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1
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Dai X, Feng S, Li T. Cold atmospheric plasma control metabolic syndromes via targeting fat mass and obesity-associated protein. Pharmacol Res 2025; 215:107720. [PMID: 40174815 DOI: 10.1016/j.phrs.2025.107720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 03/09/2025] [Accepted: 03/28/2025] [Indexed: 04/04/2025]
Abstract
Both obesity and metabolic disorders are global medical problems. Driven by prolonged inflammation, obesity increases the risk of developing metabolic syndromes such as fatty liver, diabetes, cardiovascular diseases and cancers. The fat mass and obesity-associated protein (FTO) is an m6A demethylase, elevated activity of which is known to promote the pathogenesis of many metabolic disorders, leading to the establishment of various FTO inhibitors. By combing through intrinsic connections among obesity and the four primary metabolic problems, we attribute their shared pathological cause to prolonged inflammation. By reviewing the roles of FTO in promoting these disorders and the current status of existing FTO inhibitors in treating these syndromes, we underpinned the paramount potential of resolving these clinical issues by targeting FTO and the urgent need of establishing novel FTO inhibitors with maximized efficacy and minimized side effect. Cold atmospheric plasma (CAP) is the fourth state of matter with demonstrated efficacy in treating various diseases associated with chronic inflammation. By introducing the medical characteristics of CAP, we proposed it as a possible solution to unresolved issues of current FTO inhibitors given its anti-inflammation feature and demonstrated clinical safety. We also emphasized the need of intensive investigations in exploring the feasibility of using CAP in treating obesity and associated metabolic syndromes that might function through targeting FTO.
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Affiliation(s)
- Xiaofeng Dai
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, PR China.
| | - Shuo Feng
- Department of Dermatology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, PR China
| | - Tian Li
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, PR China; Tianjin Key Laboratory of Acute Abdomen Disease-Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin Medical University, 8 Changjiang Avenue, Tianjin 300100, China.
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2
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Münte E, Hartmann P. The Role of Short-Chain Fatty Acids in Metabolic Dysfunction-Associated Steatotic Liver Disease and Other Metabolic Diseases. Biomolecules 2025; 15:469. [PMID: 40305160 PMCID: PMC12025087 DOI: 10.3390/biom15040469] [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: 02/04/2025] [Revised: 03/10/2025] [Accepted: 03/21/2025] [Indexed: 05/02/2025] Open
Abstract
With its increasing prevalence, metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a major global public health concern over the past few decades. Growing evidence has proposed the microbiota-derived metabolites short-chain fatty acids (SCFAs) as a potential factor in the pathophysiology of MASLD and related metabolic conditions, such as obesity and type 2 diabetes mellitus (T2DM). By influencing key pathways involved in energy homeostasis, insulin sensitivity, and inflammation, SCFAs play an important role in gut microbiota composition, intestinal barrier function, immune modulation, and direct metabolic signaling. Furthermore, recent animal and human studies on therapeutic strategies targeting SCFAs demonstrate their potential for treating these metabolic disorders.
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Affiliation(s)
- Eliane Münte
- Department of Pediatrics, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA
| | - Phillipp Hartmann
- Department of Pediatrics, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA
- Division of Gastroenterology, Hepatology & Nutrition, Rady Children’s Hospital San Diego, San Diego, CA 92123, USA
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3
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Lu C, Xu C, Yang J. The Beneficial Effects of GLP-1 Receptor Agonists Other than Their Anti-Diabetic and Anti-Obesity Properties. MEDICINA (KAUNAS, LITHUANIA) 2024; 61:17. [PMID: 39858999 PMCID: PMC11767243 DOI: 10.3390/medicina61010017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 12/18/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025]
Abstract
As an incretin hormone, Glucagon-like peptide-1 (GLP-1) has obvious effects on blood glucose regulation and weight loss. GLP-1 receptor (GLP-1R) agonists are synthetic products that have similar effects to GLP-1 but are less prone to degradation, and they are widely used in the treatment of type 2 diabetes and obesity. In recent years, different beneficial effects of GLP-1R agonists were discovered, such as reducing ischemia-reperfusion injury, improving the function of various organs, alleviating substance use disorder, affecting tumorigenesis, regulating bone metabolism, changing gut microbiota composition, and prolonging graft survival. Therefore, GLP-1R agonists have great potential for clinical application in various diseases. Here, we briefly summarized the beneficial effects of GLP-1R agonists other than the anti-diabetic and anti-obesity effects.
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Affiliation(s)
- Chenqi Lu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China;
| | - Cong Xu
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
| | - Jun Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China;
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Ji T, Xu G, Wu Y, Wang Y, Xiao C, Zhang B, Xu B, Xu F. Amelioration of Type 2 Diabetes Mellitus Using Rapeseed ( Brassica napus)-Derived Peptides through Stimulating Calcium-Sensing Receptor: Effects on Glucagon-Like Peptide-1 Secretion and Hepatic Lipid Metabolism. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:23804-23818. [PMID: 39425744 DOI: 10.1021/acs.jafc.4c03987] [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: 10/21/2024]
Abstract
The potential of rapeseed-derived peptides (RDPs) in the amelioration of type 2 diabetes mellitus (T2DM) has been hypothesized. However, the mechanisms of the intestinal endocrine hormones activated by RDPs have not been fully understood. This study aimed to explore the amelioration of T2DM and associated hepatic lipid metabolism disorders using RDPs by affecting glucagon-like peptide-1 (GLP-1) secretion. Eight RDPs were prepared by different stepwise enzymatic hydrolysis, wherein RCPP-3 (sequential using alcalase/flavourzyme) and RNPP-1 (sequential using alcalase/trypsin) maintained the normal blood glucose level, significantly increased the body weight (27.17 ± 0.19%) in T2DM mice compared to the positive group (p < 0.05). Western blotting and immunofluorescence experiments indicated that RCPP-3 and RNPP-1 regulated the intestinal endocrine hormones GLP-1 secretion through the calcium-sensing receptor (CaSR). Additionally, the PI3K-Akt pathway was significantly activated by GLP-1, leading to marked improvements in hepatic lipid parameters (TC, TG, LDL-c, and HDL-c) and mitigated fat accumulation (p < 0.05). Notably, the stimulating effect of RCPP-3 on GLP-1 was 10.05% ± 0.71% higher than RNPP-1. G2-R3, a fraction separated from RCPP-3, which contained 14 peptides with the best capacity to stimulate GLP-1 secretion, was identified using HPLC-QTOF-MS/MS. This study suggests the potential of RDPs as novel functional food supplements for ameliorating T2DM.
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Affiliation(s)
- Tong Ji
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, People's Republic of China
- Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230009, People's Republic of China
| | - Guosheng Xu
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, People's Republic of China
- Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230009, People's Republic of China
| | - Ying Wu
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, People's Republic of China
- Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230009, People's Republic of China
| | - Yu Wang
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, People's Republic of China
- Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230009, People's Republic of China
| | - Chuqiao Xiao
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, People's Republic of China
| | - Bao Zhang
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, People's Republic of China
- Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230009, People's Republic of China
| | - Baocai Xu
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, People's Republic of China
- Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230009, People's Republic of China
| | - Feiran Xu
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, People's Republic of China
- Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230009, People's Republic of China
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Huang T, Zhang C, Ren J, Shuai Q, Li X, Li X, Xie J, Xu J. FTO-mediated m 6A demethylation of ULK1 mRNA promotes autophagy and activation of hepatic stellate cells in liver fibrosis. Acta Biochim Biophys Sin (Shanghai) 2024; 56:1509-1520. [PMID: 39175431 PMCID: PMC11532214 DOI: 10.3724/abbs.2024098] [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: 12/03/2023] [Accepted: 03/07/2024] [Indexed: 08/24/2024] Open
Abstract
The activation of hepatic stellate cells (HSCs) is central to the occurrence and development of liver fibrosis. Our previous studies showed that autophagy promotes HSC activation and ultimately accelerates liver fibrosis. Unc-51-like autophagy activating kinase 1 (ULK1) is an autophagic initiator in mammals, and N 6-methyladenosine (m 6A) modification is closely related to autophagy. In this study, we find that the m 6A demethylase fat mass and obesity-associated protein (FTO), which is the m 6A methylase with the most significant difference in expression, is upregulated during HSC activation and bile duct ligation (BDL)-induced hepatic fibrosis. Importantly, we identify that FTO overexpression aggravates HSC activation and hepatic fibrosis via autophagy. Mechanistically, compared with other autophagy-related genes, ULK1 is a target of FTO because FTO mainly mediates the m 6A demethylation of ULK1 and upregulates its expression, thereby enhancing autophagy and the activation of HSCs. Notably, the m 6A reader YTH domain-containing protein 2 (YTHDC2) decreases ULK1 mRNA level by recognizing the m 6A binding site and ultimately inhibiting autophagy and HSC activation. Taken together, our findings highlight m 6A-dependent ULK1 as an essential regulator of HSC autophagy and reveal that ULK1 is a novel potential therapeutic target for hepatic fibrosis treatment.
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Affiliation(s)
- Tingjuan Huang
- Shanxi Key Laboratory of Birth Defect and Cell RegenerationDepartment of Biochemistry and Molecular BiologyShanxi Medical UniversityTaiyuan030001China
| | - Chunhong Zhang
- Shanxi Key Laboratory of Birth Defect and Cell RegenerationDepartment of Biochemistry and Molecular BiologyShanxi Medical UniversityTaiyuan030001China
| | - Junjie Ren
- Department of Gastroenterology and Hepatologythe First Hospital of Shanxi Medical UniversityTaiyuan030001China
| | - Qizhi Shuai
- Shanxi Key Laboratory of Birth Defect and Cell RegenerationDepartment of Biochemistry and Molecular BiologyShanxi Medical UniversityTaiyuan030001China
| | - Xiaonan Li
- Department of Cancer Radiotherapy DepartmentShanxi Provincial People’s HospitalTaiyuan030001China
| | - Xuewei Li
- Shanxi Key Laboratory of Birth Defect and Cell RegenerationDepartment of Biochemistry and Molecular BiologyShanxi Medical UniversityTaiyuan030001China
| | - Jun Xie
- Shanxi Key Laboratory of Birth Defect and Cell RegenerationDepartment of Biochemistry and Molecular BiologyShanxi Medical UniversityTaiyuan030001China
| | - Jun Xu
- Department of Hepatopancreatobiliary Surgerythe First Hospital of Shanxi Medical UniversityTaiyuan030001China
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Bu T, Sun Z, Pan Y, Deng X, Yuan G. Glucagon-Like Peptide-1: New Regulator in Lipid Metabolism. Diabetes Metab J 2024; 48:354-372. [PMID: 38650100 PMCID: PMC11140404 DOI: 10.4093/dmj.2023.0277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 01/01/2024] [Indexed: 04/25/2024] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is a 30-amino acid peptide hormone that is mainly expressed in the intestine and hypothalamus. In recent years, basic and clinical studies have shown that GLP-1 is closely related to lipid metabolism, and it can participate in lipid metabolism by inhibiting fat synthesis, promoting fat differentiation, enhancing cholesterol metabolism, and promoting adipose browning. GLP-1 plays a key role in the occurrence and development of metabolic diseases such as obesity, nonalcoholic fatty liver disease, and atherosclerosis by regulating lipid metabolism. It is expected to become a new target for the treatment of metabolic disorders. The effects of GLP-1 and dual agonists on lipid metabolism also provide a more complete treatment plan for metabolic diseases. This article reviews the recent research progress of GLP-1 in lipid metabolism.
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Affiliation(s)
- Tong Bu
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Ziyan Sun
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Yi Pan
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Xia Deng
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Guoyue Yuan
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
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7
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Liu WW, Zheng SQ, Li T, Fei YF, Wang C, Zhang S, Wang F, Jiang GM, Wang H. RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy. Signal Transduct Target Ther 2024; 9:70. [PMID: 38531882 DOI: 10.1038/s41392-024-01777-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 02/08/2024] [Accepted: 02/19/2024] [Indexed: 03/28/2024] Open
Abstract
Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of cells. Relevant studies have been constantly making inroads in our understanding of pathophysiology, and inspiring development of therapeutics. As a crucial component of epigenetics at post-transcription level, RNA modification significantly determines RNA fates, further affecting various biological processes and cellular phenotypes. To be noted, immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological contexts. In this review, we characterize the distribution features, modifying mechanisms and biological functions of 8 RNA modifications, including N6-methyladenosine (m6A), N6,2'-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N4-acetylcytosine (ac4C), N7-methylguanosine (m7G), Pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing, which are relatively the most studied types. Then regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described, categorized as glucose, lipid, amino acid, and mitochondrial metabolism. And we highlight the regulation of RNA modifications on immunometabolism, further influencing immune responses. Above all, we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy, progression of RNA modification-targeted agents, and its potential in RNA-targeted therapeutics. Eventually, we give legitimate perspectives for future researches in this field from methodological requirements, mechanistic insights, to therapeutic applications.
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Affiliation(s)
- Wei-Wei Liu
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- School of Clinical Medicine, Shandong University, Jinan, China
| | - Si-Qing Zheng
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Hefei, China
| | - Tian Li
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Hefei, China
| | - Yun-Fei Fei
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Hefei, China
| | - Chen Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Hefei, China
| | - Shuang Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Hefei, China
| | - Fei Wang
- Neurosurgical Department, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
| | - Guan-Min Jiang
- Department of Clinical Laboratory, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
| | - Hao Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
- Core Unit of National Clinical Research Center for Laboratory Medicine, Hefei, China.
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Adesanya O, Das D, Kalsotra A. Emerging roles of RNA-binding proteins in fatty liver disease. WILEY INTERDISCIPLINARY REVIEWS. RNA 2024; 15:e1840. [PMID: 38613185 PMCID: PMC11018357 DOI: 10.1002/wrna.1840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 02/08/2024] [Accepted: 03/05/2024] [Indexed: 04/14/2024]
Abstract
A rampant and urgent global health issue of the 21st century is the emergence and progression of fatty liver disease (FLD), including alcoholic fatty liver disease and the more heterogenous metabolism-associated (or non-alcoholic) fatty liver disease (MAFLD/NAFLD) phenotypes. These conditions manifest as disease spectra, progressing from benign hepatic steatosis to symptomatic steatohepatitis, cirrhosis, and, ultimately, hepatocellular carcinoma. With numerous intricately regulated molecular pathways implicated in its pathophysiology, recent data have emphasized the critical roles of RNA-binding proteins (RBPs) in the onset and development of FLD. They regulate gene transcription and post-transcriptional processes, including pre-mRNA splicing, capping, and polyadenylation, as well as mature mRNA transport, stability, and translation. RBP dysfunction at every point along the mRNA life cycle has been associated with altered lipid metabolism and cellular stress response, resulting in hepatic inflammation and fibrosis. Here, we discuss the current understanding of the role of RBPs in the post-transcriptional processes associated with FLD and highlight the possible and emerging therapeutic strategies leveraging RBP function for FLD treatment. This article is categorized under: RNA in Disease and Development > RNA in Disease.
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Affiliation(s)
| | - Diptatanu Das
- Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Auinash Kalsotra
- Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA
- Cancer Center @ Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA
- Carl R. Woese Institute of Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA
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Jiang H, Zang L. GLP-1/GLP-1RAs: New Options for the Drug Treatment of NAFLD. Curr Pharm Des 2024; 30:100-114. [PMID: 38532322 DOI: 10.2174/0113816128283153231226103218] [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: 10/12/2023] [Accepted: 12/14/2023] [Indexed: 03/28/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a global public health concern. Currently, the cornerstone of NAFLD treatment is lifestyle modification and, if necessary, weight loss. However, compliance is a challenge, and this approach alone may not be sufficient to halt and treat the more serious disease development, so medication is urgently needed. Nevertheless, no medicines are approved to treat NAFLD. Glucagon-like peptide-1 (GLP-1) is an enteropeptide hormone that inhibits glucagon synthesis, promotes insulin secretion, and delays gastric emptying. GLP-1 has been found in recent studies to be beneficial for the management of NAFLD, and the marketed GLP-1 agonist drugs have different degrees of effectiveness for NAFLD while lowering blood glucose. In this article, we review GLP-1 and its physiological roles, the pathogenesis of NAFLD, the correlation between NAFLD and GLP-1 signaling, and potential strategies for GLP-1 treatment of NAFLD.
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Affiliation(s)
- Haoran Jiang
- Laboratory of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Linquan Zang
- Laboratory of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
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Wu Y, Zeng Y, Ren Y, Yu J, Zhang Q, Xiao X. Insights into RNA N6-methyladenosine in Glucose and Lipid Metabolic Diseases and Their Therapeutic Strategies. Endocrinology 2023; 165:bqad170. [PMID: 37950364 DOI: 10.1210/endocr/bqad170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 10/20/2023] [Accepted: 11/07/2023] [Indexed: 11/12/2023]
Abstract
The incidence of glucose and lipid metabolism diseases, including type 2 diabetes, obesity, metabolic syndrome, and nonalcoholic fatty liver disease, is rising, which places an enormous burden on people around the world. However, the mechanism behind these disorders remains incompletely understood. N6-methyladenosine (m6A) is 1 type of posttranscriptional RNA modification, and research has shown that it plays a crucial role in several metabolic diseases. m6A methylation is reversibly and dynamically regulated by methyltransferases (writers), demethylases (erasers), and m6A binding proteins (readers). Dysregulation of RNA m6A modification is related to different metabolic processes. Targeting RNA m6A methylation is a potential treatment strategy for these chronic metabolic diseases. This review discusses studies on RNA m6A modification in metabolic diseases and existing therapeutic drugs, with the aim of providing a concise perspective on its potential applications in managing metabolic disorders.
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Affiliation(s)
- Yifan Wu
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yuan Zeng
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yaolin Ren
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Jie Yu
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Qian Zhang
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Xinhua Xiao
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
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11
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Chen Y, Zhu Z, Zhang L, Wang J, Ren H. Roles of N6-methyladenosine epitranscriptome in non-alcoholic fatty liver disease and hepatocellular carcinoma. SMART MEDICINE 2023; 2:e20230008. [PMID: 39188344 PMCID: PMC11235706 DOI: 10.1002/smmd.20230008] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 04/26/2023] [Indexed: 08/28/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a typical chronic liver disease connected to a high risk of developing hepatocellular carcinoma (HCC). The development of NAFLD and HCC has been associated with changes in epigenetics, such as histone modifications and micro RNA (miRNA)-mediated processes. Recently, in the realm of epitranscriptomics, RNA alterations have become important regulators. N6-methyladenosine (m6A) is the most common and crucial alteration for controlling mRNA stability, splicing, and translation. It is particularly important for controlling liver disease progression and hepatic function. This review aims to conclude recent research on the functions of m6A epitranscriptome in the molecular mechanisms behind NAFLD and HCC development, with special attention to the effects of m6A alteration on how HCC develops and its possible roles in the progression of NAFLD to HCC. Additionally, the review discusses the possible effects of m6A alteration on the treatment and diagnostic of NAFLD and HCC. It is crucial to remember that m6A modification is a reversible action controlled via the coordinated functions of the proteins that write and delete, enabling quick adaptability to environmental changes. The review also discusses m6A-binding proteins' function in mRNA alternative splicing, translation, and degradation and their ability to modulate mRNA stability and processing. Understanding RNA modification regulation and its part in the emergence of HCC and NAFLD may provide new avenues for diagnosing and treating these diseases.
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Affiliation(s)
- Yuyan Chen
- Department of Hepatobiliary SurgeryNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjingChina
| | - Zhengyi Zhu
- Department of Hepatobiliary SurgeryNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjingChina
| | - Lu Zhang
- Department of Hepatobiliary SurgeryNanjing Drum Tower Hospital Clinical College of Xuzhou Medical UniversityNanjingChina
| | - Jinglin Wang
- Department of Hepatobiliary SurgeryNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjingChina
- Department of Hepatobiliary SurgeryNanjing Drum Tower Hospital Clinical College of Xuzhou Medical UniversityNanjingChina
| | - Haozhen Ren
- Department of Hepatobiliary SurgeryNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjingChina
- Department of Hepatobiliary SurgeryNanjing Drum Tower Hospital Clinical College of Xuzhou Medical UniversityNanjingChina
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12
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Petrovic A, Igrec D, Rozac K, Bojanic K, Kuna L, Kolaric TO, Mihaljevic V, Sikora R, Smolic R, Glasnovic M, Wu GY, Smolic M. The Role of GLP1-RAs in Direct Modulation of Lipid Metabolism in Hepatic Tissue as Determined Using In Vitro Models of NAFLD. Curr Issues Mol Biol 2023; 45:4544-4556. [PMID: 37367037 PMCID: PMC10296833 DOI: 10.3390/cimb45060288] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/18/2023] [Accepted: 05/22/2023] [Indexed: 06/28/2023] Open
Abstract
Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been shown to improve glucose and lipid homeostasis, promote weight loss, and reduce cardiovascular risk factors. They are a promising therapeutic option for non-alcoholic fatty liver disease (NAFLD), the most common liver disease, associated with T2DM, obesity, and metabolic syndrome. GLP-1RAs have been approved for the treatment of T2DM and obesity, but not for NAFLD. Most recent clinical trials have suggested the importance of early pharmacologic intervention with GLP-1RAs in alleviating and limiting NAFLD, as well as highlighting the relative scarcity of in vitro studies on semaglutide, indicating the need for further research. However, extra-hepatic factors contribute to the GLP-1RA results of in vivo studies. Cell culture models of NAFLD can be helpful in eliminating extrahepatic effects on the alleviation of hepatic steatosis, modulation of lipid metabolism pathways, reduction of inflammation, and prevention of the progression of NAFLD to severe hepatic conditions. In this review article, we discuss the role of GLP-1 and GLP-1RA in the treatment of NAFLD using human hepatocyte models.
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Affiliation(s)
- Ana Petrovic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Dunja Igrec
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Karla Rozac
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Kristina Bojanic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Health Center Osijek-Baranja County, 31000 Osijek, Croatia
| | - Lucija Kuna
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Tea Omanovic Kolaric
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Vjera Mihaljevic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Renata Sikora
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Health Center Osijek-Baranja County, 31000 Osijek, Croatia
| | - Robert Smolic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Marija Glasnovic
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - George Y. Wu
- Department of Medicine, Division of Gastrenterology/Hepatology, University of Connecticut Health Center, Farmington, CT 06030, USA
| | - Martina Smolic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
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13
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Xu J, Liu X, Wu S, Zhang D, Liu X, Xia P, Ling J, Zheng K, Xu M, Shen Y, Zhang J, Yu P. RNA-binding proteins in metabolic-associated fatty liver disease (MAFLD): From mechanism to therapy. Biosci Trends 2023; 17:21-37. [PMID: 36682800 DOI: 10.5582/bst.2022.01473] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Metabolic-associated fatty liver disease (MAFLD) is the most common chronic liver disease globally and seriously increases the public health burden, affecting approximately one quarter of the world population. Recently, RNA binding proteins (RBPs)-related pathogenesis of MAFLD has received increasing attention. RBPs, vividly called the gate keepers of MAFLD, play an important role in the development of MAFLD through transcription regulation, alternative splicing, alternative polyadenylation, stability and subcellular localization. In this review, we describe the mechanisms of different RBPs in the occurrence and development of MAFLD, as well as list some drugs that can improve MAFLD by targeting RBPs. Considering the important role of RBPs in the development of MAFLD, elucidating the RNA regulatory networks involved in RBPs will facilitate the design of new drugs and biomarkers discovery.
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Affiliation(s)
- Jiawei Xu
- The Second Clinical Medical College / The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xingyu Liu
- The Second Clinical Medical College / The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Shuqin Wu
- The Second Clinical Medical College / The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Deju Zhang
- Food and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Hong Kong, China
| | - Xiao Liu
- Department of Cardiology, The Second Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Panpan Xia
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jitao Ling
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Kai Zheng
- Medical Care Strategic Customer Department, China Merchants Bank Shenzhen Branch, Shenzhen, Guangdong, Guangdong, China
| | - Minxuan Xu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yunfeng Shen
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jing Zhang
- The Second Clinical Medical College / The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Peng Yu
- The Second Clinical Medical College / The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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14
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Tan J, Wang YF, Dai ZH, Yin HZ, Mu CY, Wang SJ, Yang F. Roles of RNA m6A modification in nonalcoholic fatty liver disease. Hepatol Commun 2023; 7:e0046. [PMID: 38345896 PMCID: PMC9988276 DOI: 10.1097/hc9.0000000000000046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 12/08/2022] [Indexed: 02/15/2024] Open
Abstract
NAFLD is a series of liver disorders, and it has become the most prevalent hepatic disease to date. However, there are no approved and effective pharmaceuticals for NAFLD owing to a poor understanding of its pathological mechanisms. While emerging studies have demonstrated that m6A modification is highly associated with NAFLD. In this review, we summarize the general profile of NAFLD and m6A modification, and the role of m6A regulators including erasers, writers, and readers in NAFLD. Finally, we also highlight the clinical significance of m6A in NAFLD.
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Affiliation(s)
- Jian Tan
- The Department of Medical Genetics, Naval Medical University, Shanghai, China
| | - Yue-fan Wang
- The Department of Medical Genetics, Naval Medical University, Shanghai, China
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University, Shanghai, China
| | - Zhi-hui Dai
- The Department of Medical Genetics, Naval Medical University, Shanghai, China
| | - Hao-zan Yin
- The Department of Medical Genetics, Naval Medical University, Shanghai, China
| | - Chen-yang Mu
- The Department of Medical Genetics, Naval Medical University, Shanghai, China
| | - Si-jie Wang
- The Department of Medical Genetics, Naval Medical University, Shanghai, China
| | - Fu Yang
- The Department of Medical Genetics, Naval Medical University, Shanghai, China
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15
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Ahmed ES, Mohamed HE, Farrag MA. Luteolin loaded on zinc oxide nanoparticles ameliorates non-alcoholic fatty liver disease associated with insulin resistance in diabetic rats via regulation of PI3K/AKT/FoxO1 pathway. Int J Immunopathol Pharmacol 2022; 36:3946320221137435. [PMID: 36319192 PMCID: PMC9630902 DOI: 10.1177/03946320221137435] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
OBJECTIVE Non-alcoholic fatty liver disease (NAFLD) is a worldwide health problem with high prevalence and morbidity associated with obesity, insulin resistance, type 2 diabetes mellitus (T2DM), and dyslipidemia. Nano-formulation of luteolin with Zn oxide in the form of Lut/ZnO NPs may improve the anti-diabetic property of each alone and ameliorate the insulin resistance thus management of NAFLD. This study aimed to measure the efficiency of Lut/ZnO NPs against insulin resistance coupled with NAFLD and T2DM. METHODS A diabetic rat model with NAFLD was induced by a high-fat diet and streptozotocin (30 mg/kg I.P). Serum diabetogenic markers levels, lipid profile, and activity of liver enzymes were measured beside liver oxidative stress markers. Moreover, the hepatic expressions of PI3K/AKT/FoxO1/SERBP1c as well as heme oxygenase-1 were measured beside the histopathological examination. RESULTS Lut/ZnO NPs treatment effectively reduced hyperglycemia, hyperinsulinemia, and ameliorated insulin resistance. Additionally, Lut/ZnO NPs improved the hepatic functions, the antioxidant system, and reduced the oxidative stress markers. Furthermore, the lipid load in the liver, as well as the circulating TG and TC, was minified via the suppression of lipogenesis and gluconeogenesis. Moreover, Lut/ZnO NPs activated the PI3K/AKT signaling pathway, hence inactivating FoxO1, therefore enhancing the hepatic cells' insulin sensitivity. CONCLUSION Lut/ZnO NPs have a hepatoprotective effect and may relieve the progression of NAFLD by alleviating insulin resistance, ameliorating the antioxidant status, and regulating the insulin signal pathway.
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Affiliation(s)
- Esraa Sa Ahmed
- Radiation Biology Research, National Center for Radiation Research and Technology, 68892Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Hebatallah E Mohamed
- Radiation Biology Research, National Center for Radiation Research and Technology, 68892Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Mostafa A Farrag
- Radiation Biology Research, National Center for Radiation Research and Technology, 68892Egyptian Atomic Energy Authority, Cairo, Egypt
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16
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Xiao P, Li M, Zhou M, Zhao X, Wang C, Qiu J, Fang Q, Jiang H, Dong H, Zhou R. TTP protects against acute liver failure by regulating CCL2 and CCL5 through m6A RNA methylation. JCI Insight 2021; 6:149276. [PMID: 34877932 PMCID: PMC8675193 DOI: 10.1172/jci.insight.149276] [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: 03/04/2021] [Accepted: 10/27/2021] [Indexed: 01/02/2023] Open
Abstract
Tristetraprolin (TTP), an important immunosuppressive protein regulating mRNA decay through recognition of the AU-rich elements (AREs) within the 3′-UTRs of mRNAs, participates in the pathogenesis of liver diseases. However, whether TTP regulates mRNA stability through other mechanisms remains poorly understood. Here, we report that TTP was upregulated in acute liver failure (ALF), resulting in decreased mRNA stabilities of CCL2 and CCL5 through promotion of N6-methyladenosine (m6A) mRNA methylation. Overexpression of TTP could markedly ameliorate hepatic injury in vivo. TTP regulated the mRNA stabilization of CCL2 and CCL5. Interestingly, increased m6A methylation in CCL2 and CCL5 mRNAs promoted TTP-mediated RNA destabilization. Moreover, induction of TTP upregulated expression levels of WT1 associated protein, methyltransferase like 14, and YT521-B homology N6-methyladenosine RNA binding protein 2, which encode enzymes regulating m6A methylation, resulting in a global increase of m6A methylation and amelioration of liver injury due to enhanced degradation of CCL2 and CCL5. These findings suggest a potentially novel mechanism by which TTP modulates mRNA stabilities of CCL2 and CCL5 through m6A RNA methylation, which is involved in the pathogenesis of ALF.
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Affiliation(s)
- Pingping Xiao
- Hubei Province Key Laboratory of Allergy and Immunology and.,Department of Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.,School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Mingxuan Li
- Hubei Province Key Laboratory of Allergy and Immunology and
| | - Mengsi Zhou
- Hubei Province Key Laboratory of Allergy and Immunology and
| | - Xuejun Zhao
- Hubei Province Key Laboratory of Allergy and Immunology and.,Department of Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Cheng Wang
- Hubei Province Key Laboratory of Allergy and Immunology and
| | - Jinglin Qiu
- School of Pharmacy, Hubei University of Science and Technology, Xianning, China
| | - Qian Fang
- Hubei Province Key Laboratory of Allergy and Immunology and.,Department of Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Hong Jiang
- Department of Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Huifen Dong
- Hubei Province Key Laboratory of Allergy and Immunology and.,Department of Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Rui Zhou
- Hubei Province Key Laboratory of Allergy and Immunology and.,Department of Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
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17
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Peng XF, Huang SF, Chen LJ, Xu L, Ye WC. Targeting epigenetics and lncRNAs in liver disease: From mechanisms to therapeutics. Pharmacol Res 2021; 172:105846. [PMID: 34438063 DOI: 10.1016/j.phrs.2021.105846] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 08/16/2021] [Accepted: 08/18/2021] [Indexed: 12/19/2022]
Abstract
Early onset and progression of liver diseases can be driven by aberrant transcriptional regulation. Different transcriptional regulation processes, such as RNA/DNA methylation, histone modification, and ncRNA-mediated targeting, can regulate biological processes in healthy cells, as well also under various pathological conditions, especially liver disease. Numerous studies over the past decades have demonstrated that liver disease has a strong epigenetic component. Therefore, the epigenetic basis of liver disease has challenged our knowledge of epigenetics, and epigenetics field has undergone an important transformation: from a biological phenomenon to an emerging focus of disease research. Furthermore, inhibitors of different epigenetic regulators, such as m6A-related factors, are being explored as potential candidates for preventing and treating liver diseases. In the present review, we summarize and discuss the current knowledge of five distinct but interconnected and interdependent epigenetic processes in the context of hepatic diseases: RNA methylation, DNA methylation, histone methylation, miRNAs, and lncRNAs. Finally, we discuss the potential therapeutic implications and future challenges and ongoing research in the field. Our review also provides a perspective for identifying therapeutic targets and new hepatic biomarkers of liver disease, bringing precision research and disease therapy to the modern era of epigenetics.
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Affiliation(s)
- Xiao-Fei Peng
- Department of General Surgery, Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan 511518, Guangdong Province, China
| | - Shi-Feng Huang
- Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan 511518, Guangdong Province, China
| | - Ling-Juan Chen
- Department of Clinical Laboratory, Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan 511518, Guangdong Province, China
| | - Lingqing Xu
- Department of Clinical Laboratory, Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan 511518, Guangdong Province, China
| | - Wen-Chu Ye
- Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan 511518, Guangdong Province, China.
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18
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Köseoğlu D, Koparal SS, Özdemir Başer Ö, Berker D. Exenatide improves cardiovascular risk factors in obese patients with type 2 diabetes mellitus: a prospective study. Turk J Med Sci 2021; 51:167-174. [PMID: 32892547 PMCID: PMC7991851 DOI: 10.3906/sag-2004-154] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 08/29/2020] [Indexed: 11/15/2022] Open
Abstract
Background/aim The aim of this study was to evaluate the effects of a 6-month treatment regimen with exenatide on the lipid profile, high-sensitivity C-reactive protein (hsCRP), carotid intima media thickness (CIMT), visceral adiposity, and nonalcoholic fatty liver disease (NAFLD), all of which are important cardiovascular risk factors. Materials and methods This study included 45 obese patients with type 2 diabetes mellitus (T2DM). Baseline clinical findings, laboratory parameters, and ultrasonography findings were recorded. An exenatide recipe was given twice daily to the patients and, after 6 months of therapy, the same variables were compared. The compared parameters were lipid profiles, hsCRP, aspartat aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, liver craniocaudal diameter, visceral fat volume, subcutaneous fat thickness, and CIMT. Liver diameter, visceral fat volume, subcutaneous fat thickness, and CIMT were measured by ultrasonography. Results After therapy, statistically significant improvements were achieved in lipid profile, hsCRP, liver enzymes, body mass index, and waist and hip circumferences. Also, statistically significant decreases were obtained in liver craniocaudal diameter, subcutaneous fat thickness, visceral fat volume, and CIMT. The reduction of CIMT and liver diameter were not correlated with BMI and HbA1c reduction. Conclusion This study showed improvement in lipid profile and hsCRP levels with exenatide treatment. We also showed decrease in both visceral fat volume and subcutaneous fat thickness. We demonstrated significant decrease in liver enzymes with significant decrease in liver diameter. These findings support the use of exenatide in patients with NAFLD and T2DM. Additionally, this study showed that exenatide treatment given twice daily reduces CIMT in obese T2DM patients.
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Affiliation(s)
- Derya Köseoğlu
- Department of Endocrinology and Metabolism, Erol Olçok Education and Research Hospital, Çorum, Turkey
| | - Salih Süha Koparal
- Department of Radiology, Ankara City Hospital, Sağlık Bilimleri University, Ankara, Turkey
| | - Özden Özdemir Başer
- Department of Endocrinology and Metabolism, Yozgat State Hospital, Yozgat, Turkey
| | - Dilek Berker
- Department of Endocrinology and Metabolism, Ankara City Hospital, Sağlık Bilimleri University, Ankara, Turkey
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19
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Sun D, Zhao T, Zhang Q, Wu M, Zhang Z. Fat mass and obesity-associated protein regulates lipogenesis via m 6 A modification in fatty acid synthase mRNA. Cell Biol Int 2020; 45:334-344. [PMID: 33079435 DOI: 10.1002/cbin.11490] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/01/2020] [Accepted: 10/18/2020] [Indexed: 12/13/2022]
Abstract
As the first identified N6 -methyladenosine (m6 A) demethylase, fat mass and obesity-associated (FTO) protein is associated with fatty acid synthase (FASN) and lipid accumulation. However, little is known about the regulatory role of FTO in the expression of FASN and de novo lipogenesis through m6 A modification. In this study, we used FTO small interfering RNA to explore the effects of FTO knockdown on hepatic lipogenesis and its underlying epigenetic mechanism in HepG2 cells. We found that knockdown of FTO increased m6 A levels in total RNA and enhanced the expression of YTH domain family member 2 which serves as the m6 A-binding protein. The de novo lipogenic enzymes and intracellular lipid content were significantly decreased under FTO knockdown. Mechanistically, knockdown of FTO dramatically enhanced m6 A levels in FASN messenger RNA (mRNA), leading to the reduced expression of FASN mRNA through m6 A-mediated mRNA decay. The protein expressions of FASN along with acetyl CoA carboxylase and ATP-citrate lyase were further decreased, which inhibited de novo lipogenesis, thereby resulting in the deficiency of lipid accumulation in HepG2 cells and the induction of cellular apoptosis. The results reveal that FTO regulates hepatic lipogenesis via FTO-dependent m6 A demethylation in FASN mRNA and indicate the critical role of FTO-mediated lipid metabolism in the survival of HepG2 cells. This study provides novel insights into a unique RNA epigenetic mechanism by which FTO mediates hepatic lipid accumulation through m6 A modification and indicates that FTO could be a potential target for obesity-related diseases and cancer.
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Affiliation(s)
- Donglei Sun
- Department of Environmental and Occupational Health, West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Tianhe Zhao
- Department of Environmental and Occupational Health, West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qian Zhang
- Department of Environmental and Occupational Health, West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Mei Wu
- Department of Environmental and Occupational Health, West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zunzhen Zhang
- Department of Environmental and Occupational Health, West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
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20
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Sofogianni A, Filippidis A, Chrysavgis L, Tziomalos K, Cholongitas E. Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update. World J Hepatol 2020; 12:493-505. [PMID: 32952876 PMCID: PMC7475780 DOI: 10.4254/wjh.v12.i8.493] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 05/02/2020] [Accepted: 06/20/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the predominant cause of chronic liver disease worldwide. NAFLD progresses in some cases to non-alcoholic steatohepatitis (NASH), which is characterized, in addition to liver fat deposition, by hepatocyte ballooning, inflammation and liver fibrosis, and in some cases may lead to hepatocellular carcinoma. NAFLD prevalence increases along with the rising incidence of type 2 diabetes mellitus (T2DM). Currently, lifestyle interventions and weight loss are used as the major therapeutic strategy in the vast majority of patients with NAFLD. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used in the management of T2DM and do not have major side effects like hypoglycemia. In patients with NAFLD, the GLP-1 receptor production is down-regulated. Recently, several animal and human studies have emphasized the role of GLP-1RAs in ameliorating liver fat accumulation, alleviating the inflammatory environment and preventing NAFLD progression to NASH. In this review, we summarize the updated literature data on the beneficial effects of GLP-1RAs in NAFLD/NASH. Finally, as GLP-1RAs seem to be an attractive therapeutic option for T2DM patients with concomitant NAFLD, we discuss whether GLP-1RAs should represent the first line pharmacotherapy for these patients.
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Affiliation(s)
- Areti Sofogianni
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki 54636, Greece
| | - Athanasios Filippidis
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki 54636, Greece
| | - Lampros Chrysavgis
- First Department of Internal Medicine, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Konstantinos Tziomalos
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki 54636, Greece
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens 11527, Greece.
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21
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Zhang B, Jiang H, Dong Z, Sun A, Ge J. The critical roles of m6A modification in metabolic abnormality and cardiovascular diseases. Genes Dis 2020; 8:746-758. [PMID: 34522705 PMCID: PMC8427257 DOI: 10.1016/j.gendis.2020.07.011] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 07/21/2020] [Accepted: 07/24/2020] [Indexed: 12/20/2022] Open
Abstract
N6-methyladenosine (m6A) RNA methylation is an emerging area of epigenetics, which is a reversible and dynamic modification mediating by ‘writers’ (methylase, adding methyl groups, METTL3, METTL14, and WTAP), ‘erasers’ (demethylase, deleting methyl groups, FTO and ALKBH5), and ‘readers’ (YTHDF1-3, YTHDC1 and YTHDC2). Recent studies in human, animal models and cell levels have disclosed a critical role of m6A modification in regulating the homeostasis of metabolic processes and cardiovascular function. Evidence from these studies identify m6A as a candidate of biomarker and therapeutic target for metabolic abnormality and cardiovascular diseases (CVD). Comprehensive understanding of the complexity of m6A regulation in metabolic diseases and CVD will be helpful for us to understand the pathogenesis of CVD. In this review, we discuss the regulatory role of m6A in metabolic abnormality and CVD. We will emphasize the clinical relevance of m6A dysregulation in CVD.
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Affiliation(s)
- Beijian Zhang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China
- Shanghai Institute of Cardiovascular Diseases, Shanghai, 200003, PR China
- NHC Key Laboratory of Viral Heart Diseases, Shanghai, 200032, PR China
- Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, PR China
| | - Hao Jiang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China
- Shanghai Institute of Cardiovascular Diseases, Shanghai, 200003, PR China
- NHC Key Laboratory of Viral Heart Diseases, Shanghai, 200032, PR China
- Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, PR China
| | - Zhen Dong
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China
- Shanghai Institute of Cardiovascular Diseases, Shanghai, 200003, PR China
- NHC Key Laboratory of Viral Heart Diseases, Shanghai, 200032, PR China
- Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, PR China
| | - Aijun Sun
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China
- Shanghai Institute of Cardiovascular Diseases, Shanghai, 200003, PR China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200433, PR China
- NHC Key Laboratory of Viral Heart Diseases, Shanghai, 200032, PR China
- Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, PR China
- Corresponding author. Department of Cardiology, Zhongshan Hospital, Fudan University, No. 1609 Xietu Road, District Xuhui, Shanghai, 200025, PR China.
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China
- Shanghai Institute of Cardiovascular Diseases, Shanghai, 200003, PR China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200433, PR China
- NHC Key Laboratory of Viral Heart Diseases, Shanghai, 200032, PR China
- Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, PR China
- Corresponding author. Shanghai Institute of Cardiovascular Diseases, No. 1609 Xietu Road, District Xuhui, Shanghai, 200025, PR China.
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22
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Lu J, Qian J, Yin S, Zhou L, Zheng S, Zhang W. Mechanisms of RNA N 6-Methyladenosine in Hepatocellular Carcinoma: From the Perspectives of Etiology. Front Oncol 2020; 10:1105. [PMID: 32733807 PMCID: PMC7358598 DOI: 10.3389/fonc.2020.01105] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Accepted: 06/02/2020] [Indexed: 12/17/2022] Open
Abstract
N6-Methyladenosine (m6A) is the most common RNA internal modification in eukaryotic cells. Its regulatory effects at the post-transcriptional level on both messenger RNAs (mRNAs) and noncoding RNAs have been widely studied; these include alternative splicing, stability, translation efficiency, nucleus export, and degradation. m6A modification is implicated in a series of physiological and pathological activities, such as embryonic stem cell differentiation, immunoregulation, adipogenesis, and cancer development. Recently, the significance of m6A methylation has been identified in both viral hepatitis and non-alcohol fatty liver disease (NAFLD), which are major risk factors in the development of hepatocellular carcinoma (HCC). Given the high incidence and mortality rate of HCC worldwide, it is of great importance to elucidate the mechanisms underlying HCC initiation and progression. m6A as an emerging research focus has great potential to facilitate the understanding of HCC, particularly from an etiological perspective. Thus, in this review, we summarize recent progress in understanding m6A modification related to viral hepatitis, NAFLD, and HCC, including their mechanisms and clinical applications.
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Affiliation(s)
- Jiahua Lu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Junjie Qian
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Shengyong Yin
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Wu Zhang
- Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China.,Institution of Organ Transplantation, Zhejiang University, Hangzhou, China
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23
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Liu L, Yan H, Xia M, Zhao L, Lv M, Zhao N, Rao S, Yao X, Wu W, Pan B, Bian H, Gao X. Efficacy of exenatide and insulin glargine on nonalcoholic fatty liver disease in patients with type 2 diabetes. Diabetes Metab Res Rev 2020; 36:e3292. [PMID: 31955491 DOI: 10.1002/dmrr.3292] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 01/11/2020] [Accepted: 01/14/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND The aim of this study was to investigate the efficacy of exenatide and insulin glargine in patients with newly diagnosed type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). METHODS We performed a 24-week randomized controlled multicentre clinical trial. Seventy-six patients were randomly assigned 1:1 to receive exenatide or insulin glargine treatment. The endpoints included changes in liver fat content (LFC), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) measured by magnetic resonance spectroscopy, blood glucose, liver enzymes, lipid profile, body weight, and Fibrosis-4 index (FIB-4). RESULTS LFC, VAT, SAT, and FIB-4 were significantly reduced after exenatide treatment (ΔLFC, -17.55 ± 12.93%; ΔVAT, -43.57 ± 68.20 cm2 ; ΔSAT, -28.44 ± 51.48 cm2 ; ΔFIB-4, -0.10 ± 0.26; all P < .05). In comparison, only LFC (ΔLFC, -10.49 ± 11.38%; P < .05), and not VAT, SAT, or FIB-4 index (all P > .05), was reduced after insulin glargine treatment. Moreover, exenatide treatment resulted in greater reductions in alanine transaminase (ALT), aspartate transaminase (AST), and gamma glutamyl transpeptidase (GGT) than insulin glargine (P < 0.05). The body weight, waist circumference, postprandial plasma glucose, and low-density lipoprotein cholesterol (LDL-C) in the exenatide group also presented greater reductions than the insulin glargine group (P < .05). The proportion of adverse events were comparable between the two groups. CONCLUSION Both exenatide and insulin glargine reduced LFC in patients with drug-naive T2DM and NAFLD; however, exenatide showed greater reductions in body weight, visceral fat area, liver enzymes, FIB-4, postprandial plasma glucose, and LDL-C.
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Affiliation(s)
- Lin Liu
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hongmei Yan
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - MingFeng Xia
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lin Zhao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Minzhi Lv
- Department of Biostatistics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Naiqin Zhao
- Department of Biostatistics, School of Public Health, Fudan University, Shanghai, China
| | - Shengxiang Rao
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiuzhong Yao
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weiyun Wu
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Baishen Pan
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hua Bian
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
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24
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Saad ZA, Khodeer DM, Zaitone SA, Ahmed AAM, Moustafa YM. Exenatide ameliorates experimental non-alcoholic fatty liver in rats via suppression of toll-like receptor 4/NFκB signaling: Comparison to metformin. Life Sci 2020; 253:117725. [PMID: 32348835 DOI: 10.1016/j.lfs.2020.117725] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 04/20/2020] [Accepted: 04/21/2020] [Indexed: 02/07/2023]
Abstract
AIMS Non-alcoholic fatty liver disease (NAFLD) is a common liver disease. This study aimed to evaluate the role of exenatide compared with metformin in halting the progression of fatty liver stimulated by a high-fat diet (HiFD) in rats. MAIN METHODS Thirty male Wistar rats were allocated into 6 groups, 5 rats per each group. Group I: maintained on normal diet (normal group) for fourteen weeks. The other five groups were kept on HiFD throughout the experiment, HiFD was administered beside pharmacological treatments/or vehicle. Group II: (NAFLD control group), group III: received metformin (60 mg/kg/day, P.O.), group IV-VI: received exenatide (10, 20, and 40 μg/kg/day, S.C.) respectively for 7 weeks. At the end of the therapeutic period, fasting blood glucose was determined, and body weight was registered. Rats were sacrificed, and blood samples were taken to measure serum insulin, lipids, and liver enzymes. The liver index and homeostasis model of insulin resistance (HOMA-IR) index were calculated. Further, livers were dissected for histopathological examination and Western blot analysis. KEY FINDINGS NAFLD control group showed hyperglycemia, hyperinsulinemia, increased liver enzymes, hypertriglyceridemia, elevated hepatic lipid peroxides, and inflammatory mediators (interlukin 6, nuclear factor-κB, tumor necrosis factor-α and Toll-like receptor4) in addition to hepatic fatty degeneration. In a dose-dependent manner, exenatide significantly improved most of the above mentioned markers in comparsion with NAFLD at P≤0.05. SIGNIFICANCE The current results suggest that exenatide is equivalent to metformin in controlling insulin resistance, body weight gain, improving liver function, suppressing inflammation, and attenuating NAFLD progression in male rats.
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Affiliation(s)
- Zeinab A Saad
- Medical Administration, Suez Canal University, Ismailia, Egypt
| | - Dina M Khodeer
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
| | - Sawsan A Zaitone
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Amal A M Ahmed
- Department of Histology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
| | - Yasser M Moustafa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
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25
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Li Y, Wang J, Huang C, Shen M, Zhan H, Xu K. RNA N6-methyladenosine: a promising molecular target in metabolic diseases. Cell Biosci 2020; 10:19. [PMID: 32110378 PMCID: PMC7035649 DOI: 10.1186/s13578-020-00385-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 02/11/2020] [Indexed: 12/12/2022] Open
Abstract
N6-methyladenosine is a prevalent and abundant transcriptome modification, and its methylation regulates the various aspects of RNAs, including transcription, translation, processing and metabolism. The methylation of N6-methyladenosine is highly associated with numerous cellular processes, which plays important roles in the development of physiological process and diseases. The high prevalence of metabolic diseases poses a serious threat to human health, but its pathological mechanisms remain poorly understood. Recent studies have reported that the progression of metabolic diseases is closely related to the expression of RNA N6-methyladenosine modification. In this review, we aim to summarize the biological and clinical significance of RNA N6-methyladenosine modification in metabolic diseases, including obesity, type 2 diabetes, non-alcoholic fatty liver disease, hypertension, cardiovascular diseases, osteoporosis and immune-related metabolic diseases.
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Affiliation(s)
- Yan Li
- 1Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072 Sichuan China
| | - Jiawen Wang
- 1Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072 Sichuan China
| | - Chunyan Huang
- Houjie Hospital of Dongguan, Dongguan, 523945 Guangdong China
| | - Meng Shen
- Chengdu Tumor Hospital, Chengdu, 610041 Sichuan China
| | - Huakui Zhan
- 1Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072 Sichuan China
| | - Keyang Xu
- 4Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310023 Zhejiang China
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26
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Newsome P, Francque S, Harrison S, Ratziu V, Van Gaal L, Calanna S, Hansen M, Linder M, Sanyal A. Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. Aliment Pharmacol Ther 2019; 50:193-203. [PMID: 31246368 PMCID: PMC6617813 DOI: 10.1111/apt.15316] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 01/19/2019] [Accepted: 05/01/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Obesity and type 2 diabetes are drivers of non-alcoholic fatty liver disease (NAFLD). Glucagon-like peptide-1 analogues effectively treat obesity and type 2 diabetes and may offer potential for NAFLD treatment. AIM To evaluate the effect of the glucagon-like peptide-1 analogue, semaglutide, on alanine aminotransferase (ALT) and high-sensitivity C-reactive protein (hsCRP) in subjects at risk of NAFLD. METHODS Data from a 104-week cardiovascular outcomes trial in type 2 diabetes (semaglutide 0.5 or 1.0 mg/week) and a 52-week weight management trial (semaglutide 0.05-0.4 mg/day) were analysed. Treatment ratios vs placebo were estimated for ALT (both trials) and hsCRP (weight management trial only) using a mixed model for repeated measurements, with or without adjustment for change in body weight. RESULTS Elevated baseline ALT (men >30 IU/L; women >19 IU/L) was present in 52% (499/957) of weight management trial subjects. In this group with elevated ALT, end-of-treatment ALT reductions were 6%-21% (P<0.05 for doses≥0.2 mg/day) and hsCRP reductions 25%-43% vs placebo (P < 0.05 for 0.2 and 0.4 mg/day). Normalisation of elevated baseline ALT occurred in 25%-46% of weight management trial subjects, vs 18% on placebo. Elevated baseline ALT was present in 41% (1325/3268) of cardiovascular outcomes trial subjects. In this group with elevated ALT, no significant ALT reduction was noted at end-of-treatment for 0.5 mg/week, while a 9% reduction vs placebo was seen for 1.0 mg/week (P = 0.0024). Treatment ratios for changes in ALT and hsCRP were not statistically significant after adjustment for weight change. CONCLUSIONS Semaglutide significantly reduced ALT and hsCRP in clinical trials in subjects with obesity and/or type 2 diabetes.
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Affiliation(s)
- Philip Newsome
- National Institute for Health Research Birmingham Biomedical Research Centre and Liver Unit at University Hospitals Birmingham NHS Foundation TrustBirminghamUK,Centre for Liver & Gastrointestinal Research, Institute of Immunology and ImmunotherapyUniversity of BirminghamBirminghamUK
| | - Sven Francque
- Department of Gastroenterology and HepatologyAntwerp University HospitalEdegem, AntwerpBelgium
| | | | - Vlad Ratziu
- ICAN – Institute for Cardiometabolism and NutritionHôpital Pitié Salpêtrière, Sorbonne UniversityParisFrance
| | - Luc Van Gaal
- Department of Endocrinology, Diabetology and MetabolismAntwerp University HospitalEdegem, AntwerpBelgium
| | | | | | | | - Arun Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal MedicineVirginia Commonwealth UniversityRichmondVirginia
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27
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Yesil S, Sungu N, Kilicarslan A, Kuskonmaz SM, Kara H, Kucuk A, Polat F, Kavutcu M, Arslan M. Exenatide reduces oxidative stress and cell death in testis in iron overload rat model. Exp Ther Med 2018; 16:4349-4356. [PMID: 30546390 PMCID: PMC6256837 DOI: 10.3892/etm.2018.6795] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 04/06/2018] [Indexed: 12/11/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) has been demonstrated to affect the oxidative stress status in several in vitro, in vivo and clinical studies. The aim of the present study was to evaluate the effect of a GLP-1 analogue, exenatide, on oxidative stress parameters and apoptotic markers in testicular cells in an iron overload rat model. To obtain this model, the animals were randomly divided into three groups (n=6/group). Rats in the control group received intraperitoneal injections of saline. Intraperitoneal iron dextran (60 mg/kg/day) was given to Group FE for 5 days a week for 4 weeks. The third group (Group Fe +E) was given subcutaneous injections of 10 µg/kg exenatide in two divided doses for 4 weeks in addition to iron dextran. Testes of all rats were immediately removed for immunohistochemical staining and to measure the malondialdehyde level and superoxide dismutase enzyme activity. A significant reduction was observed in caspase-8 and -3 enzyme staining in testicular stromal and endothelial cells in exenatide injected iron overloaded rats when compared with controls. Oxidative stress markers malondialdehyde levels and superoxide dismutase enzyme activities were also significantly lower in exenatide-injected rats when compared with controls. These findings indicate that exenatide may be protective against the harmful effects of iron accumulation in testis. Further studies are required to evaluate how exenatide reduces oxidative stress and cell death in iron overloaded testis tissue.
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Affiliation(s)
- Suleyman Yesil
- Department of Urology, Gazi University Medical Faculty, Ankara 06510, Turkey
| | - Nuran Sungu
- Department of Pathology, Yıldırım Beyazıt University Medical Faculty, Ankara 06010, Turkey
| | - Aydan Kilicarslan
- Department of Pathology, Yıldırım Beyazıt University Medical Faculty, Ankara 06010, Turkey
| | - Serife Mehlika Kuskonmaz
- Department of Endocrinology and Metabolism, Gazi University Medical Faculty, Ankara 06510, Turkey
| | - Halil Kara
- Department of Pharmacology, Yıldırım Beyazıt University Medical Faculty, Ankara 06010, Turkey
| | - Aysegul Kucuk
- Department of Physiology, Kütahya Health Sciences University Medical Faculty, Kütahya 43100, Turkey
| | - Fazli Polat
- Department of Urology, Gazi University Medical Faculty, Ankara 06510, Turkey
| | - Mustafa Kavutcu
- Department of Biochemistry, Gazi University Medical Faculty, Ankara 06510, Turkey
| | - Mustafa Arslan
- Department of Anesthesiology and Reanimation, Gazi University Medical Faculty, Ankara 06510, Turkey
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