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Ou LL, Jiang JL, Guo ML, Wu JH, Zhong WW, He YH. Research progress on the roles of complement in liver injury. World J Hepatol 2025; 17:103839. [DOI: 10.4254/wjh.v17.i3.103839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/29/2025] [Accepted: 02/27/2025] [Indexed: 03/26/2025] Open
Abstract
The complement system is crucial for maintaining immunological homeostasis in the liver, playing a significant role in both innate and adaptive immune responses. Dysregulation of this system is closely linked to the pathogenesis of various liver diseases. Modulating the complement system can affect the progression of these conditions. To provide insights into treating liver injury by targeting the regulation of the complement system, we conducted a comprehensive search of major biomedical databases, including MEDLINE, PubMed, EMBASE, and Web of Science, to identify articles on complement and liver injury and reviewed the functions and mechanisms of the complement system in liver injury.
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Affiliation(s)
- Li-Li Ou
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Jin-Lian Jiang
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Man-Lu Guo
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Jin-Hua Wu
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Wei-Wei Zhong
- Department of Infectious Diseases, Jingmen Central Hospital, Jingmen Central Hospital Affiliated to Jingchu University of Technology, Jingmen 448000, Hubei Province, China
| | - Yi-Huai He
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
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Alic L, Dendinovic K, Papac-Milicevic N. The complement system in lipid-mediated pathologies. Front Immunol 2024; 15:1511886. [PMID: 39635529 PMCID: PMC11614835 DOI: 10.3389/fimmu.2024.1511886] [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: 10/15/2024] [Accepted: 10/31/2024] [Indexed: 12/07/2024] Open
Abstract
The complement system, a coordinator and facilitator of the innate immune response, plays an essential role in maintaining host homeostasis. It promotes clearance of pathogen- and danger-associated molecular patterns, regulates adaptive immunity, and can modify various metabolic processes such as energy expenditure, lipid metabolism, and glucose homeostasis. In this review, we will focus on the intricate interplay between complement components and lipid metabolism. More precisely, we will display how alterations in the activation and regulation of the complement system affect pathological outcome in lipid-associated diseases, such as atherosclerosis, obesity, metabolic syndrome, age-related macular degeneration, and metabolic dysfunction-associated steatotic liver disease. In addition to that, we will present and evaluate underlying complement-mediated physiological mechanisms, observed both in vitro and in vivo. Our manuscript will demonstrate the clinical significance of the complement system as a bridging figure between innate immunity and lipid homeostasis.
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Affiliation(s)
- Lejla Alic
- Department of Medical Biochemistry, Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Kristina Dendinovic
- Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Nikolina Papac-Milicevic
- Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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Prado LG, Nagy LE. Role of Complement in Liver Diseases. Semin Liver Dis 2024; 44:510-522. [PMID: 39608405 DOI: 10.1055/s-0044-1795143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2024]
Abstract
This review aims to summarize recent research using animal models, cell models, and human data regarding the role of complement in liver disease. Complement is part of the innate immune system and was initially characterized for its role in control of pathogens. However, evidence now indicates that complement also plays an important role in the response to cellular injury that is independent of pathogens. The liver is the main organ responsible for producing circulating complement. In response to liver injury, complement is activated and likely plays a dual role, both contributing to and protecting from injury. In uncontrolled complement activation, cell injury and liver inflammation occur, contributing to progression of liver disease. Complement activation is implicated in the pathogenesis of multiple liver diseases, including alcohol-associated liver disease, metabolic dysfunction-associated steatotic liver disease, fibrosis and cirrhosis, hepatocellular carcinoma, and autoimmune hepatitis. However, the mechanisms by which complement is overactivated in liver diseases are still being unraveled.
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Affiliation(s)
- Luan G Prado
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio
| | - Laura E Nagy
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
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Magdy A, Kim HJ, Go H, Lee JM, Sohn HA, Haam K, Jung HJ, Park JL, Yoo T, Kwon ES, Lee DH, Choi M, Kang KW, Kim W, Kim M. DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease. Clin Mol Hepatol 2024; 30:824-844. [PMID: 39048522 PMCID: PMC11540403 DOI: 10.3350/cmh.2024.0229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/22/2024] [Accepted: 07/24/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND/AIMS Blocking the complement system is a promising strategy to impede the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the interplay between complement and MASLD remains to be elucidated. This comprehensive approach aimed to investigate the potential association between complement dysregulation and the histological severity of MASLD. METHODS Liver biopsy specimens were procured from a cohort comprising 106 Korean individuals, which included 31 controls, 17 with isolated steatosis, and 58 with metabolic dysfunction-associated steatohepatitis (MASH). Utilizing the Infinium Methylation EPIC array, thorough analysis of methylation alterations in 61 complement genes was conducted. The expression and methylation of nine complement genes in a murine MASH model were examined using quantitative RT-PCR and pyrosequencing. RESULTS Methylome and transcriptome analyses of liver biopsies revealed significant (P<0.05) hypermethylation and downregulation of C1R, C1S, C3, C6, C4BPA, and SERPING1, as well as hypomethylation (P<0.0005) and upregulation (P<0.05) of C5AR1, C7, and CD59, in association with the histological severity of MASLD. Furthermore, DNA methylation and the relative expression of nine complement genes in a MASH diet mouse model aligned with human data. CONCLUSION Our research provides compelling evidence that epigenetic alterations in complement genes correlate with MASLD severity, offering valuable insights into the mechanisms driving MASLD progression, and suggests that inhibiting the function of certain complement proteins may be a promising strategy for managing MASLD.
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Affiliation(s)
- Amal Magdy
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Hee-Jin Kim
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Hanyong Go
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Jun Min Lee
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Hyun Ahm Sohn
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Keeok Haam
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Hyo-Jung Jung
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Jong-Lyul Park
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - Taekyeong Yoo
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Eun-Soo Kwon
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Biomolecular Science, KRIBB School of Bioscience, UST, Daejeon, Korea
| | - Dong Hyeon Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Murim Choi
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Keon Wook Kang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Mirang Kim
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
| | - on behalf of the Innovative Target Exploration of NAFLD (ITEN) Consortium
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
- Department of Biomolecular Science, KRIBB School of Bioscience, UST, Daejeon, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
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Chen Z, Ding C, Chen K, Lu C, Li Q. Exploring the impact of inflammatory cytokines on alcoholic liver disease: a Mendelian randomization study with bioinformatics insights into potential biological mechanisms. THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2024; 50:643-658. [PMID: 39321414 DOI: 10.1080/00952990.2024.2402569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 09/05/2024] [Accepted: 09/05/2024] [Indexed: 09/27/2024]
Abstract
Background: Alcoholic liver disease (ALD) significantly contributes to global morbidity and mortality. The role of inflammatory cytokines in alcohol-induced liver injury is pivotal yet not fully elucidated.Objectives: To establish a causal link between inflammatory cytokines and ALD using a Mendelian Randomization (MR) framework.Methods: This MR study utilized genome-wide significant variants as instrumental variables (IVs) for assessing the relationship between inflammatory cytokines and ALD risk, focusing on individuals of European descent. The approach was supported by comprehensive sensitivity analyses and augmented by bioinformatics tools including differential gene expression, protein-protein interactions (PPI), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and analysis of immune cell infiltration.Results: Our findings reveal that increased levels of stem cell growth factor beta (SCGF-β, beta = 0.141, p = .032) and interleukin-7 (IL-7, beta = 0.311, p = .002) are associated with heightened ALD risk, whereas higher levels of macrophage inflammatory protein-1α (MIP-1α, beta = -0.396, p = .004) and basic fibroblast growth factor (bFGF, beta = -0.628, p = .008) are linked to reduced risk. The sensitivity analyses support these robust causal relationships. Bioinformatics analyses around inflammatory cytokine-associated SNP loci suggest multiple pathways through which cytokines influence ALD.Conclusion: The genetic evidence from this study convincingly demonstrates that certain inflammatory cytokines play directional roles in ALD pathogenesis. These findings provide insights into the complex biological pathways involved and underscore the potential for developing targeted therapies that modulate these inflammatory responses, ultimately improving clinical outcomes for ALD patients.
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Affiliation(s)
- Zhitao Chen
- Department of Hepatobiliary Surgery, International Medical College, Shulan (Hangzhou) Hospital, Zhejiang Shuren University Shulan, Hangzhou, China
| | - Chenchen Ding
- Mental Health Centre & Hangzhou Seventh People's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Kailei Chen
- School of Medicine, Zhejiang Shuren University, Hangzhou, China
| | - Chicheng Lu
- School of Medicine, Zhejiang Shuren College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiyong Li
- Department of Hepatobiliary Surgery, International Medical College, Shulan (Hangzhou) Hospital, Zhejiang Shuren University Shulan, Hangzhou, China
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Nguyen VD, Hughes TR, Zhou Y. From complement to complosome in non-alcoholic fatty liver disease: When location matters. Liver Int 2024; 44:316-329. [PMID: 38010880 DOI: 10.1111/liv.15796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 10/21/2023] [Accepted: 11/09/2023] [Indexed: 11/29/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a growing public health threat and becoming the leading cause of liver transplantation. Nevertheless, no approved specific treatment is currently available for NAFLD. The pathogenesis of NAFLD is multifaceted and not yet fully understood. Accumulating evidence suggests a significant role of the complement system in the development and progression of NAFLD. Here, we provide an overview of the complement system, incorporating the novel concept of complosome, and summarise the up-to-date evidence elucidating the association between complement dysregulation and the pathogenesis of NAFLD. In this process, the extracellular complement system is activated through various pathways, thereby directly contributing to, or working together with other immune cells in the disease development and progression. We also introduce the complosome and assess the evidence that implicates its potential influence in NAFLD through its direct impact on hepatocytes or non-parenchymal liver cells. Additionally, we expound upon how complement system and the complosome may exert their effects in relation with hepatic zonation in NAFLD. Furthermore, we discuss the potential therapeutic implications of targeting the complement system, extracellularly and intracellularly, for NAFLD treatment. Finally, we present future perspectives towards a better understanding of the complement system's contribution to NAFLD.
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Affiliation(s)
- Van-Dien Nguyen
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK
| | - Timothy R Hughes
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK
| | - You Zhou
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK
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Jiang K, Lu S, Li D, Liu M, Jin H, Lei B, Wang S, Long K, He S, Zhong F. Blockade of C5aR1 alleviates liver inflammation and fibrosis in a mouse model of NASH by regulating TLR4 signaling and macrophage polarization. J Gastroenterol 2023; 58:894-907. [PMID: 37227481 PMCID: PMC10423130 DOI: 10.1007/s00535-023-02002-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 05/14/2023] [Indexed: 05/26/2023]
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH) is an advanced form of chronic fatty liver disease, which is a driver of hepatocellular carcinoma. However, the roles of the C5aR1 in the NASH remain poorly understood. Here, we aimed to investigate the functions and mechanisms of the C5aR1 on hepatic inflammation and fibrosis in murine NASH model. METHODS Mice were fed a normal chow diet with corn oil (ND + Oil), a Western diet with corn oil (WD + Oil) or a Western diet with carbon tetrachloride (WD + CCl4) for 12 weeks. The effects of the C5a-C5aR1 axis on the progression of NASH were analyzed and the underlying mechanisms were explored. RESULTS Complement factor C5a was elevated in NASH mice. C5 deficiency reduced hepatic lipid droplet accumulation in the NASH mice. The hepatic expression levels of TNFα, IL-1β and F4/80 were decreased in C5-deficient mice. C5 loss alleviated hepatic fibrosis and downregulated the expression levels of α-SMA and TGFβ1. C5aR1 deletion reduced inflammation and fibrosis in NASH mice. Transcriptional profiling of liver tissues and KEGG pathway analysis revealed that several pathways such as Toll-like receptor signaling, NFκB signaling, TNF signaling, and NOD-like receptor signaling pathway were enriched between C5aR1 deficiency and wild-type mice. Mechanistically, C5aR1 deletion decreased the expression of TLR4 and NLRP3, subsequently regulating macrophage polarization. Moreover, C5aR1 antagonist PMX-53 treatment mitigated the progression of NASH in mice. CONCLUSIONS Blockade of the C5a-C5aR1 axis reduces hepatic steatosis, inflammation, and fibrosis in NASH mice. Our data suggest that C5aR1 may be a potential target for drug development and therapeutic intervention of NASH.
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Affiliation(s)
- Keqing Jiang
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, 530021, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, 530021, China
| | - Shibang Lu
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, 530021, China
| | - Dongxiao Li
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, 530021, China
| | - Mingjiang Liu
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, 530021, China
| | - Hu Jin
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, 530021, China
| | - Biao Lei
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, 530021, China
| | - Sifan Wang
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, 530021, China
| | - Kang Long
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, 530021, China
| | - Songqing He
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, 530021, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, 530021, China
| | - Fudi Zhong
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, 530021, China.
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, 530021, China.
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Zhao J, Wu Y, Lu P, Wu X, Han J, Shi Y, Liu Y, Cheng Y, Gao L, Zhao J, Wang Z, Fan X. Association of complement components with the risk and severity of NAFLD: A systematic review and meta-analysis. Front Immunol 2022; 13:1054159. [PMID: 36569882 PMCID: PMC9782972 DOI: 10.3389/fimmu.2022.1054159] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 11/18/2022] [Indexed: 12/14/2022] Open
Abstract
Background It is generally believed that complement system is strongly associated with the risk of nonalcoholic fatty liver disease (NAFLD). However, complement system contains a variety of complement components, and the relationship between complement components and the risk and severity of NAFLD is inconsistent. The aim of this meta-analysis was to evaluate the association of complement components with the risk and severity of NAFLD. Methods We searched PubMed, Embase, Cochrane Library, Google Scholar, Scopus, and ZhiWang Chinese databases from inception to May 2022 for observational studies reporting the risk of NAFLD with complement components. Random-effects meta-analysis was used to obtain pooled estimates of the effect due to heterogeneity. Results We identified 18 studies with a total of 18560 included subjects. According to recent studies, levels of complement component 3 (C3) (mean difference (MD): 0.43, 95% confidence interval (CI) 0.26-0.60), complement component 4 (C4) (MD: 0.04, 95% CI 0.02-0.07), complement component 5(C5) (MD: 34.03, 95% CI 30.80-37.27), complement factor B (CFB) (MD: 0.22, 95% CI 0.13-0.31) and acylation stimulating protein (ASP) (standard mean difference (SMD): 5.17, 95% CI 2.57-7.77) in patients with NAFLD were significantly higher than those in the control group. However, no statistical significance was obtained in complement factor D (CFD) levels between NAFLD and non-NAFLD (MD=156.51, 95% CI -59.38-372.40). Moreover, the levels of C3, C5, CFB, and ASP in patients with moderate and severe NAFLD were significantly higher than those in patients with mild NAFLD. Except for C4 and CFD, the included studies did not explore the changes in the severity of NAFLD according to the concentration of C4 and CFD. Conclusions This meta-analysis demonstrates that an increase in complement components including C3, C5, CFB, and ASP is associated with an increased risk and severity of NAFLD, indicating that they may be good biomarkers and targets for the diagnosis and treatment of NAFLD. Systematic review registration PROSPERO [https://www.crd.york.ac.uk/PROSPERO/], identifier CRD42022348650.
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Affiliation(s)
- Jianbo Zhao
- Clinical Medical College, Ningxia Medical University, Yinchuan, Ningxia, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Yafei Wu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Peng Lu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Xiaoqin Wu
- Department of Inflammation and Immunity, Cleveland Clinic, OH, Cleveland, United States
| | - Junming Han
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Yingzhou Shi
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Yue Liu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Yiping Cheng
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Ling Gao
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Jiajun Zhao
- Clinical Medical College, Ningxia Medical University, Yinchuan, Ningxia, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Zhen Wang
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Xiude Fan
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
- Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China
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9
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Guo Z, Fan X, Yao J, Tomlinson S, Yuan G, He S. The role of complement in nonalcoholic fatty liver disease. Front Immunol 2022; 13:1017467. [PMID: 36248852 PMCID: PMC9562907 DOI: 10.3389/fimmu.2022.1017467] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 09/13/2022] [Indexed: 11/14/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become a leading cause of chronic liver diseases globally. NAFLD includes a range of hepatic manifestations, starting with liver steatosis and potentially evolving towards nonalcoholic steatohepatitis, cirrhosis or even hepatocellular carcinoma. Although the pathogenesis of NAFLD is incompletely understood, insulin resistance and lipid metabolism disorder are implicated. The complement system is an essential part of the immune system, but it is also involved in lipid metabolism. In particular, activation of the alternative complement pathway and the production of complement activation products such as C3a, C3adesArg (acylation stimulating protein or ASP) and C5a, are strongly associated with insulin resistance, lipid metabolism disorder, and hepatic inflammation. In this review, we briefly summarize research on the role of the complement system in NAFLD, aiming to provide a basis for the development of novel therapeutic strategies for NAFLD.
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Affiliation(s)
- Zhenya Guo
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, China
| | - Xiude Fan
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jianni Yao
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, China
| | - Stephen Tomlinson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
| | - Guandou Yuan
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, China
| | - Songqing He
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
- Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, China
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10
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Seidel F, Kleemann R, van Duyvenvoorde W, van Trigt N, Keijzer N, van der Kooij S, van Kooten C, Verschuren L, Menke A, Kiliaan AJ, Winter J, Hughes TR, Morgan BP, Baas F, Fluiter K, Morrison MC. Therapeutic Intervention with Anti-Complement Component 5 Antibody Does Not Reduce NASH but Does Attenuate Atherosclerosis and MIF Concentrations in Ldlr-/-.Leiden Mice. Int J Mol Sci 2022; 23:ijms231810736. [PMID: 36142647 PMCID: PMC9506266 DOI: 10.3390/ijms231810736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/07/2022] [Accepted: 09/10/2022] [Indexed: 11/30/2022] Open
Abstract
Background: Chronic inflammation is an important driver in the progression of non-alcoholic steatohepatitis (NASH) and atherosclerosis. The complement system, one of the first lines of defense in innate immunity, has been implicated in both diseases. However, the potential therapeutic value of complement inhibition in the ongoing disease remains unclear. Methods: After 20 weeks of high-fat diet (HFD) feeding, obese Ldlr-/-.Leiden mice were treated twice a week with an established anti-C5 antibody (BB5.1) or vehicle control. A separate group of mice was kept on a chow diet as a healthy reference. After 12 weeks of treatment, NASH was analyzed histopathologically, and genome-wide hepatic gene expression was analyzed by next-generation sequencing and pathway analysis. Atherosclerotic lesion area and severity were quantified histopathologically in the aortic roots. Results: Anti-C5 treatment considerably reduced complement system activity in plasma and MAC deposition in the liver but did not affect NASH. Anti-C5 did, however, reduce the development of atherosclerosis, limiting the total lesion size and severity independently of an effect on plasma cholesterol but with reductions in oxidized LDL (oxLDL) and macrophage migration inhibitory factor (MIF). Conclusion: We show, for the first time, that treatment with an anti-C5 antibody in advanced stages of NASH is not sufficient to reduce the disease, while therapeutic intervention against established atherosclerosis is beneficial to limit further progression.
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Affiliation(s)
- Florine Seidel
- Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
- Department Medical Imaging, Anatomy, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, 6525 EZ Nijmegen, The Netherlands
- Correspondence:
| | - Robert Kleemann
- Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
| | - Wim van Duyvenvoorde
- Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
| | - Nikki van Trigt
- Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
| | - Nanda Keijzer
- Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
| | - Sandra van der Kooij
- Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Cees van Kooten
- Department of Internal Medicine (Nephrology) and Transplant Center, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Lars Verschuren
- Department of Microbiology and Systems Biology, Netherlands Organisation for Applied Scientific Research (TNO), 3704 HE Zeist, The Netherlands
| | - Aswin Menke
- Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
| | - Amanda J. Kiliaan
- Department Medical Imaging, Anatomy, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, 6525 EZ Nijmegen, The Netherlands
| | - Johnathan Winter
- Complement Biology Group, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
- UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
| | - Timothy R. Hughes
- Complement Biology Group, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
- UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
| | - B. Paul Morgan
- Complement Biology Group, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
- UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
| | - Frank Baas
- Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Kees Fluiter
- Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Martine C. Morrison
- Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands
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11
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Xing Y, Xu C, Lin X, Zhao M, Gong D, Liu L, Geng T. Complement C3 participates in the development of goose fatty liver potentially by regulating the expression of FASN and ETNK1. Anim Sci J 2021; 92:e13527. [PMID: 33615637 DOI: 10.1111/asj.13527] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 11/24/2020] [Accepted: 01/21/2021] [Indexed: 12/13/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) occurs in humans, domestic animals and poultry. Different from upregulation of complement C3 in human NAFLD, C3 expression is inhibited in goose fatty liver (GFL), implying a specific role of C3 in GFL. This study was mainly focused on uncovering the uniqueness of goose liver cells in the regulation of C3 expression and identifying the downstream genes of C3 to improve understanding on the specific role of C3 in GFL. The results showed that C3 expression was inhibited in the liver, muscle and fat tissues of the overfed versus control (normally fed) geese. Oleate and insulin could inhibit C3 expression in goose primary hepatocytes but induce it in mouse primary hepatocytes. A total of 1,123 differentially expressed genes (DEGs) were affected by C3 overexpression and were mainly enriched in immune response/inflammation and catabolism-related KEGG pathways. Additionally, the representative downstream genes (FASN and ETNK1) of C3 could mediate the role of C3 in the development of GFL. In conclusion, the suppression of C3 in GFL is at least partially attributed to hyperinsulinemia, hyperlipidemia and uniqueness of goose liver cells. Complement C3 does not only affect hepatic steatosis but also affect inflammation/immune response in GFL.
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Affiliation(s)
- Ya Xing
- Institute of Epigenetics and Epigenomics, Yangzhou University, Yangzhou, P. R. China.,College of Animal Science and Technology, Yangzhou University, Yangzhou, P. R. China
| | - Cheng Xu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, P. R. China
| | - Xiao Lin
- College of Animal Science and Technology, Yangzhou University, Yangzhou, P. R. China
| | - Minmeng Zhao
- College of Animal Science and Technology, Yangzhou University, Yangzhou, P. R. China
| | - Daoqing Gong
- College of Animal Science and Technology, Yangzhou University, Yangzhou, P. R. China
| | - Long Liu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, P. R. China
| | - Tuoyu Geng
- Institute of Epigenetics and Epigenomics, Yangzhou University, Yangzhou, P. R. China.,College of Animal Science and Technology, Yangzhou University, Yangzhou, P. R. China
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12
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Santiesteban-Lores LE, Carneiro MC, Isaac L, Bavia L. Complement System in Alcohol-Associated Liver Disease. Immunol Lett 2021; 236:37-50. [PMID: 34111475 DOI: 10.1016/j.imlet.2021.05.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/20/2021] [Accepted: 05/25/2021] [Indexed: 12/19/2022]
Abstract
Innate immunity contributes effectively to the development of Alcohol-Associated liver disease (ALD). Particularly, human studies and murine models of ALD have shown that Complement activation plays an important role during the initial and later stages of ALD. The Complement System may contribute to the pathogenesis of this disease since it has been shown that ethanol-derived metabolic products activate the Complement cascade on liver membranes, leading to hepatocellular damage. However, studies evaluating the plasma levels of Complement proteins in ALD patients present contradictory results in some cases, and do not establish a well-marked role for each Complement component. The impairment of leukocyte chemoattractant activity observed in these patients may contribute to the susceptibility to bacterial infections in the latter stages of the disease. On the other hand, murine models of ALD have provided more detailed insights into the mechanisms that link the Complement System to the pathogenesis of the disease. It has been observed that Classical pathway can be activated via C1q binding to apoptotic cells in the liver and contributes to the development of hepatic inflammation. C3 contributes to the accumulation of triglycerides in the liver and in adipose tissue, while C5 seems to be involved with inflammation and liver injury after chronic ethanol consumption. In this review, we present a compendium of studies evaluating the role of Complement in human and murine models of ALD. We also discuss potential therapies to human ALD, highlighting the use of Complement inhibitors.
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Affiliation(s)
| | | | - Lourdes Isaac
- Institute of Biomedical Sciences, University of São Paulo, Brazil
| | - Lorena Bavia
- Institute of Biomedical Sciences, University of São Paulo, Brazil.
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13
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Identification of targets of JS-K against HBV-positive human hepatocellular carcinoma HepG2.2.15 cells with iTRAQ proteomics. Sci Rep 2021; 11:10381. [PMID: 34001947 PMCID: PMC8129129 DOI: 10.1038/s41598-021-90001-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 04/22/2021] [Indexed: 12/05/2022] Open
Abstract
JS-K, a nitric oxide-releasing diazeniumdiolates, is effective against various tumors. We have discovered that JS-K was effective against Hepatitis B virus (HBV)-positive HepG2.2.15 cells. This study used iTRAQ to identify differentially expressed proteins following JS-K treatment of HepG2.2.15 cells. Silenced Transgelin (shTAGLN-2.15) cells were constructed, and the cell viability was analyzed by the CCK8 assay after treatment with JS-K. There were 182 differentially expressed proteins in JS-K treated-HepG2.2.15 cells; 73 proteins were up-regulated and 109 proteins were down-regulated. These proteins were categorized according to GO classification. KEGG enrichment analysis showed that Endocytosis, Phagosome and Proteoglycans were the most significant pathways. RT-PCR confirmed that the expression levels of TAGLN, IGFBP1, SMTN, SERPINE1, ANXA3, TMSB10, LGALS1 and KRT19 were significantly up-regulated, and the expression levels of C5, RBP4, CHKA, SIRT5 and TRIM14 were significantly down-regulated in JS-K treated-HepG2.2.15 cells. Western blotting confirmed the increased levels of USP13 and TAGLN proteins in JS-K treated-HepG2.2.15 cells. Molecular docking revealed the binding of JS-K to TAGLN and shTAGLN-2.15 cells were resistant to JS-K cytotoxicity, suggesting that TAGLN could be an important target in JS-K anti-HBV-positive liver cancer cells. These proteomic findings could shed new insights into mechanisms underlying the effect of JS-K against HBV-related HCC.
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14
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A/J mice are more susceptible than C57BL/6 to acetaminophen-induced hepatotoxicity. J Pharmacol Toxicol Methods 2021; 108:106960. [PMID: 33766729 DOI: 10.1016/j.vascn.2021.106960] [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: 11/24/2020] [Revised: 02/02/2021] [Accepted: 02/28/2021] [Indexed: 11/20/2022]
Abstract
Acetaminophen (APAP) is commonly used to treat fever and pain. However, when in overdose is the predominant cause of hepatotoxicity. Despite advances in understanding the mechanisms of APAP-induced hepatotoxicity, the management of acute liver failure remains a challenge. Thus, more relevant experimental models are crucial to provide a better understanding of this condition. The aim of this study is to evaluate the effect of APAP-induced hepatotoxicity on A/J mice using C57BL/6 as reference experimental model. Eight- to ten-week-old male A/J and C57BL/6 mice were treated with APAP (300 or 500 mg/kg) by intraperitoneal injection. After 24 h total blood leukocyte counting, plasma levels of alanine amino transferase (ALT) and aspartate amino transferase (AST), histopathological analysis of liver, lung and kidney were evaluated. A/J mice presented reduction in circulating leukocytes concomitant with the increase in plasma levels of ALT and AST, and liver necrosis when treated with 300 and 500 mg/kg of APAP. C57BL/6 mice presented similar results only with 500 mg/kg of APAP. Our results show that A/J mice have a marked susceptibility to the effects of APAP and could be considered as an experimental model to study APAP-induced toxicity.
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15
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Núñez K, Hamed M, Fort D, Bruce D, Thevenot P, Cohen A. Links between donor macrosteatosis, interleukin-33 and complement after liver transplantation. World J Transplant 2020; 10:117-128. [PMID: 32864357 PMCID: PMC7428792 DOI: 10.5500/wjt.v10.i5.117] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 04/07/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND As prevalence of nonalcoholic fatty liver disease increases in the population, livers with steatosis will continue to infiltrate the donor pool. Safe utilization of these extended criteria grafts is paramount given the increased risk associated with their use in transplantation. Prognostic factors that can predict liver dysfunction immediately after transplantation with macrosteatotic grafts are lacking.
AIM To understand the relationship between interleukin-33 (IL-33) and complement in recipients immediately following liver reperfusion as a marker of liver dysfunction.
METHODS Cohort consisted of patients who received a liver transplant from September 2016–September 2019 at our institution. Clinical variables were retrospectively extracted from the electronic medical record. Back-table donor biopsies were obtained with donor steatosis percentage retrospectively determined by a board-certified pathologist. Blood samples were available immediately following liver transplantation. Quantification of plasma IL-33 and complement proteins, C3a and C5a, were determined by enzyme-linked immunosorbent assay. For mRNA expression, RNA was extracted from donor biopsies and used against a 780 gene panel.
RESULTS Cohort consisted of 99 donor and recipients. Donor median age was 45 years and 55% male. Recipients had a median age of 59 years with 62% male. The main etiologies were alcoholic hepatitis, nonalcoholic steatohepatitis, and hepatocellular carcinoma. Median MELD-Na at transplant was 21. Donors were grouped based on moderate macrosteatosis (≥ 30%). Recipients implanted with moderate macrosteatotic grafts had significantly higher peak alanine aminotransferase/aspartate aminotransferase (P < 0.001 and P < 0.004), and increased incidence of early allograft dysfunction (60% compared to 18%). Circulating IL-33 levels were significantly elevated in recipients of ≥ 30% macrosteatotic grafts (P < 0.05). Recipients with detectable levels of circulating IL-33 immediately following reperfusion had significantly higher alanine aminotransferase/aspartate aminotransferase (P < 0.05 and P < 0.01). Activated complement (C3a and C5a) were elevated in recipients implanted with moderate macrosteatotic grafts. RNA expression analysis of donor biopsies revealed moderate steatotic grafts upregulated genes inflammatory processes while downregulated hepatocyte-produced complement factors.
CONCLUSION Circulating IL-33 and activated complement levels immediately following liver reperfusion in recipients of moderate macrosteatotic grafts may identify which patients are at risk of early allograft dysfunction.
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Affiliation(s)
- Kelley Núñez
- Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
| | - Mohammad Hamed
- Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
| | - Daniel Fort
- Center for Outcomes and Health Services Research, Research Administration, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
| | - David Bruce
- Multi-Organ Transplant Program, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
| | - Paul Thevenot
- Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
| | - Ari Cohen
- Multi-Organ Transplant Program, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
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16
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Tao S, Zhou T, Saelao P, Wang Y, Zhu Y, Li T, Zhou H, Wang J. Intrauterine Growth Restriction Alters the Genome-Wide DNA Methylation Profiles in Small Intestine, Liver and Longissimus Dorsi Muscle of Newborn Piglets. Curr Protein Pept Sci 2019; 20:713-726. [PMID: 30678618 DOI: 10.2174/1389203720666190124165243] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 12/30/2018] [Accepted: 01/01/2019] [Indexed: 01/20/2023]
Abstract
Intrauterine growth restriction (IUGR) remains a major problem in swine production since the associated low birth weight leads to high rates of pre-weaning morbidity and mortality, and permanent retardation of growth and development. The underlying regulatory mechanisms from the aspects of epigenetic modification has received widespread attention. Studies explore the changes in genome wide methylation in small intestine (SI), liver and longissimus dorsi muscle (LDM) between IUGR and normal birth weight (NBW) newborn piglets using a methylated DNA immunoprecipitation-sequencing (MeDIP-Seq) approach. The data demonstrated that methylated peaks were prominently distributed in distal intergenic regions and the quantities of peaks in IUGR piglets were more than that of NBW piglets. IUGR piglets had relatively high methylated level in promoters, introns and coding exons in all the three tissues. Through KEGG pathway analysis of differentially methylated genes found that 33, 54 and 5 differentially methylated genes in small intestine, liver and longissimus dorsi muscle between NBW and IUGR piglets, respectively, which are related to development and differentiation, carbohydrate and energy metabolism, lipid metabolism, protein turnover, immune response, detoxification, oxidative stress and apoptosis pathway. The objective of this review is to assess the impact of differentially methylation status on developmental delay, metabolic disorders and immune deficiency of IUGR piglets.
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Affiliation(s)
- Shiyu Tao
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Tianjiao Zhou
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Perot Saelao
- Department of Animal Science, University of California, Davis, CA 95616, United States
| | - Ying Wang
- Department of Animal Science, University of California, Davis, CA 95616, United States
| | - Yuhua Zhu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Tiantian Li
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Huaijun Zhou
- Department of Animal Science, University of California, Davis, CA 95616, United States
| | - Junjun Wang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
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17
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Becerra-Verdín EM, Morales Ávila ÚM, García-Galindo HS, Montalvo-González R, Castañeda-Martínez A, Montalvo-González E. Evaluation of biochemical markers in diabetic rats fed diets supplemented with fruit purees. CYTA - JOURNAL OF FOOD 2019. [DOI: 10.1080/19476337.2019.1578267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Eduardo Mendeleev Becerra-Verdín
- Laboratorio de Investigación Clínica e Histología, Unidad Académica de Ciencias Químico Bilógicas y Farmaceúticas, Universidad Autónoma de Nayarit, Tepic Nayarit, Mexico
| | - Úrsula Mireya Morales Ávila
- Laboratorio Integral de Investigación en Alimentos, División de Estudios de Posgrado e Invesgación, Tecnológico Nacional de México/Campus Instituto Tecnológico de Tepic, Tepic Nayarit, Mexico
| | - Hugo Sergio García-Galindo
- UNIDA, División de estudios de Posgrado e Investigación, Tecnológico Nacional de México/Campus Instituto Tecnológico de Veracruz, Veracruz, Mexico
| | - Rubén Montalvo-González
- Laboratorio de Investigación Clínica e Histología, Unidad Académica de Ciencias Químico Bilógicas y Farmaceúticas, Universidad Autónoma de Nayarit, Tepic Nayarit, Mexico
| | - Alfonso Castañeda-Martínez
- Laboratorio de Investigación Clínica e Histología, Unidad Académica de Ciencias Químico Bilógicas y Farmaceúticas, Universidad Autónoma de Nayarit, Tepic Nayarit, Mexico
| | - Efigenia Montalvo-González
- Laboratorio Integral de Investigación en Alimentos, División de Estudios de Posgrado e Invesgación, Tecnológico Nacional de México/Campus Instituto Tecnológico de Tepic, Tepic Nayarit, Mexico
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18
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Núñez K, Thevenot P, Alfadhli A, Cohen A. Complement Activation in Liver Transplantation: Role of Donor Macrosteatosis and Implications in Delayed Graft Function. Int J Mol Sci 2018; 19:ijms19061750. [PMID: 29899265 PMCID: PMC6032339 DOI: 10.3390/ijms19061750] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 05/28/2018] [Accepted: 06/08/2018] [Indexed: 12/16/2022] Open
Abstract
The complement system anchors the innate inflammatory response by triggering both cell-mediated and antibody-mediated immune responses against pathogens. The complement system also plays a critical role in sterile tissue injury by responding to damage-associated molecular patterns. The degree and duration of complement activation may be a critical variable controlling the balance between regenerative and destructive inflammation following sterile injury. Recent studies in kidney transplantation suggest that aberrant complement activation may play a significant role in delayed graft function following transplantation, confirming results obtained from rodent models of renal ischemia/reperfusion (I/R) injury. Deactivating the complement cascade through targeting anaphylatoxins (C3a/C5a) might be an effective clinical strategy to dampen reperfusion injury and reduce delayed graft function in liver transplantation. Targeting the complement cascade may be critical in donor livers with mild to moderate steatosis, where elevated lipid burden amplifies stress responses and increases hepatocyte turnover. Steatosis-driven complement activation in the donor liver may also have implications in rejection and thrombolytic complications following transplantation. This review focuses on the roles of complement activation in liver I/R injury, strategies to target complement activation in liver I/R, and potential opportunities to translate these strategies to transplanting donor livers with mild to moderate steatosis.
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Affiliation(s)
- Kelley Núñez
- Institute of Translational Research, Ochsner Health System, New Orleans, LA 70121, USA.
| | - Paul Thevenot
- Institute of Translational Research, Ochsner Health System, New Orleans, LA 70121, USA.
| | - Abeer Alfadhli
- Institute of Translational Research, Ochsner Health System, New Orleans, LA 70121, USA.
| | - Ari Cohen
- Institute of Translational Research, Ochsner Health System, New Orleans, LA 70121, USA.
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19
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Jin H, Yan C, Xiao T, Yan N, Xu J, Zhou L, Zhou X, Shao Q, Xia S. High fish oil diet promotes liver inflammation and activates the complement system. Mol Med Rep 2018; 17:6852-6858. [PMID: 29512716 DOI: 10.3892/mmr.2018.8687] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 02/28/2018] [Indexed: 11/06/2022] Open
Abstract
Diets rich in n-3 polyunsaturated fatty acid (n-3 PUFA) fish oil (FO) have beneficial effects in obesity‑associated metabolic disease. However, contradictory roles in inflammatory disease intervention have been reported. Our previous work revealed that a high‑FO diet promoted myeloid cell differentiation by modifying the bone marrow microenvironment; however, its effects on liver inflammation and complement system activation remain unknown. By performing ELISA, reverse transcription‑quantitative polymerase chain reaction, flow cytometry and histology on mice fed with high‑FO and low‑fat diets, the present study demonstrated that a 4‑week high‑FO diet promoted liver inflammation in mice without affecting body or liver weight. The livers of high‑FO diet mice exhibited increased infiltration of T cells and CD11b+ Gr‑1+ myeloid cells. Additionally, a higher level of IL‑1β and MCP‑1 mRNA expression was detected, suggesting that the high‑FO diet promoted liver inflammation. Further experiments indicated that the high‑FO diet increased the total hemolytic complement activity (CH50), promoted the production of the membrane attack complex and increased the levels of various complement proteins in vivo, including complement components C3, C4b, C1qb and factor B. Furthermore, higher concentrations of triglyceride were detected in the peripheral blood of high‑FO diet mice, indicating the potential protective roles of n‑3 PUFAs in FO against lipotoxicity in hyperlipidemia. Collectively, the present study demonstrated that high FO intake induced inflammation and activated the complement system in the liver. However, further study is required to determine the exact mechanisms.
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Affiliation(s)
- Huimin Jin
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Cheng Yan
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Tengfei Xiao
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Nannan Yan
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Jie Xu
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Liping Zhou
- Department of Molecular Biology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Xiaoming Zhou
- Department of Pathology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Qixiang Shao
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Sheng Xia
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
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Dang Y, Meng X, Wang S, Li L, Zhang M, Hu M, Xu X, Shen Y, Lv L, Wang R, Li J. Mannose-binding lectin and its roles in immune responses in grass carp (Ctenopharyngodon idella) against Aeromonas hydrophila. FISH & SHELLFISH IMMUNOLOGY 2018; 72:367-376. [PMID: 29129586 DOI: 10.1016/j.fsi.2017.11.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 11/06/2017] [Accepted: 11/07/2017] [Indexed: 06/07/2023]
Abstract
The complement system is a crucial component of the innate immune system that links innate and adaptive immunity via four pathways. Mannose-binding lectin (MBL), the initiating molecule of the lectin pathway, plays a significant role in the innate immune system in mammals and fish. Herein, we identified an MBL homolog (gcMBL) in grass carp (Ctenopharyngodon idella). The full-length 948 bp gcMBL cDNA includes a 741 bp open reading frame encoding a 246 amino acid protein with a signal peptide, collagen triple helix repeat domain, and a C-type lectin-like/link domain. The gcMBL protein shares low similarity with MBL counterparts in other species, and is most closely related to Cyprinus carpio MBL. Transcription of gcMBL was widely distributed in different tissues, and was induced by Aeromonas hydrophila in vivo and in vitro. Expression of gcMBL was also affected by LPS and flagellin stimulation in vitro. In cells over-expressing gcMBL, transcripts of almost all components except gcC5 were up-regulated, and gcMBL, gcIL1β, gcTNF-α, gcIFN, gcCD59, gcC5aR and gcITGβ-2 were significantly up-regulated following exposure to A. hydrophila or stimulation by bacterial PAMPs. Meanwhile, gcMBL deficiency achieved by RNAi down-regulated transcript levels following A. hydrophila challenge, and gcMBL induced NF-κB signalling. These findings indicate a vital role of gcMBL in innate immunity in grass carp.
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Affiliation(s)
- Yunfei Dang
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, PR China; Laboratory of Biochemistry and Molecular Biology, Ningbo University, Ningbo, PR China
| | - Xinzhan Meng
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, PR China
| | - Shentong Wang
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, PR China
| | - Lisen Li
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, PR China
| | - Meng Zhang
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, PR China
| | - Moyan Hu
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, PR China
| | - Xiaoyan Xu
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, PR China; Shanghai Engineering Research Centre of Aquaculture, Shanghai Ocean University, Shanghai, PR China; National Demonstration Centre for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, PR China
| | - Yubang Shen
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, PR China; Shanghai Engineering Research Centre of Aquaculture, Shanghai Ocean University, Shanghai, PR China; National Demonstration Centre for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, PR China
| | - Liqun Lv
- National Demonstration Centre for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, PR China
| | - Rongquan Wang
- Key Laboratory of Conventional Freshwater Fish Breeding and Health Culture Technology Germplasm Resources, Suzhou Shenhang Eco-technology Development Limited Company, Suzhou, PR China
| | - Jiale Li
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Shanghai Ocean University, Shanghai, PR China; Shanghai Engineering Research Centre of Aquaculture, Shanghai Ocean University, Shanghai, PR China; National Demonstration Centre for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, PR China.
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