- Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Nephrology and Urology Research Institute of Wuhan University, Wuhan, Hubei, China
| | - Dingping Yang
- Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- Nephrology and Urology Research Institute of Wuhan University, Wuhan, Hubei, China
| | - Guohua Ding
- Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
- Nephrology and Urology Research Institute of Wuhan University, Wuhan, Hubei, China.
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Bian C, Gao J, Wang Y, Li J, Luan Z, Lu H, Ren H. Association of SIRT6 circulating levels with urinary and glycometabolic markers in pre-diabetes and diabetes. Acta Diabetol 2021; 58:1551-1562. [PMID: 34148121 DOI: 10.1007/s00592-021-01759-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 06/06/2021] [Indexed: 12/30/2022]
Abstract
AIM The study is aimed to detect the expression of serum Sirtuin 6 (SIRT6) with different severities and urinary albumin creatinine ratios (UACR) in type 2 diabetes mellitus (T2DM) patients, thus exploring the association of SIRT6 together with glycolipid metabolism and urinary protein in the cross-sectional study. METHODS T2DM patients (313 cases), pre-diabetic patients (102 cases), and healthy volunteers (100 cases) were selected. T2DM patients were divided into the normal albuminuria (103 cases, UACR < 30 mg/g), micro-albuminuria (106 cases, UACR 30-300 mg/g), and large amount of albuminuria group (104 cases, UACR > 300 mg/g) based on different UACR levels. The medical history was asked, biochemical indicators were detected, hematuria samples were taken, serum SIRT6 levels were detected, and detailed statistical analysis was conducted. RESULTS FPG, 2 h-PG, HOMA-IR, HbA1c, and LDL-C increased, while ISI and HDL-C decreased with the aggravation of diabetic status (P < 0.05). HbA1c, UACR, TNFα, HIF1α, and SIRT6 increased with UACR in T2DM patients (P < 0.05). Correlation analysis demonstrated that SIRT6 was significantly positively correlated with glycolipid metabolism in the whole samples, and correlated with UACR, TNFα, and HIF1α in T2DM patients (P < 0.05). Ridge regression analysis showed that SIRT6 was a risk factor for both glycolipid metabolism and urinary protein (P < 0.05). CONCLUSION SIRT6 increases with biomarkers in glycolipid metabolism and urinary protein in different severities of diabetes and UACR, which is expected to be a potential biomarker for early prediction and diagnosis related to glycolipid metabolism disorders and related nephropathy. Trial number: ChiCTR2000039808.
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Affiliation(s)
- Che Bian
- Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Jing Gao
- Department of Gerontology, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yuxia Wang
- Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Jia Li
- Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhilin Luan
- Advanced Institute for Medical Sciences, Dalian Medical University, Lvshun South Road west 9, Dalian, 116044, Liaoning, China
| | - Heyuan Lu
- Advanced Institute for Medical Sciences, Dalian Medical University, Lvshun South Road west 9, Dalian, 116044, Liaoning, China
| | - Huiwen Ren
- Advanced Institute for Medical Sciences, Dalian Medical University, Lvshun South Road west 9, Dalian, 116044, Liaoning, China.
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Cai X, Liu Z, Dong X, Wang Y, Zhu L, Li M, Xu Y. Hypoglycemic and lipid lowering effects of theaflavins in high-fat diet-induced obese mice. Food Funct 2021; 12:9922-9931. [PMID: 34492673 DOI: 10.1039/d1fo01966j] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Theaflavins (TFs) are the characteristic components of black tea and have been widely acknowledged for their health benefits. The current study aimed to investigate the effects and mechanism of TFs, TF1, TF2a and TF3 on glycolipid metabolism in obese mice induced by a high-fat diet (HFD). Mice were randomly divided into seven groups (n = 8 per group) as follows: low-fat diet (LFD), HFD, HFD + metformin (Met, 100 mg kg-1 d-1), HFD + TFs (TFs, 200 mg kg-1 d-1), HFD + TF1 (TF1, 100 mg kg-1 d-1), HFD + TF2a (TF2a, 100 mg kg-1 d-1), and HFD + TF3 (TF3, 100 mg kg-1 d-1). All groups were studied for 9 weeks continuously. The levels of serum glucose, insulin, TC, TG, LDL and HLD in the plasma, lipid accumulation in the liver, and injury of the liver were investigated. In addition, the effects of TFs and their monomers on the SIRT6/AMPK/SREBP-1/FASN pathway were also evaluated. The results showed that oral administration of TFs, TF1, TF2a and TF3 not only dramatically suppressed weight gain, reduced blood glucose level, and ameliorated insulin resistance but also obviously lowered the levels of serum TC, TG and LDL, suppressed the activities of ALT and AST, and ameliorated hepatic damage in mice fed a HFD when compared to the HFD group. Western blot analysis showed that TFs, TF1, TF2a and TF3 treatments increased the expression of SIRT6 and suppressed the expression levels of SREBP-1 and FASN significantly in mice fed a HFD as compared to the HFD group. The phosphorylation of AMPK in mice fed a HFD was obviously elevated by TF2a and TF3 when compared to the HFD group. These results proved for the first time that TF1, TF2a and TF3 improved the glucolipid metabolism of mice fed a HFD, and activated the SIRT6/AMPK/SREBP-1/FASN signaling pathway to inhibit the synthesis and accumulation of lipids in the liver to ameliorate obesity in mice fed a HFD. These findings indicate that TFs, TF1, TF2a and TF3 as the main functional components of black tea might potentially be used as a food additive for improving glycolipid metabolism and ameliorating obesity, and TF3 may be the best choice.
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Affiliation(s)
- Xiaqiang Cai
- State Key Laboratory of Tea Plant Biology and Utilization/Key Laboratory of Tea Biology and Tea Processing of Ministry of Agriculture/Anhui Provincial Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, Hefei, China. .,International Joint Laboratory on Tea Chemistry and Health Effects of Ministry of Education, Hefei, China
| | - Zenghui Liu
- Anhui Academy of Medical Sciences, Hefei 230061, China
| | - Xu Dong
- State Key Laboratory of Tea Plant Biology and Utilization/Key Laboratory of Tea Biology and Tea Processing of Ministry of Agriculture/Anhui Provincial Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, Hefei, China. .,International Joint Laboratory on Tea Chemistry and Health Effects of Ministry of Education, Hefei, China
| | - Ying Wang
- State Key Laboratory of Tea Plant Biology and Utilization/Key Laboratory of Tea Biology and Tea Processing of Ministry of Agriculture/Anhui Provincial Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, Hefei, China. .,International Joint Laboratory on Tea Chemistry and Health Effects of Ministry of Education, Hefei, China
| | - Luwei Zhu
- State Key Laboratory of Tea Plant Biology and Utilization/Key Laboratory of Tea Biology and Tea Processing of Ministry of Agriculture/Anhui Provincial Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, Hefei, China. .,International Joint Laboratory on Tea Chemistry and Health Effects of Ministry of Education, Hefei, China
| | - Mengli Li
- State Key Laboratory of Tea Plant Biology and Utilization/Key Laboratory of Tea Biology and Tea Processing of Ministry of Agriculture/Anhui Provincial Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, Hefei, China. .,International Joint Laboratory on Tea Chemistry and Health Effects of Ministry of Education, Hefei, China
| | - Yan Xu
- State Key Laboratory of Tea Plant Biology and Utilization/Key Laboratory of Tea Biology and Tea Processing of Ministry of Agriculture/Anhui Provincial Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, Hefei, China. .,International Joint Laboratory on Tea Chemistry and Health Effects of Ministry of Education, Hefei, China
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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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40
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Škara L, Huđek Turković A, Pezelj I, Vrtarić A, Sinčić N, Krušlin B, Ulamec M. Prostate Cancer-Focus on Cholesterol. Cancers (Basel) 2021; 13:4696. [PMID: 34572923 PMCID: PMC8469848 DOI: 10.3390/cancers13184696] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/08/2021] [Accepted: 09/15/2021] [Indexed: 12/24/2022] Open
Abstract
Prostate cancer (PC) is the most common malignancy in men. Common characteristic involved in PC pathogenesis are disturbed lipid metabolism and abnormal cholesterol accumulation. Cholesterol can be further utilized for membrane or hormone synthesis while cholesterol biosynthesis intermediates are important for oncogene membrane anchoring, nucleotide synthesis and mitochondrial electron transport. Since cholesterol and its biosynthesis intermediates influence numerous cellular processes, in this review we have described cholesterol homeostasis in a normal cell. Additionally, we have illustrated how commonly deregulated signaling pathways in PC (PI3K/AKT/MTOR, MAPK, AR and p53) are linked with cholesterol homeostasis regulation.
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Affiliation(s)
- Lucija Škara
- Department of Medical Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
- Group for Research on Epigenetic Biomarkers (Epimark), School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
- Centre of Excellence for Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Ana Huđek Turković
- Faculty of Food Technology and Biotechnology, University of Zagreb, 10000 Zagreb, Croatia;
| | - Ivan Pezelj
- Department of Urology, University Clinical Hospital Center Sestre Milosrdnice, 10000 Zagreb, Croatia;
| | - Alen Vrtarić
- Department of Clinical Chemistry, University Clinical Hospital Center Sestre Milosrdnice, 10000 Zagreb, Croatia;
| | - Nino Sinčić
- Department of Medical Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
- Group for Research on Epigenetic Biomarkers (Epimark), School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
- Centre of Excellence for Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Božo Krušlin
- Centre of Excellence for Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
- Ljudevit Jurak Clinical Department of Pathology and Cytology, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Monika Ulamec
- Group for Research on Epigenetic Biomarkers (Epimark), School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
- Centre of Excellence for Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
- Ljudevit Jurak Clinical Department of Pathology and Cytology, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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41
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Shahgaldi S, Kahmini FR. A comprehensive review of Sirtuins: With a major focus on redox homeostasis and metabolism. Life Sci 2021; 282:119803. [PMID: 34237310 DOI: 10.1016/j.lfs.2021.119803] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/24/2021] [Accepted: 07/02/2021] [Indexed: 01/01/2023]
Abstract
Sirtuins are Class III protein deacetylases with seven conserved isoforms. In general, Sirtuins are highly activated under cellular stress conditions in which NAD+ levels are increased. Nevertheless, regulation of Sirtuins extends far beyond the influences of cellular NAD+/NADH ratio and a rapidly expanding body of evidence currently suggests that their expression and catalytic activity are highly kept under control at multiple levels by various factors and processes. Owing to their intrinsic ability to enzymatically target various intracellular proteins, Sirtuins are prominently involved in the regulation of fundamental biological processes including inflammation, metabolism, redox homeostasis, DNA repair and cell proliferation and senescence. In fact, Sirtuins are well established to regulate and reprogram different redox and metabolic pathways under both pathological and physiological conditions. Therefore, alterations in Sirtuin levels can be a pivotal intermediary step in the pathogenesis of several disorders. This review first highlights the mechanisms involved in the regulation of Sirtuins and further summarizes the current findings on the major functions of Sirtuins in cellular redox homeostasis and bioenergetics (glucose and lipid metabolism).
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Affiliation(s)
- Shahab Shahgaldi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Fatemeh Rezaei Kahmini
- Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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42
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Abstract
![]()
Sirtuin 6 (SIRT6)
is an NAD+-dependent protein deacylase
and mono-ADP-ribosyltransferase of the sirtuin family with a wide
substrate specificity. In vitro and in vivo studies have indicated that SIRT6 overexpression or activation has
beneficial effects for cellular processes such as DNA repair, metabolic
regulation, and aging. On the other hand, SIRT6 has contrasting roles
in cancer, acting either as a tumor suppressor or promoter in a context-specific
manner. Given its central role in cellular homeostasis, SIRT6 has
emerged as a promising target for the development of small-molecule
activators and inhibitors possessing a therapeutic potential in diseases
ranging from cancer to age-related disorders. Moreover, specific modulators
allow the molecular details of SIRT6 activity to be scrutinized and
further validate the enzyme as a pharmacological target. In this Perspective,
we summarize the current knowledge about SIRT6 pharmacology and medicinal
chemistry and describe the features of the activators and inhibitors
identified so far.
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Affiliation(s)
- Francesco Fiorentino
- Department of Chemistry, University of Oxford, South Parks Road, Oxford OX1 3QZ, United Kingdom
| | - Antonello Mai
- Department of Drug Chemistry & Technologies, Sapienza University of Rome, P.le A Moro 5, 00185 Rome, Italy
| | - Dante Rotili
- Department of Drug Chemistry & Technologies, Sapienza University of Rome, P.le A Moro 5, 00185 Rome, Italy
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Khan D, Ara T, Ravi V, Rajagopal R, Tandon H, Parvathy J, Gonzalez EA, Asirvatham-Jeyaraj N, Krishna S, Mishra S, Raghu S, Bhati AS, Tamta AK, Dasgupta S, Kolthur-Seetharam U, Etchegaray JP, Mostoslavsky R, Rao PSM, Srinivasan N, Sundaresan NR. SIRT6 transcriptionally regulates fatty acid transport by suppressing PPARγ. Cell Rep 2021; 35:109190. [PMID: 34077730 PMCID: PMC8190874 DOI: 10.1016/j.celrep.2021.109190] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 03/08/2021] [Accepted: 05/07/2021] [Indexed: 12/27/2022] Open
Abstract
Pathological lipid accumulation is often associated with enhanced uptake of free fatty acids via specific transporters in cardiomyocytes. Here, we identify SIRT6 as a critical transcriptional regulator of fatty acid transporters in cardiomyocytes. We find that SIRT6 deficiency enhances the expression of fatty acid transporters, leading to enhanced fatty acid uptake and lipid accumulation. Interestingly, the haploinsufficiency of SIRT6 is sufficient to induce the expression of fatty acid transporters and cause lipid accumulation in murine hearts. Mechanistically, SIRT6 depletion enhances the occupancy of the transcription factor PPARγ on the promoters of critical fatty acid transporters without modulating the acetylation of histone 3 at Lys 9 and Lys 56. Notably, the binding of SIRT6 to the DNA-binding domain of PPARγ is critical for regulating the expression of fatty acid transporters in cardiomyocytes. Our data suggest exploiting SIRT6 as a potential therapeutic target for protecting the heart from metabolic diseases.
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Affiliation(s)
- Danish Khan
- Cardiovascular and Muscle Research Laboratory, Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
| | - Tarannum Ara
- Cardiovascular and Muscle Research Laboratory, Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
| | - Venkatraman Ravi
- Cardiovascular and Muscle Research Laboratory, Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
| | - Raksha Rajagopal
- Cardiovascular and Muscle Research Laboratory, Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
| | - Himani Tandon
- Molecular Biophysics Unit, Indian Institute of Science, Bengaluru, India
| | - Jayadevan Parvathy
- Molecular Biophysics Unit, Indian Institute of Science, Bengaluru, India; IISc-Mathematics Initiative, Indian Institute of Science, Bengaluru, India
| | - Edward A Gonzalez
- Department of Biological Sciences, Rutgers University, Newark, NJ, USA
| | - Ninitha Asirvatham-Jeyaraj
- Cardiovascular and Muscle Research Laboratory, Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
| | - Swati Krishna
- Cardiovascular and Muscle Research Laboratory, Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
| | - Sneha Mishra
- Cardiovascular and Muscle Research Laboratory, Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
| | - Sukanya Raghu
- Cardiovascular and Muscle Research Laboratory, Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
| | - Arvind Singh Bhati
- Cardiovascular and Muscle Research Laboratory, Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
| | - Ankit Kumar Tamta
- Cardiovascular and Muscle Research Laboratory, Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
| | - Subhajit Dasgupta
- Cardiovascular and Muscle Research Laboratory, Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
| | - Ullas Kolthur-Seetharam
- Tata Institute of Fundamental Research, Colaba, Mumbai, India; Tata Institute of Fundamental Research, Hyderabad, India
| | | | - Raul Mostoslavsky
- The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | | | | | - Nagalingam Ravi Sundaresan
- Cardiovascular and Muscle Research Laboratory, Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India.
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Cao Y, Hu G, Zhang Q, Ma L, Wang J, Li W, Ge Y, Cheng J, Yang Z, Fu S, Liu J. Kisspeptin-10 Maintains the Activation of the mTOR Signaling Pathway by Inhibiting SIRT6 to Promote the Synthesis of Milk in Bovine Mammary Epithelial Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:4093-4100. [PMID: 33818062 DOI: 10.1021/acs.jafc.0c07613] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Kisspeptin-10 (Kp-10) is a peptide hormone that regulates normal physiological processes. The mechanism of Kp-10 in milk synthesis is still unclear. Therefore, bovine mammary epithelial cells (BMECs) were used to study the mechanism by which Kp-10 affects milk synthesis in BMECs. The GPR54 inhibitor and SIRT6 overexpression plasmid and siRNA were used to study the mechanism of regulating milk protein and milk fat synthesis by Kp-10. The results showed that 100 nM Kp-10 increased milk synthesis in BMECs. SIRT6 overexpression could significantly reduce the milk protein and milk fat synthesis in BMECs. Moreover, overexpression of SIRT6 reversed the activation of the Kp-10-induced mTOR signaling pathway. Further analysis suggested that SIRT6 might regulate the signal transduction of mTOR at the transcriptional level. These results strongly suggested that Kp-10/GPR54 activated the mTOR signaling pathway by inhibiting SIRT6 expression and then increased the milk synthesis in BMECs.
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Affiliation(s)
- Yu Cao
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Guiqiu Hu
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Qing Zhang
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Lijun Ma
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Jiaxin Wang
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Wen Li
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Yusong Ge
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Ji Cheng
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Zhanqing Yang
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Shoupeng Fu
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Juxiong Liu
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
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The Two-Faced Role of SIRT6 in Cancer. Cancers (Basel) 2021; 13:cancers13051156. [PMID: 33800266 PMCID: PMC7962659 DOI: 10.3390/cancers13051156] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/27/2021] [Accepted: 03/03/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Cancer therapy relies on the employment of different strategies aimed at inducing cancer cell death through different mechanisms, including DNA damage and apoptosis induction. One of the key regulators of these pathways is the epigenetic enzyme SIRT6, which has been shown to have a dichotomous function in cell fate determination and, consequently, cancer initiation and progression. In this review, we aim to summarize the current knowledge on the role of SIRT6 in cancer. We show that it can act as both tumor suppressor and promoter, even in the same cancer type, depending on the biological context. We then describe the most promising modulators of SIRT6 which, through enzyme activation or inhibition, may impair tumor growth. These molecules can also be used for the elucidation of SIRT6 function, thereby advancing the current knowledge on this crucial protein. Abstract Sirtuin 6 (SIRT6) is a NAD+-dependent nuclear deacylase and mono-ADP-ribosylase with a wide spectrum of substrates. Through its pleiotropic activities, SIRT6 modulates either directly or indirectly key processes linked to cell fate determination and oncogenesis such as DNA damage repair, metabolic homeostasis, and apoptosis. SIRT6 regulates the expression and activity of both pro-apoptotic (e.g., Bax) and anti-apoptotic factors (e.g., Bcl-2, survivin) in a context-depending manner. Mounting evidence points towards a double-faced involvement of SIRT6 in tumor onset and progression since the block or induction of apoptosis lead to opposite outcomes in cancer. Here, we discuss the features and roles of SIRT6 in the regulation of cell death and cancer, also focusing on recently discovered small molecule modulators that can be used as chemical probes to shed further light on SIRT6 cancer biology and proposed as potential new generation anticancer therapeutics.
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46
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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: 103] [Impact Index Per Article: 25.8] [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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47
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Shabgah AG, Norouzi F, Hedayati-Moghadam M, Soleimani D, Pahlavani N, Navashenaq JG. A comprehensive review of long non-coding RNAs in the pathogenesis and development of non-alcoholic fatty liver disease. Nutr Metab (Lond) 2021; 18:22. [PMID: 33622377 PMCID: PMC7903707 DOI: 10.1186/s12986-021-00552-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 02/17/2021] [Indexed: 12/15/2022] Open
Abstract
One of the most prevalent diseases worldwide without a fully-known mechanism is non-alcoholic fatty liver disease (NAFLD). Recently, long non-coding RNAs (lncRNAs) have emerged as significant regulatory molecules. These RNAs have been claimed by bioinformatic research that is involved in biologic processes, including cell cycle, transcription factor regulation, fatty acids metabolism, and-so-forth. There is a body of evidence that lncRNAs have a pivotal role in triglyceride, cholesterol, and lipoprotein metabolism. Moreover, lncRNAs by up- or down-regulation of the downstream molecules in fatty acid metabolism may determine the fatty acid deposition in the liver. Therefore, lncRNAs have attracted considerable interest in NAFLD pathology and research. In this review, we provide all of the lncRNAs and their possible mechanisms which have been introduced up to now. It is hoped that this study would provide deep insight into the role of lncRNAs in NAFLD to recognize the better molecular targets for therapy.
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Affiliation(s)
| | - Fatemeh Norouzi
- Department of Food Hygiene, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | | | - Davood Soleimani
- Department of Nutritional Sciences, School of Nutrition Sciences and Food Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Naseh Pahlavani
- Social Development and Health Promotion Research Center, Gonabad University of Medical Sciences, Gonabad, Iran
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48
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Becherini P, Caffa I, Piacente F, Damonte P, Vellone VG, Passalacqua M, Benzi A, Bonfiglio T, Reverberi D, Khalifa A, Ghanem M, Guijarro A, Tagliafico L, Sucameli M, Persia A, Monacelli F, Cea M, Bruzzone S, Ravera S, Nencioni A. SIRT6 enhances oxidative phosphorylation in breast cancer and promotes mammary tumorigenesis in mice. Cancer Metab 2021; 9:6. [PMID: 33482921 PMCID: PMC7821730 DOI: 10.1186/s40170-021-00240-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 01/05/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Sirtuin 6 (SIRT6) is a NAD+-dependent deacetylase with key roles in cell metabolism. High SIRT6 expression is associated with adverse prognosis in breast cancer (BC) patients. However, the mechanisms through which SIRT6 exerts its pro-oncogenic effects in BC remain unclear. Here, we sought to define the role of SIRT6 in BC cell metabolism and in mouse polyoma middle T antigen (PyMT)-driven mammary tumors. METHODS We evaluated the effect of a heterozygous deletion of Sirt6 on tumor latency and survival of mouse mammary tumor virus (MMTV)-PyMT mice. The effect of SIRT6 silencing on human BC cell growth was assessed in MDA-MB-231 xenografts. We also analyzed the effect of Sirt6 heterozygous deletion, of SIRT6 silencing, and of the overexpression of either wild-type (WT) or catalytically inactive (H133Y) SIRT6 on BC cell pyruvate dehydrogenase (PDH) expression and activity and oxidative phosphorylation (OXPHOS), including respiratory complex activity, ATP/AMP ratio, AMPK activation, and intracellular calcium concentration. RESULTS The heterozygous Sirt6 deletion extended tumor latency and mouse survival in the MMTV-PyMT mouse BC model, while SIRT6 silencing slowed the growth of MDA-MB-231 BC cell xenografts. WT, but not catalytically inactive, SIRT6 enhanced PDH expression and activity, OXPHOS, and ATP/AMP ratio in MDA-MB-231 and MCF7 BC cells. Opposite effects were obtained by SIRT6 silencing, which also blunted the expression of genes encoding for respiratory chain proteins, such as UQCRFS1, COX5B, NDUFB8, and UQCRC2, and increased AMPK activation in BC cells. In addition, SIRT6 overexpression increased, while SIRT6 silencing reduced, intracellular calcium concentration in MDA-MB-231 cells. Consistent with these findings, the heterozygous Sirt6 deletion reduced the expression of OXPHOS-related genes, the activity of respiratory complexes, and the ATP/AMP ratio in tumors isolated from MMTV-PyMT mice. CONCLUSIONS Via its enzymatic activity, SIRT6 enhances PDH expression and activity, OXPHOS, ATP/AMP ratio, and intracellular calcium concentration, while reducing AMPK activation, in BC cells. Thus, overall, SIRT6 inhibition appears as a viable strategy for preventing or treating BC.
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Affiliation(s)
- Pamela Becherini
- Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, V.le Benedetto XV 6, 16132, Genoa, Italy.,Ospedale Policlinico San Martino IRCCS, Largo Rosanna Benzi 10, 16132, Genoa, Italy
| | - Irene Caffa
- Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, V.le Benedetto XV 6, 16132, Genoa, Italy.,Ospedale Policlinico San Martino IRCCS, Largo Rosanna Benzi 10, 16132, Genoa, Italy
| | - Francesco Piacente
- Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, V.le Benedetto XV 6, 16132, Genoa, Italy.,Ospedale Policlinico San Martino IRCCS, Largo Rosanna Benzi 10, 16132, Genoa, Italy.,Department of Experimental Medicine (DIMES), University of Genoa, V.le Benedetto XV 1, 16132, Genoa, Italy
| | - Patrizia Damonte
- Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, V.le Benedetto XV 6, 16132, Genoa, Italy
| | - Valerio G Vellone
- Ospedale Policlinico San Martino IRCCS, Largo Rosanna Benzi 10, 16132, Genoa, Italy.,Department of Integrated, Surgical and Diagnostic Sciences (DISC), University of Genoa, L.go Rosanna Benzi 8, 16132, Genoa, Italy
| | - Mario Passalacqua
- Department of Experimental Medicine (DIMES), University of Genoa, V.le Benedetto XV 1, 16132, Genoa, Italy
| | - Andrea Benzi
- Department of Experimental Medicine (DIMES), University of Genoa, V.le Benedetto XV 1, 16132, Genoa, Italy
| | - Tommaso Bonfiglio
- Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, V.le Benedetto XV 6, 16132, Genoa, Italy
| | - Daniele Reverberi
- Ospedale Policlinico San Martino IRCCS, Largo Rosanna Benzi 10, 16132, Genoa, Italy
| | - Amr Khalifa
- Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, V.le Benedetto XV 6, 16132, Genoa, Italy
| | - Moustafa Ghanem
- Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, V.le Benedetto XV 6, 16132, Genoa, Italy
| | - Ana Guijarro
- Ospedale Policlinico San Martino IRCCS, Largo Rosanna Benzi 10, 16132, Genoa, Italy
| | - Luca Tagliafico
- Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, V.le Benedetto XV 6, 16132, Genoa, Italy
| | - Marzia Sucameli
- Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, V.le Benedetto XV 6, 16132, Genoa, Italy
| | - Angelica Persia
- Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, V.le Benedetto XV 6, 16132, Genoa, Italy
| | - Fiammetta Monacelli
- Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, V.le Benedetto XV 6, 16132, Genoa, Italy.,Ospedale Policlinico San Martino IRCCS, Largo Rosanna Benzi 10, 16132, Genoa, Italy
| | - Michele Cea
- Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, V.le Benedetto XV 6, 16132, Genoa, Italy.,Ospedale Policlinico San Martino IRCCS, Largo Rosanna Benzi 10, 16132, Genoa, Italy
| | - Santina Bruzzone
- Department of Experimental Medicine (DIMES), University of Genoa, V.le Benedetto XV 1, 16132, Genoa, Italy
| | - Silvia Ravera
- Department of Experimental Medicine (DIMES), University of Genoa, V.le Benedetto XV 1, 16132, Genoa, Italy.
| | - Alessio Nencioni
- Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, V.le Benedetto XV 6, 16132, Genoa, Italy. .,Ospedale Policlinico San Martino IRCCS, Largo Rosanna Benzi 10, 16132, Genoa, Italy.
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Raj S, Dsouza LA, Singh SP, Kanwal A. Sirt6 Deacetylase: A Potential Key Regulator in the Prevention of Obesity, Diabetes and Neurodegenerative Disease. Front Pharmacol 2020; 11:598326. [PMID: 33442387 PMCID: PMC7797778 DOI: 10.3389/fphar.2020.598326] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 10/27/2020] [Indexed: 12/31/2022] Open
Abstract
Sirtuins, NAD + dependent proteins belonging to class III histone deacetylases, are involved in regulating numerous cellular processes including cellular stress, insulin resistance, inflammation, mitochondrial biogenesis, chromatin silencing, cell cycle regulation, transcription, and apoptosis. Of the seven mammalian sirtuins present in humans, Sirt6 is an essential nuclear sirtuin. Until recently, Sirt6 was thought to regulate chromatin silencing, but new research indicates its role in aging, diabetes, cardiovascular disease, lipid metabolism, neurodegenerative diseases, and cancer. Various murine models demonstrate that Sirt6 activation is beneficial in alleviating many disease conditions and increasing lifespan, showing that Sirt6 is a critical therapeutic target in the treatment of various disease conditions in humans. Sirt6 also regulates the pathogenesis of multiple diseases by acting on histone proteins and non-histone proteins. Endogenous and non-endogenous modulators regulate both activation and inhibition of Sirt6. Few Sirt6 specific non-endogenous modulators have been identified. Hence the identification of Sirt6 specific modulators may have potential therapeutic roles in the diseases described above. In this review, we describe the development of Sirt6, the role it plays in the human condition, the functional role and therapeutic importance in disease processes, and specific modulators and molecular mechanism of Sirt6 in the regulation of metabolic homeostasis, cardiovascular disease, aging, and neurodegenerative disease.
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Affiliation(s)
- Swapnil Raj
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Liston Augustine Dsouza
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Shailendra Pratap Singh
- Department of Biomedical Engineering, School of Engineering and Technology, Central University of Rajasthan, Kishangarh, India
| | - Abhinav Kanwal
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Bathinda, India
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Abstract
Circadian rhythms govern a large array of physiological and metabolic functions. Perturbations of the daily cycle have been linked to elevated risk of developing cancer as well as poor prognosis in patients with cancer. Also, expression of core clock genes or proteins is remarkably attenuated particularly in tumours of a higher stage or that are more aggressive, possibly linking the circadian clock to cellular differentiation. Emerging evidence indicates that metabolic control by the circadian clock underpins specific hallmarks of cancer metabolism. Indeed, to support cell proliferation and biomass production, the clock may direct metabolic processes of cancer cells in concert with non-clock transcription factors to control how nutrients and metabolites are utilized in a time-specific manner. We hypothesize that the metabolic switch between differentiation or stemness of cancer may be coupled to the molecular clockwork. Moreover, circadian rhythms of host organisms appear to dictate tumour growth and proliferation. This Review outlines recent discoveries of the interplay between circadian rhythms, proliferative metabolism and cancer, highlighting potential opportunities in the development of future therapeutic strategies.
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Affiliation(s)
- Kenichiro Kinouchi
- Center for Epigenetics and Metabolism, U1233 INSERM, Department of Biological Chemistry, University of California, Irvine, CA, USA.
- Department of Endocrinology, Metabolism, and Nephrology, School of Medicine, Keio University, Tokyo, Japan.
| | - Paolo Sassone-Corsi
- Center for Epigenetics and Metabolism, U1233 INSERM, Department of Biological Chemistry, University of California, Irvine, CA, USA.
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