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1
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Zhang Y, Ding R, Hu L, Liu E, Qu P. Epigenetics in metabolic dysfunction-associated steatohepatitis. Cell Signal 2025; 130:111684. [PMID: 39999913 DOI: 10.1016/j.cellsig.2025.111684] [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: 01/09/2025] [Revised: 02/16/2025] [Accepted: 02/19/2025] [Indexed: 02/27/2025]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a complex disease involving genetics, environment, and lifestyle, with the potential to progress to liver fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). Although the pathogenesis of MASH is not fully clear, increasing evidence has indicated that epigenetics plays an important role in the genesis and progression of MASH, during which, as drastic changes in metabolites, epigenetics undergo drastic changes. Roles of chromatin structure, chromatin accessibility, DNA methylation, histone modification, and non-coding RNAs were considered as bridges of pathogenic factors and MASH. In this review, the research progress on the epigenetics of MASH was summarized, and indepth research and therapeutic strategies based on epigenetics is expected to bring new hope to MASH patients.
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Affiliation(s)
- Yanru Zhang
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an 710049, China
| | - Ruike Ding
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an 710049, China
| | - Liangshuo Hu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Enqi Liu
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an 710049, China.
| | - Pengxiang Qu
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Centre, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an 710049, China.
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Gao F, Ma Y, Yu C, Duan Q. miR-125b-5p regulates FFA-induced hepatic steatosis in L02 cells by targeting estrogen-related receptor alpha. Gene 2025:149419. [PMID: 40113187 DOI: 10.1016/j.gene.2025.149419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 03/02/2025] [Accepted: 03/13/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND & AIMS NAFLD is a global and complex liver disease caused by multiple factors. Intrahepatocellular steatosis is the primary prerequisite for the occurrence and development of NAFLD. It has been shown that miR-125b-5p is highly correlated with NAFLD, and ESRRA is a factor that regulates lipid metabolism. The purpose of our study is to investigate whether miR-125b-5p regulates FFA-induced steatosis in L02 cells by targeting ESRRA. APPROACHES AND RESULTS Estrogen-related receptor alpha (ESRRA) was identified as a direct target of miR-125b-5p through database prediction and a dual-luciferase reporter gene assay. L02 cells were induced with free fatty acids (OA:PA, 2:1) at concentrations of 0.3 mM, 0.6 mM, 0.9 mM, 1.2 mM and 1.5 mM for 24 h, 48 h and 72 h, respectively. The degree of hepatocyte steatosis and triglyceride content were separately manifested by oil red O staining and colorimetric method. Cell viability per group was detected by CCK-8 assay. Eventually, 0.9 mM and 24 h were screened out as the optimal concentration and time for establishing the in-vitro model of hepatic steatosis. Followingly, miR-125b-5p and ESRRA were knocked down by transient transfection. We monitored the expressions of lipid metabolism factors SREBP-1c, ACC1 and FAS. The data showed that knockdown of ESRRA led to down-regulation of the expressions of SREBP-1, ACC1 and FAS. Meanwhile, knockdown of ESRRA and miR-125b-5p resulted that the expressions of ESRRA, SREBP-1, ACC1 and FAS rebounded. CONCLUSIONS MiR-125b-5p down-regulates the expressions of lipid metabolism-related factors by negatively regulating ESRRA, thereby improving hepatic steatosis.
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Affiliation(s)
- Fen Gao
- Gansu University of Chinese Medicine, Gansu 730000, China
| | - Yanhua Ma
- Gansu University of Chinese Medicine, Gansu 730000, China.
| | - Chun Yu
- Gansu University of Chinese Medicine, Gansu 730000, China
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3
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Popa ML, Ichim C, Anderco P, Todor SB, Pop-Lodromanean D. MicroRNAs in the Diagnosis of Digestive Diseases: A Comprehensive Review. J Clin Med 2025; 14:2054. [PMID: 40142862 PMCID: PMC11943142 DOI: 10.3390/jcm14062054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 03/14/2025] [Accepted: 03/15/2025] [Indexed: 03/28/2025] Open
Abstract
MicroRNAs (miRNAs) have emerged as crucial regulators in digestive pathologies, including inflammatory bowel disease (miR-31, miR-155, and miR-21), colorectal cancer (miR-21, miR-598, and miR-494), and non-alcoholic fatty liver disease (miR-21, miR-192, and miR-122). Their capacity to modulate gene expression at the post-transcriptional level makes them highly promising candidates for biomarkers and therapeutic interventions. However, despite considerable progress, their clinical application remains challenging. Research has shown that miRNA expression is highly dynamic, varying across patients, disease stages, and different intestinal regions. Their dual function as both oncogenes and tumor suppressors further complicates their therapeutic use, as targeting miRNAs may yield unpredictable effects. Additionally, while miRNA-based therapies hold great potential, significant hurdles persist, including off-target effects, immune activation, and inefficiencies in delivery methods. The intricate interplay between miRNAs and gut microbiota adds another layer of complexity, influencing disease mechanisms and treatment responses. This review examined the role of miRNAs in digestive pathologies, emphasizing their diagnostic and therapeutic potential. While they offer new avenues for disease management, unresolved challenges underscore the need for further research to refine their clinical application.
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Affiliation(s)
| | - Cristian Ichim
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (M.L.P.); (S.B.T.); (D.P.-L.)
| | - Paula Anderco
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (M.L.P.); (S.B.T.); (D.P.-L.)
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Stratakis N, Anguita-Ruiz A, Fabbri L, Maitre L, González JR, Andrusaityte S, Basagaña X, Borràs E, Keun HC, Chatzi L, Conti DV, Goodrich J, Grazuleviciene R, Haug LS, Heude B, Yuan WL, McEachan R, Nieuwenhuijsen M, Sabidó E, Slama R, Thomsen C, Urquiza J, Roumeliotaki T, Vafeiadi M, Wright J, Bustamante M, Vrijheid M. Multi-omics architecture of childhood obesity and metabolic dysfunction uncovers biological pathways and prenatal determinants. Nat Commun 2025; 16:654. [PMID: 39809770 PMCID: PMC11732992 DOI: 10.1038/s41467-025-56013-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 01/06/2025] [Indexed: 01/16/2025] Open
Abstract
Childhood obesity poses a significant public health challenge, yet the molecular intricacies underlying its pathobiology remain elusive. Leveraging extensive multi-omics profiling (methylome, miRNome, transcriptome, proteins and metabolites) and a rich phenotypic characterization across two parts of Europe within the population-based Human Early Life Exposome project, we unravel the molecular landscape of childhood obesity and associated metabolic dysfunction. Our integrative analysis uncovers three clusters of children defined by specific multi-omics profiles, one of which characterized not only by higher adiposity but also by a high degree of metabolic complications. This high-risk cluster exhibits a complex interplay across many biological pathways, predominantly underscored by inflammation-related cascades. Further, by incorporating comprehensive information from the environmental risk-scape of the critical pregnancy period, we identify pre-pregnancy body mass index and environmental pollutants like perfluorooctanoate and mercury as important determinants of the high-risk cluster. Overall, our work helps to identify potential risk factors for prevention and intervention strategies early in the life course aimed at mitigating obesity and its long-term health consequences.
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Affiliation(s)
- Nikos Stratakis
- Institute for Global Health (ISGlobal), Barcelona, Spain.
- Universitat Pompeu Fabra (UPF), Barcelona, Spain.
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
| | - Augusto Anguita-Ruiz
- Institute for Global Health (ISGlobal), Barcelona, Spain
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institute of Biomedicine of the University of Barcelona (IBUB), Universitat de Barcelona (UB), Barcelona, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition Network CB12/03/30038), Institute of Health Carlos III (ISCIII), Madrid, Spain
| | - Lorenzo Fabbri
- Institute for Global Health (ISGlobal), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Léa Maitre
- Institute for Global Health (ISGlobal), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Juan R González
- Institute for Global Health (ISGlobal), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Sandra Andrusaityte
- Department of Environmental Sciences, Vytautas Magnus University, Kaunas, Lithuania
| | - Xavier Basagaña
- Institute for Global Health (ISGlobal), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Eva Borràs
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Hector C Keun
- Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Cancer Metabolism & Systems Toxicology Group, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom
| | - Lida Chatzi
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - David V Conti
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jesse Goodrich
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Regina Grazuleviciene
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institute of Biomedicine of the University of Barcelona (IBUB), Universitat de Barcelona (UB), Barcelona, Spain
| | - Line Småstuen Haug
- Department of Food Safety, Norwegian Institute of Public Health, Oslo, Norway
- Centre for Sustainable Diets, Norwegian Institute of Public Health, Oslo, Norway
| | - Barbara Heude
- Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS), F-75004, Paris, France
| | - Wen Lun Yuan
- Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS), F-75004, Paris, France
| | - Rosemary McEachan
- Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, United Kingdom
| | - Mark Nieuwenhuijsen
- Institute for Global Health (ISGlobal), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Eduard Sabidó
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Rémy Slama
- Department of Prevention and Treatment of Chronic Diseases, Institute for Advanced Biosciences (IAB), INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France
| | - Cathrine Thomsen
- Department of Food Safety, Norwegian Institute of Public Health, Oslo, Norway
- Centre for Sustainable Diets, Norwegian Institute of Public Health, Oslo, Norway
| | - Jose Urquiza
- Institute for Global Health (ISGlobal), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Theano Roumeliotaki
- Department of Social Medicine, University of Crete, Heraklion, Crete, Greece
| | - Marina Vafeiadi
- Department of Social Medicine, University of Crete, Heraklion, Crete, Greece
| | - John Wright
- Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, United Kingdom
| | - Mariona Bustamante
- Institute for Global Health (ISGlobal), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Martine Vrijheid
- Institute for Global Health (ISGlobal), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
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Tang R, Xiao G, Liu Y, Jia D, Zeng Z, Jia C, Li D, Li Y, Jiang J, Li S, Bi X. Integrated serum pharmacochemistry, pharmacokinetics, and network analysis to explore active components of BuShao Tiaozhi Capsule on hyperlipidemia. Front Pharmacol 2025; 15:1444967. [PMID: 39830346 PMCID: PMC11738623 DOI: 10.3389/fphar.2024.1444967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 11/25/2024] [Indexed: 01/22/2025] Open
Abstract
BuShao Tiaozhi Capsule (BSTZC), a novel drug in China, has been used to treat hyperlipidemia (HLP) in clinical practice for many years. Despite our previous studies suggesting that BSTZC can treat HLP, there is a lack of a rapid and systematic method to explore its active components. Therefore, in this study, we aimed to investigate the active components and mechanisms of BSTZC in treating HLP by integrating serum pharmacology, pharmacokinetics, network analysis, and experimental validation. We first established UPLC fingerprints, calibrated 23 common peaks, and identified 13 common peaks, and the similarity was greater than 0.99 for 10 batches. A total of nine metabolites from BSTZC were identified in serum and considered as PK markers. The pharmacokinetic parameters of the PK markers were compared between the control group and the model group through the pharmacokinetics study to determine the dynamic changes of representative components in rats. Compared with the control group, the Cmax and AUC0→t of OXY, IVT, IVL, and KPF-3-G were significantly higher (P< 0.05); the AUC0→∞ of OXY, PN, and IVT was significantly higher (P< 0.05); and the t1/2 of IVT, SA, and KPF-3-G was significantly different (P< 0.05). In vivo experiments showed that BSTZC and its active components could effectively alleviate lipid metabolism disorders and liver injury, with obvious lipid-lowering effects. Further studies showed that BSTZC alleviated HLP by inhibiting the PI3K/Akt signaling pathway, which was consistent with the results of the network analysis study. Our results revealed the active components and mechanisms of BSTZC in the treatment of HLP, which could provide useful information to guide the clinical application of BSTZC.
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Affiliation(s)
- Ruiyin Tang
- School of the Fifth Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Guanlin Xiao
- Guangdong Provincial Engineering Technology Research Institute of Traditional Chinese Medicine, Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Yanchang Liu
- School of the Fifth Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Dezheng Jia
- School of the Fifth Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Zhihao Zeng
- School of the Fifth Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Canchao Jia
- School of the Fifth Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Dongmei Li
- School of the Fifth Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yangxue Li
- Guangdong Provincial Engineering Technology Research Institute of Traditional Chinese Medicine, Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Jieyi Jiang
- Guangdong Provincial Engineering Technology Research Institute of Traditional Chinese Medicine, Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Sumei Li
- Guangdong Provincial Engineering Technology Research Institute of Traditional Chinese Medicine, Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Xiaoli Bi
- Guangdong Provincial Engineering Technology Research Institute of Traditional Chinese Medicine, Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, Guangzhou, Guangdong, China
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Wang L, Jia G, Fu R, Liang J, Xue W, Zheng J, Qin Y, Zhang M, Meng J. Hepatic miR-363 promotes nonalcoholic fatty liver disease by suppressing INSIG1. J Nutr Biochem 2024; 134:109717. [PMID: 39103107 DOI: 10.1016/j.jnutbio.2024.109717] [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: 02/13/2024] [Revised: 07/29/2024] [Accepted: 07/31/2024] [Indexed: 08/07/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) constitutes one of major worldwide health problem which typically progressively results in nonalcoholic steatohepatitis (NASH) and eventually cirrhosis and liver cancer. Liver-specific deletion of INSIG1 promotes SREBP1 nuclear translocation to activate downstream lipogenic genes expression, leading to lipid accumulation. However, the underlying pathogenesis of NAFLD, and particularly involved in miRNA participation are still to be thoroughly explored. Here, we found that miR-363-3p was significantly overexpressed in high-fat, high-cholesterol (HFHC) diet mice liver tissue and fatty acid-induced steatosis cells. miR-363-3p directly targets INSIG1 to inhibit its expression, thereby facilitating the cleavage of SREBP and nuclear translocation to activate subsequent transcription of lipogenic genes in vitro and in vivo. In addition, we identified apigenin, a natural flavonoid compound, inhibited miR-363-3p expression to up-regulate INSIG1 and suppress nuclear translocation of SREBP1, thereby down-regulated lipogenic genes expression in steatosis cells and HFHC diet mice liver tissues. Taken together, our results demonstrated that miR-363-3p as a key regulator of hepatic lipid homeostasis targeted INSIG1, and apigenin alleviated NAFLD through the miR-363-3p/INSIG1/SREBP1 pathway. This indicates that reduction of miR-363-3p levels as a possible treatment of hepatic steatosis and provides a potential new therapeutic strategy for targeting miRNA to ameliorate NAFLD.
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Affiliation(s)
- Lechen Wang
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Binhai, Tianjin, China
| | - Guotao Jia
- Department of Pathology, Joint Laboratory for Translational Medicine Research, Liaocheng People's Hospital, Liaocheng, Shandong, China
| | - Rongrong Fu
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Binhai, Tianjin, China
| | - Jingjie Liang
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Binhai, Tianjin, China
| | - Wenqing Xue
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Binhai, Tianjin, China
| | - Juan Zheng
- Department of Pathology, Joint Laboratory for Translational Medicine Research, Liaocheng People's Hospital, Liaocheng, Shandong, China
| | - Yuan Qin
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Min Zhang
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Binhai, Tianjin, China; China-Russia Agricultural Products Processing Joint Laboratory, Tianjin Agricultural University, Wuqing, Tianjin, China.
| | - Jing Meng
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Binhai, Tianjin, China.
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7
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Evers P, Uguccioni SM, Ahmed N, Francis ME, Kelvin AA, Pezacki JP. miR-24-3p Is Antiviral Against SARS-CoV-2 by Downregulating Critical Host Entry Factors. Viruses 2024; 16:1844. [PMID: 39772154 PMCID: PMC11680362 DOI: 10.3390/v16121844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 11/20/2024] [Accepted: 11/26/2024] [Indexed: 01/11/2025] Open
Abstract
Despite all the progress in treating SARS-CoV-2, escape mutants to current therapies remain a constant concern. Promising alternative treatments for current and future coronaviruses are those that limit escape mutants by inhibiting multiple pathogenic targets, analogous to the current strategies for treating HCV and HIV. With increasing popularity and ease of manufacturing of RNA technologies for vaccines and drugs, therapeutic microRNAs represent a promising option. In the present work, miR-24-3p was identified to inhibit SARS-CoV-2 entry, replication, and production; furthermore, this inhibition was retained against common mutations improving SARS-CoV-2 fitness. To determine the mechanism of action, bioinformatic tools were employed, identifying numerous potential effectors promoting infection targeted by miR-24-3p. Of these targets, several key host proteins for priming and facilitating SARS-CoV-2 entry were identified: furin, NRP1, NRP2, and SREBP2. With further experimental analysis, we show that miR-24-3p directly downregulates these viral entry factors to impede infection when producing virions and when infecting the target cell. Furthermore, we compare the findings with coronavirus, HCoV-229E, which relies on different factors strengthening the miR-24-3p mechanism. Taken together, the following work suggests that miR-24-3p could be an avenue to treat current coronaviruses and those likely to emerge.
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Affiliation(s)
- Parrish Evers
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N6, Canada; (P.E.); (S.M.U.)
| | - Spencer M. Uguccioni
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N6, Canada; (P.E.); (S.M.U.)
| | - Nadine Ahmed
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N6, Canada; (P.E.); (S.M.U.)
| | - Magen E. Francis
- Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada; (M.E.F.); (A.A.K.)
- Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada
| | - Alyson A. Kelvin
- Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada; (M.E.F.); (A.A.K.)
- Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada
| | - John P. Pezacki
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N6, Canada; (P.E.); (S.M.U.)
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8
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Jorud K, Mendoza KM, Kono T, Coulombe RA, Reed KM. Differential Hepatic Expression of miRNA in Response to Aflatoxin B1 Challenge in Domestic and Wild Turkeys. Toxins (Basel) 2024; 16:453. [PMID: 39591208 PMCID: PMC11598555 DOI: 10.3390/toxins16110453] [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: 09/06/2024] [Revised: 10/08/2024] [Accepted: 10/21/2024] [Indexed: 11/28/2024] Open
Abstract
Aflatoxin B1 (AFB1) is a major foodborne mycotoxin that poses a significant economic risk to poultry due to a greater degree of susceptibility compared to other agricultural species. Domesticated turkeys (Meleagris gallopavo) are especially sensitive to AFB1; however, wild turkeys (M. g. silvestris) are more resistant. A lack of functional isoforms of hepatic glutathione S-transferases (GSTs), an enzyme that plays a role in the detoxification of aflatoxin, is suspected as the reason for the increased sensitivity. Previous studies comparing the gene expression of domesticated and wild turkeys exposed to AFB1 identified hepatic genes responding differentially to AFB1, but could not fully explain the difference in response. The current study examined differences in the expression of microRNAs (miRNAs) in the livers of wild and domesticated turkeys fed dietary AFB1 (320 μg/kg in feed). Short-read RNA sequencing and expression analysis examined both domesticated and wild turkeys exposed to AFB1 compared to controls. A total of 25 miRNAs was identified as being significantly differentially expressed (DEM) in pairwise comparisons. The majority of these have mammalian orthologs with known dysregulation in liver disease. The largest number of DEMs occurred between controls, suggesting an underlying difference in liver potential. Sequences of the DEMs were used to identify potential miRNA binding sites in target genes, resulting in an average of 4302 predicted target sites per DEM. These DEMs and gene targets provide hypotheses for future investigations into the role of miRNAs in AFB1 resistance.
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Affiliation(s)
- Kade Jorud
- College of Veterinary Medicine, University of Minnesota, St Paul, MN 55108, USA
| | - Kristelle M. Mendoza
- Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA
| | - Thomas Kono
- Minnesota Supercomputing Institute, University of Minnesota, St Paul, MN 55108, USA
| | - Roger A. Coulombe
- Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT 84322, USA;
| | - Kent M. Reed
- Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA
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Ashiqueali SA, Schneider A, Zhu X, Juszczyk E, Mansoor MAM, Zhu Y, Fang Y, Zanini BM, Garcia DN, Hayslip N, Medina D, McFadden S, Stockwell R, Yuan R, Bartke A, Zasloff M, Siddiqi S, Masternak MM. Early life interventions metformin and trodusquemine metabolically reprogram the developing mouse liver through transcriptomic alterations. Aging Cell 2024; 23:e14227. [PMID: 38798180 PMCID: PMC11488326 DOI: 10.1111/acel.14227] [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: 01/23/2024] [Revised: 04/23/2024] [Accepted: 05/03/2024] [Indexed: 05/29/2024] Open
Abstract
Recent studies have demonstrated the remarkable potential of early life intervention strategies at influencing the course of postnatal development, thereby offering exciting possibilities for enhancing longevity and improving overall health. Metformin (MF), an FDA-approved medication for type II diabetes mellitus, has recently gained attention for its promising anti-aging properties, acting as a calorie restriction mimetic, and delaying precocious puberty. Additionally, trodusquemine (MSI-1436), an investigational drug, has been shown to combat obesity and metabolic disorders by inhibiting the enzyme protein tyrosine phosphatase 1b (Ptp1b), consequently reducing hepatic lipogenesis and counteracting insulin and leptin resistance. In this study, we aimed to further explore the effects of these compounds on young, developing mice to uncover biomolecular signatures that are central to liver metabolic processes. We found that MSI-1436 more potently alters mRNA and miRNA expression in the liver compared with MF, with bioinformatic analysis suggesting that cohorts of differentially expressed miRNAs inhibit the action of phosphoinositide 3-kinase (Pi3k), protein kinase B (Akt), and mammalian target of rapamycin (Mtor) to regulate the downstream processes of de novo lipogenesis, fatty acid oxidation, very-low-density lipoprotein transport, and cholesterol biosynthesis and efflux. In summary, our study demonstrates that administering these compounds during the postnatal window metabolically reprograms the liver through induction of potent epigenetic changes in the transcriptome, potentially forestalling the onset of age-related diseases and enhancing longevity. Future studies are necessary to determine the impacts on lifespan and overall quality of life.
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Affiliation(s)
- Sarah A. Ashiqueali
- Burnett School of Biomedical SciencesUniversity of Central Florida College of MedicineOrlandoFloridaUSA
| | | | - Xiang Zhu
- Burnett School of Biomedical SciencesUniversity of Central Florida College of MedicineOrlandoFloridaUSA
| | | | - Mishfak A. M. Mansoor
- Burnett School of Biomedical SciencesUniversity of Central Florida College of MedicineOrlandoFloridaUSA
| | - Yun Zhu
- Department of Internal MedicineSouthern Illinois University School of MedicineSpringfieldIllinoisUSA
| | - Yimin Fang
- Department of Internal MedicineSouthern Illinois University School of MedicineSpringfieldIllinoisUSA
| | - Bianka M. Zanini
- Faculdade de NutriçãoUniversidade Federal de PelotasPelotasBrazil
| | - Driele N. Garcia
- Faculdade de NutriçãoUniversidade Federal de PelotasPelotasBrazil
| | - Natalie Hayslip
- Burnett School of Biomedical SciencesUniversity of Central Florida College of MedicineOrlandoFloridaUSA
| | - David Medina
- Department of Internal MedicineSouthern Illinois University School of MedicineSpringfieldIllinoisUSA
| | - Samuel McFadden
- Department of Internal MedicineSouthern Illinois University School of MedicineSpringfieldIllinoisUSA
| | - Robert Stockwell
- Department of Internal MedicineSouthern Illinois University School of MedicineSpringfieldIllinoisUSA
| | - Rong Yuan
- Department of Internal MedicineSouthern Illinois University School of MedicineSpringfieldIllinoisUSA
| | - Andrzej Bartke
- Department of Internal MedicineSouthern Illinois University School of MedicineSpringfieldIllinoisUSA
| | - Michael Zasloff
- MedStar Georgetown Transplant InstituteGeorgetown University School of MedicineWashingtonDCUSA
| | - Shadab Siddiqi
- Burnett School of Biomedical SciencesUniversity of Central Florida College of MedicineOrlandoFloridaUSA
| | - Michal M. Masternak
- Burnett School of Biomedical SciencesUniversity of Central Florida College of MedicineOrlandoFloridaUSA
- Department of Head and Neck SurgeryPoznan University of Medical SciencesPoznanPoland
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10
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Erratum: Inhibition of microRNA-24 expression in liver prevents hepatic lipid accumulation and hyperlipidemia. Hepatology 2024; 79:E102. [PMID: 38289039 DOI: 10.1097/hep.0000000000000730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/18/2024]
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11
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Engin AB, Engin A. MicroRNAs as Epigenetic Regulators of Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:595-627. [PMID: 39287866 DOI: 10.1007/978-3-031-63657-8_20] [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: 09/19/2024]
Abstract
In obesity, the process of adipogenesis largely determines the number of adipocytes in body fat depots. Adipogenesis is regulated by several adipocyte-selective micro-ribonucleic acids (miRNAs) and transcription factors that modulate adipocyte proliferation and differentiation. However, some miRNAs block the expression of master regulators of adipogenesis. Since the specific miRNAs display different expressions during adipogenesis, in mature adipocytes and permanent obesity, their use as biomarkers or therapeutic targets is feasible. Upregulated miRNAs in persistent obesity are downregulated during adipogenesis. Moreover, some of the downregulated miRNAs in obese individuals are upregulated in mature adipocytes. Induction of adipocyte stress and hypertrophy leads to the release of adipocyte-derived exosomes (AdEXs) that contain the cargo molecules, miRNAs. miRNAs are important messengers for intercellular communication involved in metabolic responses and have very specific signatures that direct the metabolic activity of target cells. While each miRNA targets multiple messenger RNAs (mRNAs), which may coordinate or antagonize each other's functions, several miRNAs are dysregulated in other tissues during obesity-related comorbidities. Deletion of the miRNA-processing enzyme DICER in pro-opiomelanocortin-expressing cells results in obesity, which is characterized by hyperphagia, increased adiposity, hyperleptinemia, defective glucose metabolism, and alterations in the pituitary-adrenal axis. In recent years, RNA-based therapeutical approaches have entered clinical trials as novel therapies against overweight and its complications. Development of lipid droplets, macrophage accumulation, macrophage polarization, tumor necrosis factor receptor-associated factor 6 activity, lipolysis, lipotoxicity, and insulin resistance are effectively controlled by miRNAs. Thereby, miRNAs as epigenetic regulators are used to determine the new gene transcripts and therapeutic targets.
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Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
| | - Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey
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12
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Zhu Z, Zhang X, Pan Q, Zhang L, Chai J. In-depth analysis of de novo lipogenesis in non-alcoholic fatty liver disease: Mechanism and pharmacological interventions. LIVER RESEARCH (BEIJING, CHINA) 2023; 7:285-295. [PMID: 39958779 PMCID: PMC11791917 DOI: 10.1016/j.livres.2023.11.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 09/28/2023] [Accepted: 11/15/2023] [Indexed: 02/18/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by the abnormal buildup of lipids in the liver tissue. Non-alcoholic fatty liver (NAFL) may progress to non-alcoholic steatohepatitis. Triglycerides in the liver can originate from various sources, including de novo lipogenesis (DNL). Research indicates that DNL significantly escalates in NAFLD, worsening steatosis. However, the precise regulatory mechanism of DNL in the development of this disease is not fully understood. Therefore, the targeted reduction of DNL could be a crucial therapeutic strategy. Currently, numerous pharmaceutical agents targeting DNL have been developed, attracting significant attention. This review examines the mechanism of DNL upregulation in NAFLD, assessing its potential as a therapeutic target for hepatic steatosis. Furthermore, we thoroughly examine hepatocellular lipotoxicity and provide an extensive review of the application and limitations of relevant therapeutic drugs, with a focus on key enzymes involved in DNL. The implementation of these pharmacological strategies is expected to significantly improve the management and overall outcomes for patients with NAFLD.
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Affiliation(s)
- Zhixian Zhu
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
- Institute of Digestive Diseases of PLA, Third Military Medical University (Army Medical University), Chongqing, China
- Center for Metabolic Associated Fatty Liver Disease and Cholestatic Liver Diseases Center, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
| | - Xiaoxun Zhang
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
- Institute of Digestive Diseases of PLA, Third Military Medical University (Army Medical University), Chongqing, China
- Center for Metabolic Associated Fatty Liver Disease and Cholestatic Liver Diseases Center, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
| | - Qiong Pan
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
- Institute of Digestive Diseases of PLA, Third Military Medical University (Army Medical University), Chongqing, China
- Center for Metabolic Associated Fatty Liver Disease and Cholestatic Liver Diseases Center, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
| | - Liangjun Zhang
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
- Institute of Digestive Diseases of PLA, Third Military Medical University (Army Medical University), Chongqing, China
- Center for Metabolic Associated Fatty Liver Disease and Cholestatic Liver Diseases Center, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
| | - Jin Chai
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
- Institute of Digestive Diseases of PLA, Third Military Medical University (Army Medical University), Chongqing, China
- Center for Metabolic Associated Fatty Liver Disease and Cholestatic Liver Diseases Center, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
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13
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Ramezani M, Zobeiry M, Abdolahi S, Hatami B, Zali MR, Baghaei K. A crosstalk between epigenetic modulations and non-alcoholic fatty liver disease progression. Pathol Res Pract 2023; 251:154809. [PMID: 37797383 DOI: 10.1016/j.prp.2023.154809] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 09/08/2023] [Accepted: 09/08/2023] [Indexed: 10/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a major public health concern worldwide due to its rapidly rising prevalence and its potential to progress into end-stage liver disease. While the precise pathophysiology underlying NAFLD remains incompletely understood, it is strongly associated with various environmental triggers and other metabolic disorders. Epigenetics examines changes in gene expression that are not caused by alterations in the DNA sequence itself. There is accumulating evidence that epigenetics plays a key role in linking environmental cues to the onset and progression of NAFLD. Our understanding of how epigenetic mechanisms contribute to NAFLD pathophysiology has expanded considerably in recent years as research on the epigenetics of NAFLD has developed. This review summarizes recent insights into major epigenetic processes that have been implicated in NAFLD pathogenesis including DNA methylation, histone acetylation, and microRNAs that have emerged as promising targets for further investigation. Elucidating epigenetic mechanisms in NAFLD may uncover novel diagnostic biomarkers and therapeutic targets for this disease. However, many questions have remained unanswered regarding how epigenetics promotes NAFLD onset and progression. Additional studies are needed to further characterize the epigenetic landscape of NAFLD and validate the potential of epigenetic markers as clinical tools. Nevertheless, an enhanced understanding of the epigenetic underpinnings of NAFLD promises to provide key insights into disease mechanisms and pave the way for novel prognostic and therapeutic approaches.
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Affiliation(s)
- Meysam Ramezani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Shahrokh Abdolahi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Behzad Hatami
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Gastroenterology and Liver Diseases Research center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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14
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Okuka N, Schuh V, Krammer U, Polovina S, Sumarac-Dumanovic M, Milinkovic N, Velickovic K, Djordjevic B, Haslberger A, Ivanovic ND. Epigenetic Aspects of a New Probiotic Concept-A Pilot Study. Life (Basel) 2023; 13:1912. [PMID: 37763315 PMCID: PMC10533075 DOI: 10.3390/life13091912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/02/2023] [Accepted: 09/12/2023] [Indexed: 09/29/2023] Open
Abstract
Several studies report the important role of an altered gut microbiota in the development of obesity, highlighting the potential use of probiotics in the treatment of obesity. The aim of this study is to investigate the effect of a novel probiotic approach on the expression of specific miRNAs and mRNAs associated with obesity in combination with the hypocholesterolemic octacosanol. Twenty overweight/obese women participated in a randomized, placebo-controlled, double-blind study and were randomly divided into two groups: the intervention group (daily one capsule containing Lactobacillus plantarum 299v (DSM9843), Saccharomyces cerevisiae var. boulardii, and 40 mg octacosanol; N = 12) and the placebo group (N = 8). Changes in lipid parameters and expression of miRNAs and mRNAs were assessed before (T0) and after the 12-week intervention (T1). After the intervention, the expression of miR-155-5p (9.38 ± 0.85 vs. 8.38 ± 1.06, p = 0.05) and miR-24-3p (3.42 ± 0.38 vs. 2.71 ± 0.97, p = 0.031) showed significant decreases in the intervention group when compared to the control group. At T1, the expression of miR-155-5p (8.69 ± 1.31 vs. 9.3 ± 0.85, p = 0.04), miR-125b-5p (5.41 ± 1.18 vs. 5.99 ± 1.36, p = 0.049), and TNF-α (10.24 ± 1.66 vs. 11.36 ± 1.12, p = 0.009) were significantly decreased in the intervention group. No changes in lipids and anthropometric parameters were observed. The novel probiotic approach had a positive effect on regulating the expression of certain miRNAs and mRNAs important for regulating inflammation and adipogenesis, which are essential for obesity onset and control.
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Affiliation(s)
- Nina Okuka
- Department of Bromatology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina;
| | | | | | - Snezana Polovina
- Clinic for Endocrinology, Diabetes and Diseases of Metabolism, Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Mirjana Sumarac-Dumanovic
- School of Medicine, University of Belgrade, Clinic for Endocrinology, Diabetes and Diseases of Metabolism, 11000 Belgrade, Serbia
| | - Neda Milinkovic
- Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, 11000 Belgrade, Serbia
| | - Ksenija Velickovic
- Department of Cell and Tissue Biology, Faculty of Biology, University of Belgrade; 11000 Belgrade, Serbia
| | - Brizita Djordjevic
- Department of Bromatology, Faculty of Pharmacy, University of Belgrade, 11000 Belgrade, Serbia
| | | | - Nevena Dj. Ivanovic
- Department of Bromatology, Faculty of Pharmacy, University of Belgrade, 11000 Belgrade, Serbia
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15
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Bandyopadhyay D, Basu S, Mukherjee I, Chakrabarti S, Chakrabarti P, Mukherjee K, Bhattacharyya SN. Accelerated export of Dicer1 from lipid-challenged hepatocytes buffers cellular miRNA-122 levels and prevents cell death. J Biol Chem 2023; 299:104999. [PMID: 37394005 PMCID: PMC10413358 DOI: 10.1016/j.jbc.2023.104999] [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: 01/03/2023] [Revised: 06/19/2023] [Accepted: 06/20/2023] [Indexed: 07/04/2023] Open
Abstract
Hepatocytes on exposure to high levels of lipids reorganize the metabolic program while fighting against the toxicity associated with elevated cellular lipids. The mechanism of this metabolic reorientation and stress management in lipid-challenged hepatocytes has not been well explored. We have noted the lowering of miR-122, a liver-specific miRNA, in the liver of mice fed with either a high-fat diet or a methionine-choline-deficient diet that is associated with increased fat accumulation in mice liver. Interestingly, low miR-122 levels are attributed to the enhanced extracellular export of miRNA processor enzyme Dicer1 from hepatocytes in the presence of high lipids. Export of Dicer1 can also account for the increased cellular levels of pre-miR-122-the substrate of Dicer1. Interestingly, restoration of Dicer1 levels in the mouse liver resulted in a strong inflammatory response and cell death in the presence of high lipids. Increasing death of hepatocytes was found to be caused by increased miR-122 levels in hepatocytes restored for Dicer1. Thus, the Dicer1 export by hepatocytes seems to be a key mechanism to combat lipotoxic stress by shunting out miR-122 from stressed hepatocytes. Finally, as part of this stress management, we determined that the Ago2-interacting pool of Dicer1, responsible for mature microribonucleoprotein formation in mammalian cells, gets depleted. miRNA-binder and exporter protein HuR is found to accelerate Ago2-Dicer1 uncoupling to ensure export of Dicer1 via extracellular vesicles in lipid-loaded hepatocytes.
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Affiliation(s)
- Diptankar Bandyopadhyay
- RNA Biology Research Laboratory, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Sudarshana Basu
- RNA Biology Research Laboratory, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India; Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute (NCRI) Kolkata, India
| | - Ishita Mukherjee
- Structural Biology and Bio-Informatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Saikat Chakrabarti
- Structural Biology and Bio-Informatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Partha Chakrabarti
- Metabolic Disease Laboratory, Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Kamalika Mukherjee
- RNA Biology Research Laboratory, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center (UNMC), Omaha, Nebraska, USA
| | - Suvendra N Bhattacharyya
- RNA Biology Research Laboratory, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center (UNMC), Omaha, Nebraska, USA.
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16
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Zhang W, Zhao Y, He Q, Lang R. Therapeutically targeting essential metabolites to improve immunometabolism manipulation after liver transplantation for hepatocellular carcinoma. Front Immunol 2023; 14:1211126. [PMID: 37492564 PMCID: PMC10363744 DOI: 10.3389/fimmu.2023.1211126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 06/26/2023] [Indexed: 07/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent primary liver malignancy worldwide and is associated with a poor prognosis. Sophisticated molecular mechanisms and biological characteristics need to be explored to gain a better understanding of HCC. The role of metabolites in cancer immunometabolism has been widely recognized as a hallmark of cancer in the tumor microenvironment (TME). Recent studies have focused on metabolites that are derived from carbohydrate, lipid, and protein metabolism, because alterations in these may contribute to HCC progression, ischemia-reperfusion (IR) injury during liver transplantation (LT), and post-LT rejection. Immune cells play a central role in the HCC microenvironment and the duration of IR or rejection. They shape immune responses through metabolite modifications and by engaging in complex crosstalk with tumor cells. A growing number of publications suggest that immune cell functions in the TME are closely linked to metabolic changes. In this review, we summarize recent findings on the primary metabolites in the TME and post-LT metabolism and relate these studies to HCC development, IR injury, and post-LT rejection. Our understanding of aberrant metabolism and metabolite targeting based on regulatory metabolic pathways may provide a novel strategy to enhance immunometabolism manipulation by reprogramming cell metabolism.
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Affiliation(s)
- Wenhui Zhang
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, China
| | - Yu Zhao
- Department of Urology Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, China
| | - Qiang He
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, China
| | - Ren Lang
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, China
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17
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Goncalves BDS, Meadows A, Pereira DG, Puri R, Pillai SS. Insight into the Inter-Organ Crosstalk and Prognostic Role of Liver-Derived MicroRNAs in Metabolic Disease Progression. Biomedicines 2023; 11:1597. [PMID: 37371692 PMCID: PMC10295788 DOI: 10.3390/biomedicines11061597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 05/19/2023] [Accepted: 05/27/2023] [Indexed: 06/29/2023] Open
Abstract
Dysfunctional hepatic metabolism has been linked to numerous diseases, including non-alcoholic fatty liver disease, the most common chronic liver disorder worldwide, which can progress to hepatic fibrosis, and is closely associated with insulin resistance and cardiovascular diseases. In addition, the liver secretes a wide array of metabolites, biomolecules, and microRNAs (miRNAs) and many of these secreted factors exert significant effects on metabolic processes both in the liver and in peripheral tissues. In this review, we summarize the involvement of liver-derived miRNAs in biological processes with an emphasis on delineating the communication between the liver and other tissues associated with metabolic disease progression. Furthermore, the review identifies the primary molecular targets by which miRNAs act. These consolidated findings from numerous studies provide insight into the underlying mechanism of various metabolic disease progression and suggest the possibility of using circulatory miRNAs as prognostic predictors and therapeutic targets for improving clinical intervention strategies.
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Affiliation(s)
- Bruno de Souza Goncalves
- Department of Surgery and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA
| | - Avery Meadows
- Department of Surgery and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA
| | - Duane G Pereira
- Department of Surgery and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA
| | - Raghav Puri
- Department of Surgery and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA
| | - Sneha S Pillai
- Department of Surgery and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA
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Zhu Y, Tan JK, Wong SK, Goon JA. Therapeutic Effects of microRNAs on Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH): A Systematic Review and Meta-Analysis. Int J Mol Sci 2023; 24:ijms24119168. [PMID: 37298120 DOI: 10.3390/ijms24119168] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/26/2023] [Accepted: 04/28/2023] [Indexed: 06/12/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as a global health problem that affects people even at young ages due to unhealthy lifestyles. Without intervention, NAFLD will develop into nonalcoholic steatohepatitis (NASH) and eventually liver cirrhosis and hepatocellular carcinoma. Although lifestyle interventions are therapeutic, effective implementation remains challenging. In the efforts to establish effective treatment for NAFLD/NASH, microRNA (miRNA)-based therapies began to evolve in the last decade. Therefore, this systematic review aims to summarize current knowledge on the promising miRNA-based approaches in NAFLD/NASH therapies. A current systematic evaluation and a meta-analysis were conducted according to the PRISMA statement. In addition, a comprehensive exploration of PubMed, Cochrane, and Scopus databases was conducted to perform article searches. A total of 56 different miRNAs were reported as potential therapeutic agents in these studies. miRNA-34a antagonist/inhibitor was found to be the most studied variant (n = 7), and it significantly improved the hepatic total cholesterol, total triglyceride, Aspartate Aminotransferase (AST), and Alanine Transaminase (ALT) levels based on a meta-analysis. The biological processes mediated by these miRNAs involved hepatic fat accumulation, inflammation, and fibrosis. miRNAs have shown enormous therapeutic potential in the management of NAFLD/NASH, wherein miRNA-34a antagonist has been found to be an exceptional potential agent for the treatment of NAFLD/NASH.
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Affiliation(s)
- Yuezhi Zhu
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Jen Kit Tan
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Sok Kuan Wong
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Jo Aan Goon
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
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Pan Q, Fan JG, Yilmaz Y. Pathogenetic Pathways in Nonalcoholic Fatty Liver Disease: An Incomplete Jigsaw Puzzle. Clin Liver Dis 2023; 27:317-332. [PMID: 37024210 DOI: 10.1016/j.cld.2023.01.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD)-a condition of excess fat accumulation in hepatocytes associated with metabolic dysfunction-has surpassed viral hepatitis to become the most prevalent chronic liver disease worldwide. As of now, only modestly effective pharmacological therapies for NAFLD exist. The uncomplete understanding of the pathophysiology underlying the heterogeneous disease spectrum known as NAFLD remains one of the major obstacles to the development of novel therapeutic approaches. This review compiles current knowledge on the principal signaling pathways and pathogenic mechanisms involved in NAFLD, which are analyzed in relation to its main pathological hallmarks (ie, hepatic steatosis, steatohepatitis, and liver fibrosis).
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Affiliation(s)
- Qin Pan
- Research Center, Zhoupu Hospital Affiliated to the Shanghai University of Medicine & Health Sciences, Shanghai 201318, China; Department of Gastroenterology, Xinhua Hospital Affiliated to the Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital Affiliated to the Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China.
| | - Yusuf Yilmaz
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize 53200, Turkey; Liver Research Unit, Institute of Gastroenterology, Marmara University, İstanbul 34840, Turkey.
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20
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Ataei S, Ganjali S, Banach M, Karimi E, Sahebkar A. The effect of PCSK9 immunization on the hepatic level of microRNAs associated with the PCSK9/LDLR pathway. Arch Med Sci 2023; 19:203-208. [PMID: 36817686 PMCID: PMC9897094 DOI: 10.5114/aoms/152000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 07/09/2022] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION MicroRNAs (miRNAs) are a class of gene expression epigenetic regulators that play roles in regulating genes involved in cholesterol homeostasis, including low-density lipoprotein receptor (LDLR) and PCSK9; therefore, miRNAs have been suggested as potential therapeutic targets for treating cardiometabolic disorders. Thus, the present study aimed to assess the effect of immunotherapy with the PCSK9 peptide vaccine on the hepatic expression levels of microRNAs associated with the LDLR pathway, including miRNA-27a, miRNA-30c, and miRNA-191, in normal vaccinated mice. MATERIAL AND METHODS PCSK9 immunogenic peptide and 0.4% alum adjuvant were mixed at a 1 : 1 ratio and used as a vaccine formulation. Male albino mice were randomly assigned to the vaccine or control group. Mice in the vaccine group were injected four times at two-week intervals with a PCSK9 peptide vaccine, and mice in the control group were injected with phosphate-buffered saline (PBS). Animal livers were sampled 2 weeks after the last injection to assess miRNA expression levels. The hepatic expression levels of miRNA-27a, miRNA-30c, and miRNA-191 were evaluated by SYBR Green real-time PCR, quantified by a comparative (2- Δ Δ CT) method (fold change (FC)) and normalized to U6 small nuclear RNA (U6snRNA) expression as an internal control. RESULTS The hepatic expression level of miRNA-27a was significantly lower in mice following immunotherapy with the PCSK9 peptide vaccine compared to the control group (FC: 0.731 ±0.1, p = 0.027). Also, there was a borderline significantly lower hepatic expression level of miRNA-30c in the vaccinated group compared to the control (FC: 0.569 ±0.1, p = 0.078). However, no significant differences were found in the hepatic expression level of miRNA-191 between the two studied groups (FC: 0.852 ±0.1, p = 0.343). CONCLUSIONS According to the findings, the PCSK9 peptide vaccine could effectively reduce the hepatic expression level of miRNA-27a and may be helpful in the management of LDL-C level and atherosclerosis, which may be mediated through the LDLR pathway.
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Affiliation(s)
- Sarina Ataei
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shiva Ganjali
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maciej Banach
- Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Lodz, Poland
- Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland
| | - Ehsan Karimi
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Medicine, The University of Western Australia, Perth, Australia
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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21
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Functional and miRNA regulatory characteristics of INSIG genes highlight the key role of lipid synthesis in the liver of chicken (Gallus gallus). Poult Sci 2022; 102:102380. [PMID: 36571872 PMCID: PMC9800209 DOI: 10.1016/j.psj.2022.102380] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 11/29/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022] Open
Abstract
The insulin-induced genes (INSIG1 and INSIG2) have been demonstrated to play a vital role in regulating lipid metabolism in mammals, however the function and regulation mechanism of them remains unknown in poultry. In this study, firstly the phylogenetic trees of INSIGs among various species were constructed and their subcellular locations were mapped in chicken LMH. Then the spatiotemporal expression profiles, over-expression and knockdown assays of chicken INSIGs were conducted. Furthermore, conservation of potential miRNA binding sites in INSIGs among species were analyzed, and the miRNA biological function and regulatory role were verified. The results showed that chicken INSIGs located in cellular endoplasmic reticulum, and were originated from the common ancestors of their mammalian counterparts. The INSIGs were widely expressed in all detected tissues, and their expression levels in the liver of chicken at 30 wk were significantly higher than that at 20 wk (P < 0.01). Over-expression of INSIGs led no significant increase in mRNA abundance of lipid metabolism-related genes and the contents of triacylglycerol (TG) and cholesterol (TC) in LMH cells. Knockdown of INSIG1 led to the decreased expressions of ACSL1, MTTP-L, ApoB, ApoVLDLII genes and TG, TC contents (P < 0.05). Knockdown of INSIG2 could significantly decrease the contents of TG and TC, and expressions of key genes related to the lipid metabolism (P < 0.05). Moreover, INSIG1 was directly targeted by both miR-130b-3p and miR-218-5p, and INSIG2 was directly targeted by miR-130b-3p. MiR-130b-3p mimic and miR-218-5p mimic treatment could significant decrease the mRNA and protein levels of INSIGs, mRNA levels of genes related to lipid metabolism, and the contents of TG and TC in LMH cells. The inhibition of miR-130b-3p and miR-218-5p on TG and TC contents could be restored by the overexpression of INSIGs, respectively. No significant alteration in expressions of sterol regulatory element binding protein (SREBPs) and SREBP cleavage-activating protein (SCAP) were observed when INSIGs were over-expressed. SCAP was down-regulated when INSIG1 was knocked down, while SREBP1 was down-regulated when INSIG2 was knocked down. Taken together, these results highlight the role of INSIG1 and INSIG2 in lipid metabolism and their regulatory mechanism in chicken.
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22
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Comparison of Body Composition, Muscle Strength and Cardiometabolic Profile in Children with Prader-Willi Syndrome and Non-Alcoholic Fatty Liver Disease: A Pilot Study. Int J Mol Sci 2022; 23:ijms232315115. [PMID: 36499438 PMCID: PMC9739027 DOI: 10.3390/ijms232315115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/25/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022] Open
Abstract
Syndromic and non-syndromic obesity conditions in children, such as Prader-Willi syndrome (PWS) and non-alcoholic fatty liver disease (NAFLD), both lower quality of life and increase risk for chronic health complications, which further increase health service utilization and cost. In a pilot observational study, we compared body composition and muscle strength in children aged 7−18 years with either PWS (n = 9), NAFLD (n = 14), or healthy controls (n = 16). Anthropometric and body composition measures (e.g., body weight, circumferences, skinfolds, total/segmental composition, and somatotype), handgrip strength, six minute-walk-test (6MWT), physical activity, and markers of liver and cardiometabolic dysfunction (e.g., ALT, AST, blood pressure, glucose, insulin, and lipid profile) were measured using standard procedures and validated tools. Genotyping was determined for children with PWS. Children with PWS had reduced lean body mass (total/lower limb mass), lower handgrip strength, 6MWT and increased sedentary activity compared to healthy children or those with NAFLD (p < 0.05). Children with PWS, including those of normal body weight, had somatotypes consistent with relative increased adiposity (endomorphic) and reduced skeletal muscle robustness (mesomorphic) when compared to healthy children and those with NAFLD. Somatotype characterizations were independent of serum markers of cardiometabolic dysregulation but were associated with increased prevalence of abnormal systolic and diastolic blood pressure Z-scores (p < 0.05). Reduced lean body mass and endomorphic somatotypes were associated with lower muscle strength/functionality and sedentary lifestyles, particularly in children with PWS. These findings are relevant as early detection of deficits in muscle strength and functionality can ensure effective targeted treatments that optimize physical activity and prevent complications into adulthood.
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23
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Qian G, Morral N. Role of non-coding RNAs on liver metabolism and NAFLD pathogenesis. Hum Mol Genet 2022; 31:R4-R21. [PMID: 35417923 DOI: 10.1093/hmg/ddac088] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/22/2022] [Accepted: 04/08/2022] [Indexed: 11/14/2022] Open
Abstract
Obesity and type 2 diabetes are major contributors to the growing prevalence of non-alcoholic fatty liver disease (NAFLD), a chronic liver condition characterized by the accumulation of fat in individuals without a significant amount of alcohol intake. The NAFLD spectrum ranges from simple steatosis (early stages, known as NAFL) to non-alcoholic steatohepatitis, which can progress to fibrosis and cirrhosis or hepatocellular carcinoma. Obesity, type 2 diabetes and NAFLD are strongly associated with insulin resistance. In the liver, insulin resistance increases hepatic glucose output, lipogenesis and very-low-density lipoprotein secretion, leading to a combination of hyperglycemia and hypertriglyceridemia. Aberrant gene expression is a hallmark of insulin resistance. Non-coding RNAs (ncRNAs) have emerged as prominent regulators of gene expression that operate at the transcriptional, post-transcriptional and post-translational levels. In the last couple of decades, a wealth of studies have provided evidence that most processes of liver metabolism are orchestrated by ncRNAs. This review focuses on the role of microRNAs, long non-coding RNAs and circular RNAs as coordinators of hepatic function, as well as the current understanding on how their dysregulation contributes to abnormal metabolism and pathophysiology in animal models of insulin resistance and NAFLD. Moreover, ncRNAs are emerging as useful biomarkers that may be able to discriminate between the different stages of NAFLD. The potential of ncRNAs as therapeutic drugs for NAFLD treatment and as biomarkers is discussed.
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Affiliation(s)
- Gene Qian
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Núria Morral
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
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24
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Li R, Ye Z, She D, Fang P, Zong G, Hu K, Kong D, Xu W, Li L, Zhou Y, Zhang K, Xue Y. Semaglutide May Alleviate Hepatic Steatosis in T2DM Combined with NFALD Mice via miR-5120/ABHD6. Drug Des Devel Ther 2022; 16:3557-3572. [PMID: 36238196 PMCID: PMC9553160 DOI: 10.2147/dddt.s384884] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 10/06/2022] [Indexed: 11/06/2022] Open
Abstract
Objective Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) has been extensively studied, the role of its underlying pathogenesis remains unclear, and there is currently no approved therapeutic strategy for NAFLD. The purpose of this study was to observe the beneficial effects of Semaglutide on NAFLD in vivo and in vitro, as well as its potential molecular mechanisms. Methods Semaglutide was used to treat type 2 diabetes mellitus (T2DM) combined with NAFLD mice for 12 weeks. Hepatic function and structure were evaluated by liver function, blood lipids, liver lipids, H&E staining, oil red staining and Sirius staining. The expression of α/β hydrolase domain-6 (ABHD6) was measured by qPCR and Western blotting in vivo and in vitro. Then, dual-luciferase reporter assay was performed to verify the regulation of the upstream miR-5120 on ABHD6. Results Our data revealed that Semaglutide administration significantly improved liver function and hepatic steatosis in T2DM combined with NAFLD mice. Furthermore, compared with controls, up-regulation of ABHD6 and down-regulation of miR-5120 were found in the liver of T2DM+NAFLD mice and HG+FFA-stimulated Hepa 1-6 hepatocytes. Interestingly, after Semaglutide intervention, ABHD6 expression was significantly decreased in the liver of T2DM+NAFLD mice and in HG+FFA-stimulated Hepa 1-6 hepatocytes, while miR-5120 expression was increased. We also found that miR-5120 could regulate the expression of ABHD6 in hepatocytes, while Semaglutide could modulate the expression of ABHD6 through miR-5120. In addition, GLP-1R was widely expressed in mouse liver tissues and Hepa 1-6 cells. Semaglutide could regulate miR-5120/ABHD6 expression through GLP-1R. Conclusion Our data revealed the underlying mechanism by which Semaglutide improves hepatic steatosis in T2DM+NAFLD, and might shed new light on the pathological role of miR-5120/ABHD6 in the pathogenesis of T2DM+NAFLD.
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Affiliation(s)
- Ran Li
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Zhengqin Ye
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Dunmin She
- Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China,Department of Endocrinology, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, People’s Republic of China
| | - Ping Fang
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Guannan Zong
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Kerong Hu
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Dehong Kong
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Wei Xu
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Ling Li
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Yun Zhou
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Keqin Zhang
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Ying Xue
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China,Correspondence: Ying Xue; Keqin Zhang, Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, No. 389, Xincun Road, Shanghai, 200065, People’s Republic of China, Tel +86-021-66111061, Email ;
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25
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Nguyen HD, Kim MS. Cadmium, lead, and mercury mixtures interact with non-alcoholic fatty liver diseases. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 309:119780. [PMID: 35841990 DOI: 10.1016/j.envpol.2022.119780] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 06/19/2022] [Accepted: 07/11/2022] [Indexed: 06/15/2023]
Abstract
There is a scarcity of studies on the interactions between heavy metals and non-alcoholic fatty liver disease (NAFLD). Using a variety of statistical approaches, we investigated the impact of three common heavy metals on liver enzymes and NAFLD markers in a Korean adult population. We observed that cadmium, mercury, and lead all demonstrated positive correlations with liver enzymes and NAFLD indices. Our findings were mostly robust in secondary analysis, which included three novel mixture modeling approaches (WQS, qgcomp, and BKMR) as well as in silico investigation of molecular mechanisms (genes, miRNAs, biological processes, pathways, and illnesses). The 16 genes interacted with a mixture of heavy metals, which was linked to the development of NAFLD. Co-expression was discovered in nearly half of the interactions between the 18 NAFLD-linked genes. Key molecular pathways implicated in the pathogenesis of NAFLD generated by the heavy metal combination include activated oxidative stress, altered lipid metabolism, and increased cytokines and inflammatory response. Heavy metal exposure levels were related to liver enzymes and NAFLD indices, and cutoff criteria were revealed. More studies are needed to validate our findings and gain knowledge about the effects of chronic combined heavy metal exposure on adult and child liver function and the likelihood of developing NAFLD. To reduce the occurrence of NAFLD, early preventative and regulatory actions (half-yearly screening of workers at high-risk facilities; water filtration; avoiding excessive amounts of seafood, etc.) should be taken.
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Affiliation(s)
- Hai Duc Nguyen
- Department of Pharmacy, College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Sunchon, Jeonnam, Republic of Korea
| | - Min-Sun Kim
- Department of Pharmacy, College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Sunchon, Jeonnam, Republic of Korea.
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26
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Huang L, Luo J, Gao W, Song N, Tian H, Zhu L, Jiang Q, Loor JJ. CRISPR/Cas9-Induced Knockout of miR-24 Reduces Cholesterol and Monounsaturated Fatty Acid Content in Primary Goat Mammary Epithelial Cells. Foods 2022; 11:2012. [PMID: 35885255 PMCID: PMC9316712 DOI: 10.3390/foods11142012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 06/30/2022] [Accepted: 07/04/2022] [Indexed: 12/02/2022] Open
Abstract
In nonruminants, microRNA (miRNA)-24 plays an important role in lipid metabolism in adipose tissue and the liver. Although the abundance of miR-24 in ruminant mammary glands is the highest during peak lactation, its potential role in regulating the synthesis and secretion of fat into milk is unclear. This study aimed to identify the function of miR-24 in these processes using CRISPR/Cas9 technology in primary goat mammary epithelial cells (GMEC). A single clone containing a 66-nucleotide deletion between two sgRNAs mediating double-strand break (DSB) sites was obtained. The abundance of miR-24-3p and miR-24-5p encoded by the deleted sequence was decreased, whereas the target genes INSIG1 and FASN increased. In addition, miR-24 knockout reduced the gene abundance of genes associated with fatty acid and TAG synthesis and transcription regulator. Similarly, the content of cholesterol and monounsaturated fatty acid (MUFA) C18:1 decreased, whereas that of polyunsaturated fatty acids (PUFA) C18:2, C20:3, C20:4 and C20:5 increased. Subsequently, knocking down of INSIG1 but not FASN reversed the effect of miR-24 knockout, indicating that miR-24 modulated cholesterol and fatty acid synthesis mainly by targeting INSIG1. Overall, the present in vitro data demonstrated a critical role for miR-24 in regulating lipid and fatty acid synthesis and highlighted the possibility of manipulating milk components in dairy goats.
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Affiliation(s)
- Lian Huang
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang 712100, China; (L.H.); (W.G.); (N.S.); (H.T.); (L.Z.)
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu 610000, China
| | - Jun Luo
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang 712100, China; (L.H.); (W.G.); (N.S.); (H.T.); (L.Z.)
| | - Wenchang Gao
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang 712100, China; (L.H.); (W.G.); (N.S.); (H.T.); (L.Z.)
| | - Ning Song
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang 712100, China; (L.H.); (W.G.); (N.S.); (H.T.); (L.Z.)
| | - Huibin Tian
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang 712100, China; (L.H.); (W.G.); (N.S.); (H.T.); (L.Z.)
| | - Lu Zhu
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang 712100, China; (L.H.); (W.G.); (N.S.); (H.T.); (L.Z.)
| | - Qianming Jiang
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, IL 61801, USA;
| | - Juan J. Loor
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, IL 61801, USA;
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27
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Patsenker E, Thangapandi VR, Knittelfelder O, Palladini A, Hefti M, Beil-Wagner J, Rogler G, Buch T, Shevchenko A, Hampe J, Stickel F. The Pnpla3 Variant I148M Reveals Protective Effects Towards Hepatocellular Carcinoma in Mice via Restoration of Omega-3 Polyunsaturated Fats. J Nutr Biochem 2022; 108:109081. [PMID: 35691594 DOI: 10.1016/j.jnutbio.2022.109081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 02/02/2022] [Accepted: 05/03/2022] [Indexed: 12/02/2022]
Abstract
Alcohol consumption and high caloric diet are leading causes of progressive fatty liver disease. Genetic variant rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3 rs738409 C>G) has been repeatedly described as one of the major risk loci for alcoholic liver cirrhosis (ALC) and hepatocellular carcinoma (HCC) in humans, however, the mechanism behind this association is incompletely understood. We generated mice carrying the rs738409 variant (PNPLA3 I148M) in order to detect genotype-phenotype relationships in mice upon chow and alcohol-high fat/high sugar diet (EtOH/WD). We could clearly demonstrate that the presence of rs738409 per se is sufficient to induce spontaneous development of steatosis after one year in mice on a chow diet, whereas in the setting of unhealthy diet feeding, PNPLA3 I148M did not affect hepatic inflammation or fibrosis, but induced a striking lipid remodelling, microvesicular steatosis and protected from HCC formation. Using shot gun lipidomics, we detected a striking restoration of reduced long chain-polyunsaturated fatty acids (LC-PUFA)-containing TGs, docosapentaenoic acid (C22:5 n3) and omega-3-derived eicosanoids (5-HEPE, 20-HEPE, 19,20-EDP, 21-HDHA) in PNPLA3 I148M mice upon EtOH/WD. At the molecular level, PNPLA3 I148M modulated enzymes for fatty acid and TG transport and metabolism. These findings suggest (dietary) lipids as an important and independent driver of hepatic tumorigenesis. Genetic variant in PNPLA3 exerted protective effects in mice, conflicting with findings in humans. Species-related differences in physiology and metabolism should be taken into account when modelling unhealthy human lifestyle, as genetic mouse models may not always allow for translation of insight gained in humans.
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Affiliation(s)
- Eleonora Patsenker
- Department of Gastroenterology and Hepatology, University of Zurich, 8091 Zurich, Switzerland.
| | - Veera Raghavan Thangapandi
- Department of Gastroenterology and Hepatology, Universitätsklinikum Dresden, 01304 Dresden, Germany; Center for Regenerative Therapies, TU Dresden, 01307 Dresden, Germany
| | - Oskar Knittelfelder
- Max Plank Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
| | - Alessandra Palladini
- Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; German Center for Diabetes Research, 85764 Neuherberg, Germany
| | - Michaela Hefti
- Department of Gastroenterology and Hepatology, University of Zurich, 8091 Zurich, Switzerland
| | - Jane Beil-Wagner
- Institute of Laboratory Animal Science, University of Zurich, 8952 Schlieren, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University of Zurich, 8091 Zurich, Switzerland
| | - Thorsten Buch
- Institute of Laboratory Animal Science, University of Zurich, 8952 Schlieren, Switzerland
| | - Andrej Shevchenko
- Max Plank Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
| | - Jochen Hampe
- Department of Gastroenterology and Hepatology, Universitätsklinikum Dresden, 01304 Dresden, Germany; Center for Regenerative Therapies, TU Dresden, 01307 Dresden, Germany
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University of Zurich, 8091 Zurich, Switzerland
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28
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Ru L, Wang XM, Niu JQ. The miR-23-27-24 cluster: an emerging target in NAFLD pathogenesis. Acta Pharmacol Sin 2022; 43:1167-1179. [PMID: 34893685 PMCID: PMC9061717 DOI: 10.1038/s41401-021-00819-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 11/08/2021] [Indexed: 12/13/2022]
Abstract
The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing globally, being the most widespread form of chronic liver disease in the west. NAFLD includes a variety of disease states, the mildest being non-alcoholic fatty liver that gradually progresses to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Small non-coding single-stranded microRNAs (miRNAs) regulate gene expression at the miRNA or translational level. Numerous miRNAs have been shown to promote NAFLD pathogenesis and progression through increasing lipid accumulation, oxidative stress, mitochondrial damage, and inflammation. The miR-23-27-24 clusters, composed of miR-23a-27a-24-2 and miR-23b-27b-24-1, have been implicated in various biological processes as well as many diseases. Herein, we review the current knowledge on miR-27, miR-24, and miR-23 in NAFLD pathogenesis and discuss their potential significance in NAFLD diagnosis and therapy.
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Affiliation(s)
- Lin Ru
- grid.430605.40000 0004 1758 4110Department of Hepatology, The First Hospital of Jilin University, Changchun, 130021 China
| | - Xiao-mei Wang
- grid.430605.40000 0004 1758 4110Department of Hepatology, The First Hospital of Jilin University, Changchun, 130021 China ,grid.430605.40000 0004 1758 4110Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, 130021 China
| | - Jun-qi Niu
- grid.430605.40000 0004 1758 4110Department of Hepatology, The First Hospital of Jilin University, Changchun, 130021 China ,grid.430605.40000 0004 1758 4110Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, 130021 China
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29
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Miao Y, Fu C, Liao M, Fang F. Differences in Liver microRNA profiling in pigs with low and high
feed efficiency. JOURNAL OF ANIMAL SCIENCE AND TECHNOLOGY 2022; 64:312-329. [PMID: 35530409 PMCID: PMC9039951 DOI: 10.5187/jast.2022.e4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/20/2021] [Accepted: 01/09/2022] [Indexed: 11/21/2022]
Abstract
Feed cost is the main factor affecting the economic benefits of pig industry.
Improving the feed efficiency (FE) can reduce the feed cost and improve the
economic benefits of pig breeding enterprises. Liver is a complex metabolic
organ which affects the distribution of nutrients and regulates the efficiency
of energy conversion from nutrients to muscle or fat, thereby affecting feed
efficiency. MicroRNAs (miRNAs) are small non-coding RNAs that can regulate feed
efficiency through the modulation of gene expression at the post-transcriptional
level. In this study, we analyzed miRNA profiling of liver tissues in High-FE
and Low-FE pigs for the purpose of identifying key miRNAs related to feed
efficiency. A total 212~221 annotated porcine miRNAs and 136~281 novel
miRNAs were identified in the pig liver. Among them, 188 annotated miRNAs were
co-expressed in High-FE and Low-FE pigs. The 14 miRNAs were significantly
differentially expressed (DE) in the livers of high-FE pigs and low-FE pigs, of
which 5 were downregulated and 9 were upregulated. Kyoto Encyclopedia of Genes
and Genomes analysis of liver DE miRNAs in high-FE pigs and low-FE pigs
indicated that the target genes of DE miRNAs were significantly enriched in
insulin signaling pathway, Gonadotropin-releasing hormone signaling pathway, and
mammalian target of rapamycin signaling pathway. To verify the reliability of
sequencing results, 5 DE miRNAs were randomly selected for quantitative reverse
transcription-polymerase chain reaction (qRT-PCR). The qRT-PCR results of miRNAs
were confirmed to be consistent with sequencing data. DE miRNA data indicated
that liver-specific miRNAs synergistically acted with mRNAs to improve feed
efficiency. The liver miRNAs expression analysis revealed the metabolic pathways
by which the liver miRNAs regulate pig feed efficiency.
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Affiliation(s)
- Yuanxin Miao
- College of Bioengineering,Jingchu
University of Technology, Jingmen 448000, Hubei, China
- Key Laboratory of Agricultural Animal
Genetics, Breeding and Reproduction of Ministry of Education, Huazhong
Agricultural University, Wuhan 430070, China
| | - Chuanke Fu
- Key Laboratory of Agricultural Animal
Genetics, Breeding and Reproduction of Ministry of Education, Huazhong
Agricultural University, Wuhan 430070, China
| | - Mingxing Liao
- Key Laboratory of Agricultural Animal
Genetics, Breeding and Reproduction of Ministry of Education, Huazhong
Agricultural University, Wuhan 430070, China
| | - Fang Fang
- Key Laboratory of Agricultural Animal
Genetics, Breeding and Reproduction of Ministry of Education, Huazhong
Agricultural University, Wuhan 430070, China
- National Center for International Research
on Animal Genetics, Breeding and Reproduction (NCIRAGBR), Huazhong
Agricultural University, Wuhan 430070, China
- Corresponding author: Fang Fang, Key Laboratory of
Agricultural Animal Genetics, Breeding and Reproduction of Ministry of
Education, Huazhong Agricultural University, Wuhan 430070, China. Tel:
+86-278-728-2091, E-mail:
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Zhang D, Niu S, Ma Y, Chen H, Wen Y, Li M, Zhou B, Deng Y, Shi C, Pu G, Yang M, Wang X, Zou C, Chen Y, Ma L. Fenofibrate Improves Insulin Resistance and Hepatic Steatosis and Regulates the Let-7/SERCA2b Axis in High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease Mice. Front Pharmacol 2022; 12:770652. [PMID: 35126113 PMCID: PMC8807641 DOI: 10.3389/fphar.2021.770652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 12/27/2021] [Indexed: 12/20/2022] Open
Abstract
Fenofibrate is widely used in clinical therapy to effectively ameliorate the development of non-alcoholic fatty liver disease (NAFLD); however, its specific molecular mechanism of action remains largely unknown. MicroRNAs (miRNAs) are key mediators in regulating endoplasmic reticulum (ER) stress during NAFLD, and the deregulation of miRNAs has been demonstrated in NAFLD pathophysiology. The present study aimed to identify whether fenofibrate could influence miRNA expression in NAFLD and investigate the specific mechanism of action of fenofibrate in lipid metabolism disorder-associated diseases. We found that fenofibrate alleviated ER stress and increased the levels of SERCA2b, which serves as a regulator of ER stress. Additionally, the levels of let-7 miRNA were regulated by fenofibrate; let-7 was found to target the 3′ untranslated region of SERCA2b. The present data suggest that the protective effects of fenofibrate against insulin resistance and its suppressive activity against excessive hepatic lipid accumulation may be related to the alteration of the let-7/SERCA2b axis and alleviation of ER stress.
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Affiliation(s)
- Dan Zhang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Shanzhuang Niu
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, China
| | - Yicheng Ma
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, China
| | - Hang Chen
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Yu Wen
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Mingke Li
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Bo Zhou
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Yi Deng
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Chunjing Shi
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Guangyu Pu
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Meng Yang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Xianmei Wang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Chenggang Zou
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, China
| | - Yuanli Chen
- Faculty of Basic Medicine, Kunming Medical University, Kunming, China
- *Correspondence: Yuanli Chen, ; Lanqing Ma,
| | - Lanqing Ma
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
- *Correspondence: Yuanli Chen, ; Lanqing Ma,
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Mukherjee S, Shelar B, Krishna S. Versatile role of miR-24/24-1*/24-2* expression in cancer and other human diseases. Am J Transl Res 2022; 14:20-54. [PMID: 35173828 PMCID: PMC8829624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 10/08/2021] [Indexed: 06/14/2023]
Abstract
MiRNAs (miRs) have been proven to be well-validated therapeutic targets. Emerging evidence has demonstrated that intricate, intrinsic and paradoxical functions of miRs are context-dependent because of their multiple upstream regulators, broad spectrum of downstream molecular targets and distinct expression in various tissues, organs and disease states. Targeted therapy has become an emerging field of research. One key for the development of successful miR-based/targeted therapy is to acquire integrated knowledge of its regulatory network and its association with disease phenotypes to identify critical nodes of the underlying pathogenesis. Herein, we systematically summarized the comprehensive role of miR-24-3p (miR-24), along with its passenger strands miR-24-1-5p* (miR-24-1) and miR-24-2-5p* (miR-24-2), emphasizing their microenvironment, intracellular targets, and associated gene networks and regulatory phenotypes in 18 different cancer types and 13 types of other disorders. MiR-24 targets and regulates numerous genes in various cancer types and enhances the expression of several oncogenes (e.g., cMyc, BCL2 and HIF1), which are challenging in terms of druggability. In contrast, several tumor suppressor proteins (p21 and p53) have been reported to be downregulated by miR-24. MiR-24 also regulates the cell cycle and is associated with numerous cancer hallmarks such as apoptosis, proliferation, metastasis, invasion, angiogenesis, autophagy, drug resistance and other diseases pathogenesis. Overall, miR-24 plays an emerging role in the diagnosis, prognosis and pathobiology of various diseases. MiR-24 is a potential target for targeted therapy in the era of precision medicine, which expands the landscape of targetable macromolecules, including undruggable proteins.
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Affiliation(s)
| | | | - Sudhir Krishna
- National Centre for Biological Sciences (NCBS), Tata Institute of Fundamental Research (TIFR)Bellary Road, Bangalore 560065, Karnataka, India
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Bardhi E, McDaniels J, Rousselle T, Maluf DG, Mas VR. Nucleic acid biomarkers to assess graft injury after liver transplantation. JHEP REPORTS : INNOVATION IN HEPATOLOGY 2022; 4:100439. [PMID: 35243279 PMCID: PMC8856989 DOI: 10.1016/j.jhepr.2022.100439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/13/2021] [Accepted: 12/20/2021] [Indexed: 02/07/2023]
Abstract
Many risk factors and complications impact the success of liver transplantation, such as ischaemia-reperfusion injury, acute rejection, and primary graft dysfunction. Molecular biomarkers have the potential to accurately diagnose, predict, and monitor injury progression or organ failure. There is a critical opportunity for reliable and non-invasive biomarkers to reduce the organ shortage by enabling i) the assessment of donor organ quality, ii) the monitoring of short- and long-term graft function, and iii) the prediction of acute and chronic disease development. To date, no established molecular biomarkers have been used to guide clinical decision-making in transplantation. In this review, we outline the recent advances in cell-free nucleic acid biomarkers for monitoring graft injury in liver transplant recipients. Prior work in this area can be divided into two categories: biomarker discovery and validation studies. Circulating nucleic acids (CNAs) can be found in the extracellular environment pertaining to different biological fluids such as bile, blood, urine, and perfusate. CNAs that are packaged into extracellular vesicles may facilitate intercellular and interorgan communication. Thus, decoding their biological function, cellular origins and molecular composition is imperative for diagnosing causes of graft injury, guiding immunosuppression and improving overall patient survival. Herein, we discuss the most promising molecular biomarkers, their state of development, and the critical aspects of study design in biomarker research for early detection of post-transplant liver injury. Future advances in biomarker studies are expected to personalise post-transplant therapy, leading to improved patient care and outcomes.
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Cao C, Duan P, Li W, Guo Y, Zhang J, Gui Y, Yuan S. Lack of miR-379/miR-544 Cluster Resists High-Fat Diet-Induced Obesity and Prevents Hepatic Triglyceride Accumulation in Mice. Front Cell Dev Biol 2021; 9:720900. [PMID: 34527673 PMCID: PMC8435714 DOI: 10.3389/fcell.2021.720900] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 08/10/2021] [Indexed: 12/21/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) affects obesity-associated metabolic syndrome, which exhibits hepatic steatosis, insulin insensitivity and glucose intolerance. Emerging evidence suggests that microRNAs (miRNAs) are essential for the metabolic homeostasis of liver tissues. Many hepatic miRNAs located in the miR-379/miR-544 cluster were significantly increased in leptin-receptor-deficient type 2 mice (db/db), a mouse model of diabetes. However, the function of the miR-379/miR-544 cluster in the process of hepatic steatosis remains unclear. Here, we report that the novel function of miR-379/miR-544 cluster in regulating obesity-mediated metabolic dysfunction. Genetical mutation of miR-379/miR-544 cluster in mice displayed resistance to high-fat diet (HFD)-induced obesity with moderate hepatic steatosis and hypertriglyceridemia. In vitro studies revealed that silencing of miR-379 in human hepatocellular carcinoma (HepG2) cells ameliorated palmitic acid-induced elevation of cellular triglycerides, and overexpression of miR-379 had the opposite effect. Moreover, Igf1r (Insulin-like growth factor 1 receptor) and Dlk1 (Delta-like homolog 1) were directly targeted by miR-379 and miR-329, respectively, and elevated in the livers of the miR-379/miR-544 cluster knockout mice fed on HFD. Further transcriptome analyses revealed that the hepatic gene expressions are dysregulated in miR-379/miR-544 knockout mice fed with HFD. Collectively, our findings identify the miR-379/miR-544 cluster as integral components of a regulatory circuit that functions under conditions of metabolic stress to control hepatic steatosis. Thus, this miRNA cluster provides potential targets for pharmacologic intervention in obesity and NAFLD.
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Affiliation(s)
- Congcong Cao
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen-Peking University - The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
| | - Peng Duan
- Department of Obstetrics and Gynaecology, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, China
| | - Wencun Li
- The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yang Guo
- College of Pharmacy, Hubei University of Medicine, Shiyan, China
| | - Jin Zhang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaoting Gui
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen-Peking University - The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
| | - Shuiqiao Yuan
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China
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Merve Bayram H, Eren F, Esra Gunes F. The relationship between polyphenols and miRNAs: A novel therapeutic strategy for metabolic associated fatty liver disease. HEPATOLOGY FORUM 2021; 2:128-136. [PMID: 35784906 PMCID: PMC9138948 DOI: 10.14744/hf.2021.2021.0037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 09/10/2021] [Indexed: 06/15/2023]
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a public health problem that is increasingly recognized, currently affecting up to a quarter of the world's adult population. Although a biopsy is the current gold standard to diagnose MAFLD, there are potentially serious complications, making it inadequate. Thus far, noninvasive methods have not been able to determine the stage and the subtype of MAFLD. The development and prognosis of MAFLD are modulated by epigenetic factors, including microRNAs (miRNAs), which may be potential biomarkers for MAFLD. Polyphenols, found in many fruits and vegetables, may be useful, as they alter gene expression with epigenetic factors, such as miRNAs. This review presents an overview of the relationship between polyphenols and miRNAs in MAFLD. The literature suggests that miRNAs could be used as a diagnostic method for MAFLD, especially miRNA-122 and miRNA-34a. However, though it has been demonstrated that polyphenols may contribute to improving MAFLD, to our knowledge, no study to date has shown the relationship between polyphenols and miRNAs in MAFLD. The exact mechanisms of polyphenols on miRNAs in MAFLD remain unclear. Future studies may provide hope for diet therapy for MAFLD patients as well as the development of polyphenol-related foods or drugs that target miRNAs to treat MAFLD.
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Affiliation(s)
- Hatice Merve Bayram
- Department of Nutrition and Dietetics, Istanbul Gelisim University Faculty of Health Sciences, Istanbul, Turkey
| | - Fatih Eren
- Institute of Gastroenterology, Marmara University, Istanbul, Turkey
- Department of Medical Biology, Marmara University School of Medicine, Istanbul, Turkey
| | - Fatma Esra Gunes
- Department of Nutrition and Dietetics, Marmara University Faculty of Health Sciences, Istanbul, Turkey
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Targeting miRNA by Natural Products: A Novel Therapeutic Approach for Nonalcoholic Fatty Liver. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6641031. [PMID: 34426744 PMCID: PMC8380168 DOI: 10.1155/2021/6641031] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 08/02/2021] [Indexed: 02/07/2023]
Abstract
The increasing prevalence of nonalcoholic fatty liver disease (NAFLD) as multifactorial chronic liver disease and the lack of a specific treatment have begun a new era in its treatment using gene expression changes and microRNAs. This study aimed to investigate the potential therapeutic effects of natural compounds in NAFLD by regulating miRNA expression. MicroRNAs play essential roles in regulating the cell's biological processes, such as apoptosis, migration, lipid metabolism, insulin resistance, and adipocyte differentiation, by controlling the posttranscriptional gene expression level. The impact of current NAFLD pharmacological management, including drug and biological therapies, is uncertain. In this context, various dietary fruits or medicinal herbal sources have received worldwide attention versus NAFLD development. Natural ingredients such as berberine, lychee pulp, grape seed, and rosemary possess protective and therapeutic effects against NAFLD by modifying the gene's expression and noncoding RNAs, especially miRNAs.
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MicroRNA Sequences Modulated by Beta Cell Lipid Metabolism: Implications for Type 2 Diabetes Mellitus. BIOLOGY 2021; 10:biology10060534. [PMID: 34203703 PMCID: PMC8232095 DOI: 10.3390/biology10060534] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 12/23/2022]
Abstract
Alterations in lipid metabolism within beta cells and islets contributes to dysfunction and apoptosis of beta cells, leading to loss of insulin secretion and the onset of type 2 diabetes. Over the last decade, there has been an explosion of interest in understanding the landscape of gene expression which influences beta cell function, including the importance of small non-coding microRNA sequences in this context. This review sought to identify the microRNA sequences regulated by metabolic challenges in beta cells and islets, their targets, highlight their function and assess their possible relevance as biomarkers of disease progression in diabetic individuals. Predictive analysis was used to explore networks of genes targeted by these microRNA sequences, which may offer new therapeutic strategies to protect beta cell function and delay the onset of type 2 diabetes.
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Paul S, Bravo Vázquez LA, Uribe SP, Manzanero Cárdenas LA, Ruíz Aguilar MF, Chakraborty S, Sharma A. Roles of microRNAs in carbohydrate and lipid metabolism disorders and their therapeutic potential. Biochimie 2021; 187:83-93. [PMID: 34082043 DOI: 10.1016/j.biochi.2021.05.015] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/19/2021] [Accepted: 05/25/2021] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) are small (∼21 nucleotides), endogenous, non-coding RNA molecules implicated in the post-transcriptional gene regulation performed through target mRNA cleavage or translational inhibition. In recent years, several investigations have demonstrated that miRNAs are involved in regulating both carbohydrate and lipid homeostasis in humans and other organisms. Moreover, it has been observed that the dysregulation of these metabolism-related miRNAs leads to the development of several metabolic disorders, such as type 2 diabetes, obesity, nonalcoholic fatty liver, insulin resistance, and hyperlipidemia. Hence, in this current review, with the aim to impulse the research arena of the micro-transcriptome implications in vital metabolic pathways as well as to highlight the remarkable potential of miRNAs as therapeutic targets for metabolic disorders in humans, we provide an overview of the regulatory roles of metabolism-associated miRNAs in humans and murine models.
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Affiliation(s)
- Sujay Paul
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Queretaro, Av. Epigmenio Gonzalez, No. 500 Fracc, San Pablo, CP 76130, Querétaro, Mexico.
| | - Luis Alberto Bravo Vázquez
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Queretaro, Av. Epigmenio Gonzalez, No. 500 Fracc, San Pablo, CP 76130, Querétaro, Mexico
| | - Samantha Pérez Uribe
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Queretaro, Av. Epigmenio Gonzalez, No. 500 Fracc, San Pablo, CP 76130, Querétaro, Mexico
| | - Luis Aarón Manzanero Cárdenas
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Ciudad de Mexico, Calle del Puente, No. 222 Col. Ejidos de Huipulco, Tlalpan, CP 14380, Mexico City, Mexico
| | - María Fernanda Ruíz Aguilar
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Ciudad de Mexico, Calle del Puente, No. 222 Col. Ejidos de Huipulco, Tlalpan, CP 14380, Mexico City, Mexico
| | - Samik Chakraborty
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, MA, 02115, USA
| | - Ashutosh Sharma
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Queretaro, Av. Epigmenio Gonzalez, No. 500 Fracc, San Pablo, CP 76130, Querétaro, Mexico.
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Ubilla CG, Prado Y, Angulo J, Obreque I, Paez I, Saavedra N, Saavedra K, Zambrano T, Salazar LA. MicroRNA-33b is a Potential Non-Invasive Biomarker for Response to Atorvastatin Treatment in Chilean Subjects With Hypercholesterolemia: A Pilot Study. Front Pharmacol 2021; 12:674252. [PMID: 34093203 PMCID: PMC8175777 DOI: 10.3389/fphar.2021.674252] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 05/06/2021] [Indexed: 11/13/2022] Open
Abstract
Evidence accumulated so far indicates that circulating levels of microRNAs (miRNAs) are associated with several pathologies. Therefore, differential expression of extracellular miRNAs exhibits promising potential for screening and diagnosis purposes. We evaluated plasma miRNAs in response to the lipid-lowering drug atorvastatin in patients with hypercholesterolemia (HC) and controls. METHODS We selected miRNAs based on previous data reported by our group and also by employing bioinformatics tools to identify 10 miRNAs related to cholesterol metabolism and statin response genes. Following miRNA identification, we determined plasma levels of miRNA-17-5p, miRNA-30c-5p, miRNA-24-3p, miRNA-33a-5p, miRNA-33b-5p, miRNA-29a-3p, miRNA-29b-3p, miRNA-454-3p, miRNA-590-3p and miRNA-27a-3p in 20 HC patients before and after 1 month of 20 mg/day atorvastatin treatment, evaluating the same miRNA set in a group of 20 healthy subjects, and employing qRT-PCR to determine differential miRNAs expression. RESULTS HC individuals showed significant overexpression of miRNA-30c-5p and miRNA-29b-3p vs. NL (p = 0.0008 and p = 0.0001, respectively). Once cholesterol-lowering treatment was concluded, HC individuals showed a substantial increase of three extracellular miRNAs (miRNA-24-3p, miRNA-590, and miRNA-33b-5p), the latter elevated more than 37-fold (p = 0.0082). CONCLUSION Data suggest that circulating miRNA-30c-5p and miRNA-29b-3p are associated with hypercholesterolemia. Also, atorvastatin induces a strong elevation of miRNA-33b-5p levels in HC individuals, which could indicate an important function that this miRNA may exert upon atorvastatin therapy. Additional studies are needed to clarify the role of this particular miRNA in statin treatment.
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Affiliation(s)
- Carmen Gloria Ubilla
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco, Chile
| | - Yalena Prado
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco, Chile
| | - Jeremy Angulo
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco, Chile
| | - Ignacio Obreque
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco, Chile
| | - Isis Paez
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco, Chile
| | - Nicolás Saavedra
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco, Chile
| | - Kathleen Saavedra
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco, Chile
| | - Tomás Zambrano
- Department of Medical Technology, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Luis A Salazar
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco, Chile
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Sun L, Gao M, Qian Q, Guo Z, Zhu P, Wang X, Wang H. Triclosan-induced abnormal expression of miR-30b regulates fto-mediated m 6A methylation level to cause lipid metabolism disorder in zebrafish. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 770:145285. [PMID: 33515893 DOI: 10.1016/j.scitotenv.2021.145285] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 01/04/2021] [Accepted: 01/14/2021] [Indexed: 06/12/2023]
Abstract
Chronic exposure of triclosan (TCS) to zebrafish triggers high incidence of fatty liver and hepatitis; however, the underlying molecular mechanisms remain unclear. Herein, we identified miR-30b as a sensitive biomarker to TCS stress, reflecting in that its decreased expression caused metabolic toxicity, abnormal development and behavior, and lipid-metabolism disorder. By microinjecting the inhibitor and mimic experiments, miR-30b was proved to regulate lipid metabolism by its main target gene fto. Over-expression of FTO resulted in fat accumulation, elevation of the TG and TC levels and up-regulation of the PPARγ and CEBPα, as well as decrease of the global m6A level in larvae. On the contrary, the knock-down of FTO using MO caused the anti-lipogenic effect, decrease of the TG and T-CHO levels, and abnormal changes of cebpɑ, acsl5, fasn, ppap2c and pparγ etc. Further fortification tests of cycloleucine and betaine evidenced that the toxic effect was strongly dependent on regulation of the m6A level. The toxicity effects in the treatments of methylated donors and receptors were consistent with the changes in physiological functions of FTO knockdown and overexpression. The effects of cycloleucine on m6A level and lipid metabolism generally consisted with those of FTO, but this was not the case for betaine, reflecting in increased m6A level and lipid accumulation in larval liver. Consequently, we posit that TCS exposure caused zebrafish lipid-metabolism disorder by decreasing miR-30b expression to regulate fto-mediated m6A methylation level. These findings contribute to our deep understanding of the underlying molecular mechanisms regarding contaminant-originating fatty liver and hepatocellular carcinoma, and also have practical significance in pollution warning and target therapy for related diseases.
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Affiliation(s)
- Limei Sun
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China; Department of Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China
| | - Ming Gao
- National and Local Joint Engineering Laboratory of Municipal Sewage Resource Utilization Technology, School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou 215009, China
| | - Qiuhui Qian
- National and Local Joint Engineering Laboratory of Municipal Sewage Resource Utilization Technology, School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou 215009, China
| | - Ziyi Guo
- National and Local Joint Engineering Laboratory of Municipal Sewage Resource Utilization Technology, School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou 215009, China
| | - Peng Zhu
- National and Local Joint Engineering Laboratory of Municipal Sewage Resource Utilization Technology, School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou 215009, China
| | - Xuedong Wang
- National and Local Joint Engineering Laboratory of Municipal Sewage Resource Utilization Technology, School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou 215009, China.
| | - Huili Wang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China.
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The Beneficial Effects of Edible Kynurenic Acid from Marine Horseshoe Crab ( Tachypleus tridentatus) on Obesity, Hyperlipidemia, and Gut Microbiota in High-Fat Diet-Fed Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8874503. [PMID: 34055199 PMCID: PMC8112934 DOI: 10.1155/2021/8874503] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 03/08/2021] [Accepted: 04/07/2021] [Indexed: 12/20/2022]
Abstract
The marine horseshoe crab (Tachypleus tridentatus) has been considered as food and traditional medicine for many years. Kynurenic acid (KA) was isolated from horseshoe crab in this study for the first time in the world. A previous study in 2018 reported that intraperitoneal administration of KA prevented high-fat diet- (HFD-) induced body weight gain. Now, we investigated the effects of intragastric gavage of KA on HFD mice and found that KA (5 mg/kg/day) inhibited both the body weight gain and the increase of average daily energy intake. KA reduced serum triglyceride and increased serum high-density lipoprotein cholesterol. KA inhibited HFD-induced the increases of serum low-density lipoprotein cholesterol, coronary artery risk index, and atherosclerosis index. KA also suppressed HFD-induced the increase of the ratio of Firmicutes to Bacteroidetes (two dominant gut microbial phyla). KA partially reversed HFD-induced the changes in the composition of gut microbial genera. These overall effects of KA on HFD mice were similar to that of simvastatin (positive control). But the effects of 1.25 mg/kg/day KA on HFD-caused hyperlipidemia were similar to the effects of 5 mg/kg/day simvastatin. The pattern of relative abundance in 40 key genera of gut microbiota from KA group was closer to that from the normal group than that from the simvastatin group. In addition, our in vitro results showed the potential antioxidant activity of KA, which suggests that the improvement effects of KA on HFD mice may be partially associated with antioxidant activity of KA. Our findings demonstrate the potential role of KA as a functional food ingredient for the treatment of obesity and hyperlipidemia as well as the modulation of gut microbiota.
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Fang Z, Dou G, Wang L. MicroRNAs in the Pathogenesis of Nonalcoholic Fatty Liver Disease. Int J Biol Sci 2021; 17:1851-1863. [PMID: 33994867 PMCID: PMC8120467 DOI: 10.7150/ijbs.59588] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/14/2021] [Indexed: 12/13/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), or, more accurately, metabolic associated fatty liver disease, accounts for a large proportion of chronic liver disorders worldwide and is closely associated with other conditions such as cardiovascular disease, obesity, and type 2 diabetes mellitus. NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and can progress to cirrhosis and, eventually, also hepatocellular carcinoma. The morbidity and mortality associated with NAFLD are increasing rapidly year on year. Consequently, there is an urgent need to understand the etiology and pathogenesis of NAFLD and identify effective therapeutic targets. MicroRNAs (miRNAs), important epigenetic factors, have recently been proposed to participate in NAFLD pathogenesis. Here, we review the roles of miRNAs in lipid metabolism, inflammation, apoptosis, fibrosis, hepatic stellate cell activation, insulin resistance, and oxidative stress, key factors that contribute to the occurrence and progression of NAFLD. Additionally, we summarize the role of miRNA-enriched extracellular vesicles in NAFLD. These miRNAs may comprise suitable therapeutic targets for the treatment of this condition.
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Affiliation(s)
- Zhiqiang Fang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Guorui Dou
- Department of Ophthalmology, Xi-Jing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an 710032, China
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Epigenetics in NAFLD/NASH: Targets and therapy. Pharmacol Res 2021; 167:105484. [PMID: 33771699 DOI: 10.1016/j.phrs.2021.105484] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 12/15/2022]
Abstract
Recently non-alcoholic fatty liver disease (NAFLD) has grabbed considerable scientific attention, owing to its rapid increase in prevalence worldwide and growing burden on end-stage liver diseases. Metabolic syndrome including obesity, diabetes, and hypertension poses a grave risk to NAFLD etiology and progression. With no drugs available, the mainstay of NAFLD management remains lifestyle changes with exercise and dietary modifications. Nonselective drugs such as metformin, thiazolidinediones (TZDs), ursodeoxycholic acid (UDCA), silymarin, etc., are also being used to target the interrelated pathways for treating NAFLD. Considering the enormous disease burden and the unmet need for drugs, fresh insights into pathogenesis and drug discovery are required. The emergence of the field of epigenetics offers a convincing explanation for the basis of lifestyle, environmental, and other risk factors to influence NAFLD pathogenesis. Therefore, understanding these epigenetic modifications to target the primary cause of the disease might prove a rational strategy to prevent the disease and develop novel therapeutic interventions. Apart from describing the role of epigenetics in the pathogenesis of NAFLD as in other reviews, this review additionally provides an elaborate discussion on exploiting the high plasticity of epigenetic modifications in response to environmental cues, for developing novel therapeutics for NAFLD. Besides, this extensive review provides evidence for epigenetic mechanisms utilized by several potential drugs for NAFLD.
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Xu X, Chen W, Yu S, Lei Q, Han L, Ma W. Inhibition of preadipocyte differentiation by Lycium barbarum polysaccharide treatment in 3T3-L1 cultures. ELECTRON J BIOTECHN 2021. [DOI: 10.1016/j.ejbt.2021.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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Grieco GE, Brusco N, Licata G, Fignani D, Formichi C, Nigi L, Sebastiani G, Dotta F. The Landscape of microRNAs in βCell: Between Phenotype Maintenance and Protection. Int J Mol Sci 2021; 22:ijms22020803. [PMID: 33466949 PMCID: PMC7830142 DOI: 10.3390/ijms22020803] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/11/2021] [Accepted: 01/12/2021] [Indexed: 12/19/2022] Open
Abstract
Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by chronic hyperglycaemia mainly due to pancreatic β cell death and/or dysfunction, caused by several types of stress such as glucotoxicity, lipotoxicity and inflammation. Different patho-physiological mechanisms driving β cell response to these stresses are tightly regulated by microRNAs (miRNAs), a class of negative regulators of gene expression, involved in pathogenic mechanisms occurring in diabetes and in its complications. In this review, we aim to shed light on the most important miRNAs regulating the maintenance and the robustness of β cell identity, as well as on those miRNAs involved in the pathogenesis of the two main forms of diabetes mellitus, i.e., type 1 and type 2 diabetes. Additionally, we acknowledge that the understanding of miRNAs-regulated molecular mechanisms is fundamental in order to develop specific and effective strategies based on miRNAs as therapeutic targets, employing innovative molecules.
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Affiliation(s)
- Giuseppina Emanuela Grieco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (G.E.G.); (N.B.); (G.L.); (D.F.); (C.F.); (L.N.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Noemi Brusco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (G.E.G.); (N.B.); (G.L.); (D.F.); (C.F.); (L.N.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Giada Licata
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (G.E.G.); (N.B.); (G.L.); (D.F.); (C.F.); (L.N.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Daniela Fignani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (G.E.G.); (N.B.); (G.L.); (D.F.); (C.F.); (L.N.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Caterina Formichi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (G.E.G.); (N.B.); (G.L.); (D.F.); (C.F.); (L.N.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Laura Nigi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (G.E.G.); (N.B.); (G.L.); (D.F.); (C.F.); (L.N.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Guido Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (G.E.G.); (N.B.); (G.L.); (D.F.); (C.F.); (L.N.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (G.E.G.); (N.B.); (G.L.); (D.F.); (C.F.); (L.N.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
- Tuscany Centre for Precision Medicine (CReMeP), 53100 Siena, Italy
- Correspondence: ; Tel.: +39-0577-231283
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Loss of miR-23b/27b/24-1 Cluster Impairs Glucose Tolerance via Glycolysis Pathway in Mice. Int J Mol Sci 2021; 22:ijms22020550. [PMID: 33430468 PMCID: PMC7826568 DOI: 10.3390/ijms22020550] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/23/2020] [Accepted: 01/05/2021] [Indexed: 01/07/2023] Open
Abstract
Alterations in miRNAs are associated with many metabolic disorders, such as type 2 diabetes (T2DM). The miR-23b/27b/24-1 cluster contains miR-23b, miR-27b, and miR-24-1, which are located within 881 bp on chromosome 9. Studies examining the roles of miR-23b, miR-27b, and miR-24-1 have demonstrated their multifaceted functions in variable metabolic disorders. However, their joint roles in metabolism in vivo remain elusive. To investigate this subject, we constructed miR-23b/27b/24-1 cluster knockout (KO) mice. Compared with wild-type (WT) mice, the KO mice exhibited impaired glucose tolerance, which was accompanied by a reduction in the respiratory exchange rate (RER). These alterations were more noticeable after a high-fat diet (HFD) induction. Hepatic metabolomic results showed decreased expression of reduced nicotinamide adenine dinucleotide (NADH), nicotinamide adenine dinucleotide (NAD), phosphoenolpyruvic acid (PEP), and phosphoric acid, which are involved in the glycolysis pathway. The transcriptomic results indicated that genes involved in glycolysis showed a downregulation trend. qPCR and Western blot revealed that pyruvate kinase (PKLR), the key rate-limiting enzyme in glycolysis, was significantly reduced after the deletion of the miR-23b/27b/24-1 cluster. Together, these observations suggest that the miR-23b/27b/24-1 cluster is involved in the regulation of glucose homeostasis via the glycolysis pathway.
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Ni Y, Xu Z, Li C, Zhu Y, Liu R, Zhang F, Chang H, Li M, Sheng L, Li Z, Hou M, Chen L, You H, McManus DP, Hu W, Duan Y, Liu Y, Ji M. Therapeutic inhibition of miR-802 protects against obesity through AMPK-mediated regulation of hepatic lipid metabolism. Am J Cancer Res 2021; 11:1079-1099. [PMID: 33391522 PMCID: PMC7738900 DOI: 10.7150/thno.49354] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 10/22/2020] [Indexed: 12/25/2022] Open
Abstract
Background: The host-parasite relationship is based on subtle interplay between parasite survival strategies and host defense mechanisms. It is well known that helminth infection, which afflicts more than one billion people globally, correlates with a decreased prevalence of obesity. Dissecting the underlying mechanisms can provide new targets for treating obesity from the host-parasite interaction perspective. Methods: C57BL/6 mice received a normal or high-fat diet (HFD) with or without Sjp40 (one main component of schistosome-derived soluble egg antigens) treatment. Both the loss and gain-of-function experiments by the inhibitor suppression and lentivirus treatment of miR-802 were utilized to elucidate the role of miR-802/AMPK axis in host lipid metabolism. Hepatocyte lipogenesis assay and metabolic parameters were assessed both in vivo and in vitro. The potential interactions among Sjp40, CD36, miR-802, Prkab1, and AMPK were clarified by pull-down, miRNA expression microarray, quantitative RT-PCR, dual-luciferase reporter assay, and western blotting analysis. Results: We showed a link between decreased miR-802 and impaired lipid metabolism in Schistosoma japonicum infected mice. The decreased miR-802 promotes murine Prkab1 or human Prkaa1 expression, respectively, which increases levels of phosphorylated AMPK, resulting in a decrease in hepatic lipogenesis. Also, injection with schistosome-derived soluble egg antigens (SEA) attenuated metabolism. We demonstrated that Sjp40 as a main component of SEA interacted with CD36 on hepatocytes to inhibit miR-802, resulting in the activation of AMPK pathway and subsequent attenuation of lipogenesis. Collectively: Our study reveals the significant role of miR-802/AMPK axis in hepatic lipid metabolism and identifies the therapeutic potential of Sjp40 in treating obesity-related fatty liver.
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Liu W, Nakano M, Nakanishi T, Nakajima M, Tamai I. Post-transcriptional regulation of OATP2B1 transporter by a microRNA, miR-24. Drug Metab Pharmacokinet 2020; 35:515-521. [DOI: 10.1016/j.dmpk.2020.07.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 07/17/2020] [Accepted: 07/30/2020] [Indexed: 12/26/2022]
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Ying Y, Wan H, Zhao X, Yu L, He Y, Jin W. Pharmacokinetic-Pharmacodynamic Modeling of the Antioxidant Activity of Quzhou Fructus Aurantii Decoction in a Rat Model of Hyperlipidemia. Biomed Pharmacother 2020; 131:110646. [PMID: 32942150 DOI: 10.1016/j.biopha.2020.110646] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 08/03/2020] [Accepted: 08/16/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Quzhou Fructus Aurantii (QFA) is an herb that is commonly used to alleviate inflammation in individuals dealing with obesity.To date, however, no systematic pharmacokinetic (PK) or pharmacodynamic (PD) analyses of the clinical efficacy of QFA under hyperlipemia-associated oxidative stress conditions have been conducted. The present study, was therefore designed to construct a PK-PD model for this herb, with the goal of linking QFA PK profiles to key therapeutic outlines to guide the therapeutic use of this herb in clinical settings. METHODS Rats were fed a high-fat diet in order to establish a model of hyperlipidemia, after which they were randomized into a normal control group (NCG), a normal treatment group (NTG), a model control group (MCG), and a model treated group (MTG) (n = 6 each). QAF decoction was used to treat rats in the NTG and MTG groups (25 g/kg), while equivalent volumes of physiological saline were administered to rats in the NCG and MCG groups. Plasma samples were collected from the mandibular vein for animals at appropriate time points and analyzed via high-performance liquid chromatography (HPLC). We evaluated PK properties for three QAF components and compared these dynamics between the NTG and MTG groups, while also measuring levels of lipid peroxidation (LPO) in the plasma of rats in all four treatment groups. We then constructed a PK-PD model based upon plasma neohesperidin, luteolin, and nobiletin concentrations and LPO levels using a three-compartment PK model together with a Sigmoid Emax PD model. This model thereby enabled us to assess the antioxidative impact of neohesperidin, luteolin, and nobiletin on hyperlipidemia in rats. RESULTS When comparing the NTG and MTG groups, we detected significant differences in the following parameters pertaining to neohesperidin, luteolin, and nobiletin:t1/2β, V1, t1/2γ, CL1 (p < 0.01) and AUC0-t, Tmax, Cmax (p < 0.05). Relative to NTG group rats, AUC0-t, TmaxandCmaxvalues significantly higher for MTG group rats (p < 0.01), while t1/2β, V1, and t1/2γ values were significantly lower in MTG group rats (p < 0.01) in MTG rats. QAF decoction also exhibited excellent PD efficacy in MTG rats, with significant reductions in plasma LPO levels relative to NTG rats (p < 0.01) following treatment. This therapeutic efficacy may be attributable to the activity of neohesperidin, luteolin, and nobiletin, as LPO levels and plasma concentrations of these compounds were negatively correlated in treated rats. Based upon Akaike Information Criterion (AIC) values, we determined that neohesperidin, luteolin, and nobiletin PK processes were consistent with a three-compartment model. Together, these findings indicated that three active components in QAF decoction (neohesperidin, luteolin, and nobiletin) may exhibit antioxidant activity in vivo. CONCLUSION Our in vivo data indicated that neohesperidin, luteolin and nobiletin components of QAF decoctions exhibit distinct PK and PD properties. Together, these findings suggest that hyperlipidemia-related oxidative stress can significantly impact QFA decoction PK and PD parameters. Our data additionally offer fundamental insights that can be used to design appropriate dosing regimens for individualized clinical QAF decoction treatment.
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Affiliation(s)
- Yuqi Ying
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China.
| | - Haoyu Wan
- College of Medical Technology, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China.
| | - Xixi Zhao
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China.
| | - Li Yu
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China.
| | - Yu He
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China.
| | - Weifeng Jin
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China.
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Cloherty AP, Olmstead AD, Ribeiro CM, Jean F. Hijacking of Lipid Droplets by Hepatitis C, Dengue and Zika Viruses-From Viral Protein Moonlighting to Extracellular Release. Int J Mol Sci 2020; 21:E7901. [PMID: 33114346 PMCID: PMC7662613 DOI: 10.3390/ijms21217901] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 10/15/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
Hijacking and manipulation of host cell biosynthetic pathways by human enveloped viruses are essential for the viral lifecycle. Flaviviridae members, including hepatitis C, dengue and Zika viruses, extensively manipulate host lipid metabolism, underlining the importance of lipid droplets (LDs) in viral infection. LDs are dynamic cytoplasmic organelles that can act as sequestration platforms for a unique subset of host and viral proteins. Transient recruitment and mobilization of proteins to LDs during viral infection impacts host-cell biological properties, LD functionality and canonical protein functions. Notably, recent studies identified LDs in the nucleus and also identified that LDs are transported extracellularly via an autophagy-mediated mechanism, indicating a novel role for autophagy in Flaviviridae infections. These developments underline an unsuspected diversity and localization of LDs and potential moonlighting functions of LD-associated proteins during infection. This review summarizes recent breakthroughs concerning the LD hijacking activities of hepatitis C, dengue and Zika viruses and potential roles of cytoplasmic, nuclear and extracellular LD-associated viral proteins during infection.
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Affiliation(s)
- Alexandra P.M. Cloherty
- Amsterdam UMC, Amsterdam Institute for Infection & Immunity, Department of Experimental Immunology, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (A.P.M.C.); (C.M.S.R.)
| | - Andrea D. Olmstead
- Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, 3559–2350 Health Sciences Mall, Vancouver, BC V6T1Z3, Canada;
| | - Carla M.S. Ribeiro
- Amsterdam UMC, Amsterdam Institute for Infection & Immunity, Department of Experimental Immunology, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (A.P.M.C.); (C.M.S.R.)
| | - François Jean
- Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, 3559–2350 Health Sciences Mall, Vancouver, BC V6T1Z3, Canada;
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Lee DH, Park SH, Ahn J, Hong SP, Lee E, Jang YJ, Ha TY, Huh YH, Ha SY, Jeon TI, Jung CH. Mir214-3p and Hnf4a/Hnf4α reciprocally regulate Ulk1 expression and autophagy in nonalcoholic hepatic steatosis. Autophagy 2020; 17:2415-2431. [PMID: 33078654 PMCID: PMC8496708 DOI: 10.1080/15548627.2020.1827779] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Macroautophagy/autophagy, a self-degradative process, regulates metabolic homeostasis in response to various stress conditions and is a therapeutic target for nonalcoholic fatty liver disease. We found that autophagic activity was inhibited as a result of a significant reduction in the expression of autophagy-related genes such as Ulk1 in a mouse model and patients with fatty liver. This downregulation was caused by increased Mir214-3p levels and decreased Hnf4a/Hnf4α mRNA levels in hepatocytes. Mir214-3p suppressed Ulk1 expression through direct binding at a 3' untranslated region sequence. Hnf4a directly activated transcription of Ulk1. We investigated lipid accumulation and the expression of autophagy-related genes in the livers of mice treated with anti-Mir214-3p. Hepatic steatosis was alleviated, and Ulk1 mRNA levels were significantly increased by locked nucleic acid-mediated Mir214-3p silencing. Additionally, autophagosome formation and MAP1LC3/LC3-II protein levels were increased, indicating an increase in autophagic activity. Interestingly, suppression of Mir214-3p did not ameliorate fatty liver under Ulk1 suppression, suggesting that reduced Mir214-3p levels mitigate hepatic steatosis through upregulation of Ulk1. These results demonstrate that inhibition of Mir214-3p expression ameliorated fatty liver disease through increased autophagic activity by increasing the expression of Ulk1. Thus, Mir214-3p is a potential therapeutic target for nonalcoholic fatty disease.Abbreviations: AMPK: adenosine monophosphate-activated protein kinase; ATG: autophagy-related; ChIP: chromatin immunoprecipitation; CTSB: cathepsin B; CTSL: cathepsin L; CQ: chloroquine; HFD: high-fat diet; HNF4A: hepatocyte nuclear factor 4, alpha; IF: immunofluorescence; IHC: immunohistochemistry; LDs: lipid droplets; Leup: leupeptin; LFD: low-fat diet; LNA: locked nucleic acid; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; miRNA: microRNA; MTOR: mechanistic target of rapamycin kinase; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; PCR: polymerase chain reaction; TEM: transmission electron microscopy; TF: transcription factor; TLDA: TaqMan low-density array; ULK1: unc-51 like kinase 1; UTR: untranslated region.
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Affiliation(s)
- Da-Hye Lee
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Republic of Korea
| | - So-Hyun Park
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Republic of Korea
| | - Jiyun Ahn
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Republic of Korea
| | - Seung Pyo Hong
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Eunyoung Lee
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Young-Jin Jang
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Tae-Youl Ha
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Republic of Korea
| | - Yang Hoon Huh
- Center for Electron Microscopy Research, Korea Basic Science Institute, Cheongju, Republic of Korea
| | - Seung-Yeon Ha
- Department of Pathology, Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Tae-Il Jeon
- Department of Animal Science, Chonnam National University, Gwangju, Republic of Korea
| | - Chang Hwa Jung
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Republic of Korea
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