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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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Radosavljevic T, Brankovic M, Djuretić J, Grujic-Milanovic J, Kovacic M, Jevtic J, Stankovic S, Samardzic J, Vucevic D, Jakovljevic V. Alpinetin Exhibits Antioxidant and Anti-Inflammatory Effects in C57BL/6 Mice with Alcoholic Liver Disease Induced by the Lieber-DeCarli Ethanol Liquid Diet. Int J Mol Sci 2024; 26:86. [PMID: 39795945 PMCID: PMC11720451 DOI: 10.3390/ijms26010086] [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: 10/25/2024] [Revised: 11/14/2024] [Accepted: 11/17/2024] [Indexed: 01/13/2025] Open
Abstract
Alcohol-associated liver disease (ALD) is a common non-communicable chronic liver disease characterized by a spectrum of conditions ranging from steatosis and alcohol-associated steatohepatitis (AH) to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The pathogenesis of ALD involves a complex interplay of various molecular, biochemical, genetic, epigenetic, and environmental factors. While the mechanisms are well studied, therapeutic options remain limited. Alpinetin, a natural flavonoid with antioxidant and anti-inflammatory properties, has shown potential hepatoprotective effects, though its efficacy in ALD remains unexplored. This study investigated the hepatoprotective effects of alpinetin using a Lieber-DeCarli ethanol liquid diet model of ALD in C57BL/6 mice. Mice were divided into three groups: the control group, the ethanol group, and the ethanol group treated with alpinetin. Serum activity of ALT, AST, γ-GT, and ALP was measured to assess liver function, along with antioxidative and oxidative/nitrosative stress markers in liver tissue. Pro-inflammatory cytokines and endoplasmic reticulum (ER) stress parameters in liver tissue were also evaluated. Histological assessment of disease activity was performed using the SALVE grading and staging system. Treatment with alpinetin significantly reduced serum levels of ALT, AST, γ-GT, and oxidative/nitrosative stress markers while increasing antioxidative markers. The levels of pro-inflammatory cytokines and ER stress parameters were significantly decreased. Histological analysis demonstrated reduced steatosis, hepatocyte ballooning, and inflammation. These findings suggest that alpinetin holds promise as a potential therapeutic agent for managing ALD.
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Affiliation(s)
- Tatjana Radosavljevic
- Institute of Pathophysiology “Ljubodrag Buba Mihailović”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Milica Brankovic
- Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (M.B.); (J.S.)
| | - Jasmina Djuretić
- Department of Pathobiology, Faculty of Pharmacy, University of Belgrade, 11000 Belgrade, Serbia;
| | - Jelica Grujic-Milanovic
- Institute for Medical Research, National Institute of the Republic of Serbia, Department of Cardiovascular Research, University of Belgrade, 11000 Belgrade, Serbia;
| | - Marijana Kovacic
- Group of Immunology, Institute for Medical Research, National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia;
| | - Jovan Jevtic
- Institute of Pathology ‘Dr Đorđe Joannović’, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Sanja Stankovic
- Centre for Medical Biochemistry, University Clinical Centre of Serbia, 11000 Belgrade, Serbia;
- Department of Biochemistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Janko Samardzic
- Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (M.B.); (J.S.)
| | - Danijela Vucevic
- Institute of Pathophysiology “Ljubodrag Buba Mihailović”, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Vladimir Jakovljevic
- Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia;
- Center of Excellence for the Study of Redox Balance in Cardiovascular and Metabolic Disorders, University of Kragujevac, 34000 Kragujevac, Serbia
- Department of Human Pathology, First Moscow State Medical University I.M. Sechenov, Trubetskaya Street 8, Str. 2, 119991 Moscow, Russia
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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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Xu KH, Yang DF, Liu MY, Xu W, Li YH, Xiao WJ. Hepatoprotective effects and mechanisms of l-theanine and epigallocatechin gallate combined intervention in alcoholic fatty liver rats. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2024; 104:8230-8239. [PMID: 38873964 DOI: 10.1002/jsfa.13658] [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: 03/20/2024] [Revised: 05/23/2024] [Accepted: 05/29/2024] [Indexed: 06/15/2024]
Abstract
BACKGROUND Chronic excessive alcohol consumption can lead to alcoholic fatty liver, posing substantial health risks. l-Theanine (LTA) and epigallocatechin gallate (EGCG) in tea exert antioxidant and hepatoprotective effects. However, the combined effects of LTA and EGCG on rats with alcoholic fatty liver, and the underlying mechanisms of such effects, remain unclear. In this study, Sprague Dawley (SD) rats were fed with alcohol for 6 weeks to induce alcoholic fatty liver. Subsequently, for another 6 weeks, the rats were administered LTA (200 mg kg-1 day-1), EGCG (200 mg kg-1 day-1), or a combination of LTA with EGCG (40 mg kg-1 day-1 l-Thea +160 mg kg-1 day-1 EGCG), respectively. RESULTS The combined use of LTA and EGCG for alcoholic fatty liver disease had more significant effects than their individual administration. This combination reduced the activity of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as well as the levels of hepatic triglyceride (TG), malondialdehyde (MDA), and reactive oxygen species (ROS) in the rats. The combined intervention also increased hepatic superoxide dismutase (SOD) and glutathione peroxidase activity. Reductions in hepatic fat accumulation and inflammatory responses were observed. The mechanism underlying these effects primarily involved the inhibition of fatty acid synthesis and the alleviation of lipid peroxidation through the downregulation of the mRNA and protein expression of TNF-α, SREBP1c, and CYP2E1 and the upregulation of the mRNA and protein expression of ADH1, ALDH2, Lipin-1, PPARαPPARα, AMPK, and PGC-1α, thereby promoting the oxidative decomposition of fatty acids and reducing the synthesis of cholesterol and glucose. CONCLUSION l-Theanine and EGCG appear to be able to alleviate alcoholic fatty liver by modulating lipid metabolism and ameliorating oxidative stress, indicating their potential as natural active ingredients in anti-alcoholic fatty liver food products. © 2024 Society of Chemical Industry.
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Affiliation(s)
- Kai-Hang Xu
- Key Lab of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, China
| | - Di-Fei Yang
- Key Lab of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, China
| | - Meng-Yuan Liu
- Key Lab of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, China
| | - Wei Xu
- Key Lab of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, China
| | - Yin-Hua Li
- Key Lab of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, China
| | - Wen-Jun Xiao
- Key Lab of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, China
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Roychowdhury S, Pant B, Cross E, Scheraga R, Vachharajani V. Effect of ethanol exposure on innate immune response in sepsis. J Leukoc Biol 2024; 115:1029-1041. [PMID: 38066660 PMCID: PMC11136611 DOI: 10.1093/jleuko/qiad156] [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: 05/10/2023] [Revised: 11/08/2023] [Accepted: 11/17/2023] [Indexed: 01/06/2024] Open
Abstract
Alcohol use disorder, reported by 1 in 8 critically ill patients, is a risk factor for death in sepsis patients. Sepsis, the leading cause of death, kills over 270,000 patients in the United States alone and remains without targeted therapy. Immune response in sepsis transitions from an early hyperinflammation to persistent inflammation and immunosuppression and multiple organ dysfunction during late sepsis. Innate immunity is the first line of defense against pathogen invasion. Ethanol exposure is known to impair innate and adaptive immune response and bacterial clearance in sepsis patients. Specifically, ethanol exposure is known to modulate every aspect of innate immune response with and without sepsis. Multiple molecular mechanisms are implicated in causing dysregulated immune response in ethanol exposure with sepsis, but targeted treatments have remained elusive. In this article, we outline the effects of ethanol exposure on various innate immune cell types in general and during sepsis.
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Affiliation(s)
- Sanjoy Roychowdhury
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
| | - Bishnu Pant
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
| | - Emily Cross
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
| | - Rachel Scheraga
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
- Department of Pulmonary and Critical Care Medicine, Integrated Hospital-Care Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland OH 44195, United States
| | - Vidula Vachharajani
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
- Department of Pulmonary and Critical Care Medicine, Integrated Hospital-Care Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland OH 44195, United States
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Taiwo M, Huang E, Pathak V, Bellar A, Welch N, Dasarathy J, Streem D, McClain CJ, Mitchell MC, Barton BA, Szabo G, Dasarathy S, Schaefer EA, Luther J, Z. Day L, Ouyang X, Suyavaran A, Mehal WZ, Jacobs JM, Goodman RP, Rotroff DM, Nagy LE. Proteomics identifies complement protein signatures in patients with alcohol-associated hepatitis. JCI Insight 2024; 9:e174127. [PMID: 38573776 PMCID: PMC11141929 DOI: 10.1172/jci.insight.174127] [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: 07/24/2023] [Accepted: 03/27/2024] [Indexed: 04/06/2024] Open
Abstract
Diagnostic challenges continue to impede development of effective therapies for successful management of alcohol-associated hepatitis (AH), creating an unmet need to identify noninvasive biomarkers for AH. In murine models, complement contributes to ethanol-induced liver injury. Therefore, we hypothesized that complement proteins could be rational diagnostic/prognostic biomarkers in AH. Here, we performed a comparative analysis of data derived from human hepatic and serum proteome to identify and characterize complement protein signatures in severe AH (sAH). The quantity of multiple complement proteins was perturbed in liver and serum proteome of patients with sAH. Multiple complement proteins differentiated patients with sAH from those with alcohol cirrhosis (AC) or alcohol use disorder (AUD) and healthy controls (HCs). Serum collectin 11 and C1q binding protein were strongly associated with sAH and exhibited good discriminatory performance among patients with sAH, AC, or AUD and HCs. Furthermore, complement component receptor 1-like protein was negatively associated with pro-inflammatory cytokines. Additionally, lower serum MBL associated serine protease 1 and coagulation factor II independently predicted 90-day mortality. In summary, meta-analysis of proteomic profiles from liver and circulation revealed complement protein signatures of sAH, highlighting a complex perturbation of complement and identifying potential diagnostic and prognostic biomarkers for patients with sAH.
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Affiliation(s)
| | | | - Vai Pathak
- Department of Quantitative Health Sciences, and
| | | | - Nicole Welch
- Department of Inflammation and Immunity
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jaividhya Dasarathy
- Department of Family Medicine, Metro Health Medical Center, Cleveland, Ohio, USA
| | - David Streem
- Department of Psychiatry and Psychology, Cleveland Clinic Lutheran Hospital, Cleveland, Ohio, USA
| | - Craig J. McClain
- Department of Medicine, University of Louisville, Louisville, Kentucky, USA
| | - Mack C. Mitchell
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Bruce A. Barton
- Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Srinivasan Dasarathy
- Department of Inflammation and Immunity
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | | | - Esperance A. Schaefer
- Alcohol Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Jay Luther
- Alcohol Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Le Z. Day
- Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington, USA
| | - Xinshou Ouyang
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Arumugam Suyavaran
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Wajahat Z. Mehal
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
- West Haven VA Medical Center, West Haven, Connecticut, USA
| | - Jon M. Jacobs
- Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington, USA
| | - Russell P. Goodman
- Alcohol Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Endocrine Unit, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Daniel M. Rotroff
- Department of Quantitative Health Sciences, and
- Endocrine and Metabolism Institute and
- Center for Quantitative Metabolic Research, Cleveland Clinic, Cleveland, Ohio, USA
| | - Laura E. Nagy
- Department of Inflammation and Immunity
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
- See Supplemental Acknowledgments for information on the AlcHepNet Consortium
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7
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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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Tiniakos DG, Anstee QM, Brunt EM, Burt AD. Fatty Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:330-401. [DOI: 10.1016/b978-0-7020-8228-3.00005-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Jung E, Baek EB, Hong EJ, Kang JH, Park S, Park S, Hong EJ, Cho YE, Ko JW, Won YS, Kwon HJ. TXNIP in liver sinusoidal endothelial cells ameliorates alcohol-associated liver disease via nitric oxide production. Int J Biol Sci 2024; 20:606-620. [PMID: 38169654 PMCID: PMC10758096 DOI: 10.7150/ijbs.90781] [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: 10/05/2023] [Accepted: 12/02/2023] [Indexed: 01/05/2024] Open
Abstract
Dysregulation of liver sinusoidal endothelial cell (LSEC) differentiation and function has been reported in alcohol-associated liver disease (ALD). Impaired nitric oxide (NO) production stimulates LSEC capillarization and dysfunction; however, the mechanism underlying NO production remains unclear. Here, we investigated the role of thioredoxin-interacting protein (TXNIP), an important regulator of redox homeostasis, in endothelial cell NO production and its subsequent effects on ALD progression. We found that hepatic TXNIP expression was upregulated in patients with ALD and in ethanol diet-fed mice with high expression in LSECs. Endothelial cell-specific Txnip deficiency (TxnipΔEC) in mice exacerbated alcohol-induced liver injury, inflammation, fibrosis, and hepatocellular carcinoma development. Deletion of Txnip in LSECs led to sinusoidal capillarization, downregulation of NO production, and increased release of proinflammatory cytokines and adhesion molecules, whereas TXNIP overexpression had the opposite effects. Mechanistically, TXNIP interacted with transforming growth factor β-activated kinase 1 (TAK1) and subsequently suppressed the TAK1 pathway. Inhibition of TAK1 activation restored NO production and decreased the levels of proinflammatory cytokines, thereby, blocking liver injury and inflammation in TxnipΔEC mice. Our findings indicate that upregulated TXNIP expression in LSECs serves a protective role in ameliorating ALD. Enhancing TXNIP expression could, therefore, be a potential therapeutic approach for ALD.
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Affiliation(s)
- Eunhye Jung
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Eun Bok Baek
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Eun-Ju Hong
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Jee Hyun Kang
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Suyoung Park
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Sehee Park
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 28116, Republic of Korea
| | - Eui-Ju Hong
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Young-Eun Cho
- Andong National University, Andong 36729, Republic of Korea
| | - Je-Won Ko
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Young-Suk Won
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 28116, Republic of Korea
| | - Hyo-Jung Kwon
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea
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10
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Shi Y, Dong H, Sun S, Wu X, Fang J, Zhao J, Han J, Li Z, Wu H, Liu L, Wu W, Tian Y, Yuan G, Fan X, Xu C. Protein-centric omics analysis reveals circulating complements linked to non-viral liver diseases as potential therapeutic targets. Clin Mol Hepatol 2024; 30:80-97. [PMID: 38061333 PMCID: PMC10776287 DOI: 10.3350/cmh.2023.0343] [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: 09/03/2023] [Revised: 12/04/2023] [Accepted: 12/07/2023] [Indexed: 01/11/2024] Open
Abstract
BACKGROUND/AIMS To evaluate the causal correlation between complement components and non-viral liver diseases and their potential use as druggable targets. METHODS We conducted Mendelian randomization (MR) to assess the causal role of circulating complements in the risk of non-viral liver diseases. A complement-centric protein interaction network was constructed to explore biological functions and identify potential therapeutic options. RESULTS In the MR analysis, genetically predicted levels of complement C1q C chain (C1QC) were positively associated with the risk of autoimmune hepatitis (odds ratio 1.125, 95% confidence interval 1.018-1.244), while complement factor H-related protein 5 (CFHR5) was positively associated with the risk of primary sclerosing cholangitis (PSC;1.193, 1.048- 1.357). On the other hand, CFHR1 (0.621, 0.497-0.776) and CFHR2 (0.824, 0.703-0.965) were inversely associated with the risk of alcohol-related cirrhosis. There were also significant inverse associations between C8 gamma chain (C8G) and PSC (0.832, 0.707-0.979), as well as the risk of metabolic dysfunction-associated steatotic liver disease (1.167, 1.036-1.314). Additionally, C1S (0.111, 0.018-0.672), C7 (1.631, 1.190-2.236), and CFHR2 (1.279, 1.059-1.546) were significantly associated with the risk of hepatocellular carcinoma. Proteins from the complement regulatory networks and various liver diseaserelated proteins share common biological processes. Furthermore, potential therapeutic drugs for various liver diseases were identified through drug repurposing based on the complement regulatory network. CONCLUSION Our study suggests that certain complement components, including C1S, C1QC, CFHR1, CFHR2, CFHR5, C7, and C8G, might play a role in non-viral liver diseases and could be potential targets for drug development.
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Affiliation(s)
- Yingzhou Shi
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; 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 Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for 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
| | - Hang Dong
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; 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 Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for 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
| | - Shiwei Sun
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; 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 Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for 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
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
| | - Jiansong Fang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Jianbo Zhao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; 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 Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for 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
- Clinical Medical College, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Junming Han
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; 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 Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for 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
| | - Zongyue Li
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; 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 Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for 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
| | - Huixiao Wu
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; 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 Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for 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
| | - Luna Liu
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; 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 Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for 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
| | - Wanhong Wu
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; 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 Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for 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
| | - Yang Tian
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; 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 Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for 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
| | - Guandou Yuan
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xiude Fan
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; 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 Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for 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
| | - Chao Xu
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; 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 Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- “Chuangxin China” Innovation Base of Stem Cell and Gene Therapy for Endocrine Metabolic diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for 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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Liu Z, Yang M, Shu H, Zhou J. A novel prognostic and therapeutic target biomarker based on complement-related gene signature in gastric cancer. Transl Cancer Res 2023; 12:3565-3580. [PMID: 38192986 PMCID: PMC10774048 DOI: 10.21037/tcr-23-628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 10/18/2023] [Indexed: 01/10/2024]
Abstract
Background Gastric cancer (GC) is one of the most prevalent cancer types that reduce human life expectancy. The current tumor-node-metastasis (TNM) staging system is inadequate in identifying higher or lower risk of GC patients because of tumor heterogeneity. Research shows that complement plays a dual role in the tumor development and progression of GC. Methods We downloaded GC data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A complement-related risk signature was constructed through bioinformatics analysis. Subsequently, the predictive ability of this signature was validated with GSE84437 dataset, and a nomogram integrating risk score and common clinical factors was established. Besides, we evaluated the association of risk score with the immune and stromal cell infiltration in TCGA. Furthermore, immunotherapy response prediction and drug susceptibility analysis were conducted to access the ability of the risk signature in predicting the therapeutic effect. Results A complement-related gene (CRG) signature, based on six genes (SPLG, C9, ITIH1, ZFPM2, CD36, and SERPINE1), was established. In both the training and validation sets, the overall survival of GC patients in the high-risk group was lower than that of the low-risk group, and the nomogram to predict the 1-, 2-, and 3-year survival rates of GC patients was developed. In addition, CIBERSORT algorithm showed the high-risk patients had higher levels of immune cell infiltration than low-risk patients, and the ESTIMATE results implied that the high-risk group had more stromal component in tumor microenvironment. Besides, compared to the low-risk group, there were higher expressions of most immune checkpoint genes and HLA genes in the high-risk group, and the high-risk patients showed higher sensitivity to the chemotherapy and targeted drugs (axitinib, dasatinib, pazopanib, saracatinib, sunitinib and temsirolimus). Conclusions The novel CRG signature may act as a reliable, efficient tool for prognostic prediction and treatment guidance in future clinical practice.
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Affiliation(s)
- Zuming Liu
- Digestive Department, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, China
| | - Mingwei Yang
- Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hang Shu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jianmei Zhou
- Digestive Department, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, China
- Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
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12
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Wang D, Wang J, Wu Y, Liu C, Huang Y, Chen Y, Ding Z, Guan Y, Wu Q. Amelioration of Acute Alcoholic Liver Injury via Attenuating Oxidative Damage and Modulating Inflammation by Means of Ursodeoxycholic Acid-Zein Nanoparticles. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:17080-17096. [PMID: 38104279 DOI: 10.1021/acs.jafc.3c04786] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
Ursodeoxycholic acid (UDCA) has been broadly adopted for the clinical treatment of hepatic and biliary diseases; however, its poor water-solubility becomes an obstacle in wide applications. To overcome these challenges, herein, a two-tier UDCA-embedded system of zein nanoparticles (NPs) along with a polyelectrolyte complex was designed under facile conditions. Both the UDCA-zein NPs and their inclusion microcapsules showed a spherical shape with a uniform size. A typical wall plus capsule/core structure was formed in which UDCA-zein NPs distributed evenly in the interior. The UDCA inclusion microcapsules had an encapsulation rate of 67% and were released in a non-Fickian or anomalous transport manner. The bioavailability and efficacy of UDCA-zein NPs were assessed in vivo through the alcoholic liver disease (ALD) mouse model via intragastric administration. UDCA-zein NPs ameliorated the symptoms of ALD mice remarkably, which were mainly exerted through attenuation of antioxidant stress levels. Meanwhile, it notably upregulated the intestinal tight junction protein expression and improved and maintained the integrity of the mucosal barrier effectively. Collectively, with the improvement of bioavailability, the UDCA-zein NPs prominently alleviated the oxidative damage induced by alcohol, modulating the inflammation so as to restore ALD. It is anticipated that UDCA-zein NPs have great therapeutic potential as sustained-nanovesicles in ALD treatment.
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Affiliation(s)
- Dong Wang
- School of Life Sciences, Key Laboratory of Eco-engineering and Biotechnology of Anhui Province and Anhui Key Laboratory of Modern Biomanufacturing, Anhui University, Hefei 230601, Anhui, PR China
| | - Jing Wang
- School of Life Sciences, Key Laboratory of Eco-engineering and Biotechnology of Anhui Province and Anhui Key Laboratory of Modern Biomanufacturing, Anhui University, Hefei 230601, Anhui, PR China
| | - Yingchao Wu
- School of Life Sciences, Key Laboratory of Eco-engineering and Biotechnology of Anhui Province and Anhui Key Laboratory of Modern Biomanufacturing, Anhui University, Hefei 230601, Anhui, PR China
| | - Caixia Liu
- School of Life Sciences, Key Laboratory of Eco-engineering and Biotechnology of Anhui Province and Anhui Key Laboratory of Modern Biomanufacturing, Anhui University, Hefei 230601, Anhui, PR China
| | - Yuzhe Huang
- School of Life Sciences, Key Laboratory of Eco-engineering and Biotechnology of Anhui Province and Anhui Key Laboratory of Modern Biomanufacturing, Anhui University, Hefei 230601, Anhui, PR China
| | - Yan Chen
- School of Life Sciences, Key Laboratory of Eco-engineering and Biotechnology of Anhui Province and Anhui Key Laboratory of Modern Biomanufacturing, Anhui University, Hefei 230601, Anhui, PR China
| | - Zhifeng Ding
- Department of Chemistry, The University of Western Ontario, London, Ontario N6A 5B7, Canada
| | - Yixin Guan
- College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
| | - Qingxi Wu
- School of Life Sciences, Key Laboratory of Eco-engineering and Biotechnology of Anhui Province and Anhui Key Laboratory of Modern Biomanufacturing, Anhui University, Hefei 230601, Anhui, PR China
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Liu XQ, Wang JJ, Wu X, Liu ZN, Wu BM, Lv XW. Blocking ATP-P1Rs axis attenuate alcohol-related liver fibrosis. Life Sci 2023; 328:121896. [PMID: 37385371 DOI: 10.1016/j.lfs.2023.121896] [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: 04/18/2023] [Revised: 06/17/2023] [Accepted: 06/26/2023] [Indexed: 07/01/2023]
Abstract
AIMS The aim of this study was to explore the fibrogenic effects of ATP-P1Rs axis and ATP-P2Rs axis on alcohol-related liver fibrosis (ALF). MATERIALS AND METHODS C57BL/6J CD73 knock out (KO) mice were used in our study. 8-12 weeks male mice were used as an ALF model in vivo. In conclusion, after one week of adaptive feeding, 5 % alcohol liquid diet was given for 8 weeks. High-concentration alcohol (31.5 %, 5 g/kg) was administered by gavage twice weekly, and 10 % CCl4 intraperitoneal injections (1 ml/kg) were administered twice weekly for the last two weeks. The mice in the control group were injected intraperitoneally with an equivalent volume of normal saline. Fasting for 9 h after the last injection, blood samples were collected, and related indicators were tested. In vitro, rat hepatic stellate cells (HSCs) were treated with 200 μM acetaldehyde to establish an alcoholic liver fibrosis for 48 h, then tested related indicators. KEY FINDINGS We found that both adenosine receptors including adenosine A1, A2A, A2B, A3 receptors (A1R, A2AR, A2BR, A3R) and ATP receptors including P2X7, P2Y2 receptors (P2X7R, P2Y2R) were expressed increased in ALF. After CD73 was knocked out, we found that adenosine receptors expression decreased, ATP expression increased, and fibrosis degree decreased. SIGNIFICANCE Based on the research, we discovered that adenosine plays a more important role in ALF. Therefore, blocking the ATP-P1Rs axis represented a potential treatment for ALF, and CD73 will become a potential therapeutic target.
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Affiliation(s)
- Xue-Qi Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Jun-Jie Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Xue Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Zhen-Ni Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Bao-Ming Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Xiong-Wen Lv
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Institute for Liver Diseases of Anhui Medical University, Hefei, China.
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Wu X, Fan X, Miyata T, Kim A, Cajigas-Du Ross CK, Ray S, Huang E, Taiwo M, Arya R, Wu J, Nagy LE. Recent Advances in Understanding of Pathogenesis of Alcohol-Associated Liver Disease. ANNUAL REVIEW OF PATHOLOGY 2023; 18:411-438. [PMID: 36270295 PMCID: PMC10060166 DOI: 10.1146/annurev-pathmechdis-031521-030435] [Citation(s) in RCA: 99] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Alcohol-associated liver disease (ALD) is one of the major diseases arising from chronic alcohol consumption and is one of the most common causes of liver-related morbidity and mortality. ALD includes asymptomatic liver steatosis, fibrosis, cirrhosis, and alcohol-associated hepatitis and its complications. The progression of ALD involves complex cell-cell and organ-organ interactions. We focus on the impact of alcohol on dysregulation of homeostatic mechanisms and regulation of injury and repair in the liver. In particular, we discuss recent advances in understanding the disruption of balance between programmed cell death and prosurvival pathways, such as autophagy and membrane trafficking, in the pathogenesis of ALD. We also summarize current understanding of innate immune responses, liver sinusoidal endothelial cell dysfunction and hepatic stellate cell activation, and gut-liver and adipose-liver cross talk in response to ethanol. In addition,we describe the current potential therapeutic targets and clinical trials aimed at alleviating hepatocyte injury, reducing inflammatory responses, and targeting gut microbiota, for the treatment of ALD.
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Affiliation(s)
- Xiaoqin Wu
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Xiude Fan
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Tatsunori Miyata
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Adam Kim
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Christina K Cajigas-Du Ross
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Semanti Ray
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Emily Huang
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Moyinoluwa Taiwo
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Rakesh Arya
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Jianguo Wu
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Laura E Nagy
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, USA
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Mackowiak B, Xu M, Lin Y, Guan Y, Seo W, Ren R, Feng D, Jones JW, Wang H, Gao B. Hepatic CYP2B10 is highly induced by binge ethanol and contributes to acute-on-chronic alcohol-induced liver injury. Alcohol Clin Exp Res 2022; 46:2163-2176. [PMID: 36224745 PMCID: PMC9771974 DOI: 10.1111/acer.14954] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 09/10/2022] [Accepted: 10/05/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND The chronic-plus-binge model of ethanol consumption, where chronically (8-week) ethanol-fed mice are gavaged a single dose of ethanol (E8G1), is known to induce steatohepatitis in mice. However, how chronically ethanol-fed mice respond to multiple binges of ethanol remains unknown. METHODS We extended the E8G1 model to three gavages of ethanol (E8G3) spaced 24 h apart, sacrificed each group 9 h after the final gavage, analyzed liver injury, and examined gene expression changes using microarray analyses in each group to identify mechanisms contributing to liver responses to binge ethanol. RESULTS Surprisingly, E8G3 treatment induced lower levels of liver injury, steatosis, inflammation, and fibrosis as compared to mice after E8G1 treatment. Microarray analyses identified several pathways that may contribute to the reduced liver injury after E8G3 treatment compared to E8G1 treatment. The gene encoding cytochrome P450 2B10 (Cyp2b10) was one of the top upregulated genes in the E8G1 group and was further upregulated in the E8G3 group, but only moderately induced after chronic ethanol consumption, as confirmed by RT-qPCR and western blot analyses. Genetic disruption of Cyp2b10 worsened liver injury in E8G1 and E8G3 mice with higher blood ethanol levels compared to wild-type control mice, while in vitro experiments revealed that CYP2b10 did not directly promote ethanol metabolism. Metabolomic analyses revealed significant differences in hepatic metabolites from E8G1-treated Cyp2b10 knockout and WT mice, and these metabolic alterations may contribute to the reduced liver injury in Cyp2b10 knockout mice. CONCLUSION Hepatic Cyp2b10 expression is highly induced after ethanol binge, and such upregulation reduces acute-on-chronic ethanol-induced liver injury via the indirect modification of ethanol metabolism.
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Affiliation(s)
- Bryan Mackowiak
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Mingjiang Xu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yuhong Lin
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yukun Guan
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Wonhyo Seo
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ruixue Ren
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jace W. Jones
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA
| | - Hongbing Wang
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
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Goldberg AR, Ferguson M, Pal S, Cohen R, Orlicky DJ, McCullough RL, Rutkowski JM, Burchill MA, Tamburini BAJ. Oxidized low density lipoprotein in the liver causes decreased permeability of liver lymphatic- but not liver sinusoidal-endothelial cells via VEGFR-3 regulation of VE-Cadherin. Front Physiol 2022; 13:1021038. [PMID: 36338478 PMCID: PMC9626955 DOI: 10.3389/fphys.2022.1021038] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/05/2022] [Indexed: 01/27/2023] Open
Abstract
The lymphatic vasculature of the liver is vital for liver function as it maintains fluid and protein homeostasis and is important for immune cell transport to the lymph node. Chronic liver disease is associated with increased expression of inflammatory mediators including oxidized low-density lipoprotein (oxLDL). Intrahepatic levels of oxLDL are elevated in nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C infection (HCV), alcohol-associated liver disease (ALD), and cholestatic liver diseases. To determine if liver lymphatic function is impaired in chronic liver diseases, in which increased oxLDL has been documented, we measured liver lymphatic function in murine models of NAFLD, ALD and primary sclerosing cholangitis (PSC). We found that Mdr2-/- (PSC), Lieber-DeCarli ethanol fed (ALD) and high fat and high cholesterol diet fed (NAFLD) mice all had a significant impairment in the ability to traffic FITC labeled dextran from the liver parenchyma to the liver draining lymph nodes. Utilizing an in vitro permeability assay, we found that oxLDL decreased the permeability of lymphatic endothelial cells (LEC)s, but not liver sinusoidal endothelial cells (LSEC)s. Here we demonstrate that LECs and LSECs differentially regulate SRC-family kinases, MAPK kinase and VE-Cadherin in response to oxLDL. Furthermore, Vascular Endothelial Growth Factor (VEGF)C or D (VEGFR-3 ligands) appear to regulate VE-Cadherin expression as well as decrease cellular permeability of LECs in vitro and in vivo after oxLDL treatment. These findings suggest that oxLDL acts to impede protein transport through the lymphatics through tightening of the cell-cell junctions. Importantly, engagement of VEGFR-3 by its ligands prevents VE-Cadherin upregulation and improves lymphatic permeability. These studies provide a potential therapeutic target to restore liver lymphatic function and improve liver function.
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Affiliation(s)
- Alyssa R. Goldberg
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology & Nutrition. Children’s Hospital Colorado, Digestive Health Institute- Pediatric Liver Center, University of Colorado School of Medicine, Aurora, CO, United States
| | - Megan Ferguson
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Sarit Pal
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Rachel Cohen
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, United States
| | - David J. Orlicky
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Rebecca L. McCullough
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado School of Medicine, Aurora, CO, United States
| | - Joseph M. Rutkowski
- Division of Lymphatic Biology, Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX, United States
| | - Matthew A. Burchill
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Beth A. Jirón Tamburini
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, United States
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
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Eguchi A, Iwasa M, Sugimoto R, Tempaku M, Yoshikawa K, Yoshizawa N, Povero D, Sugimoto K, Hasegawa H, Takei Y, Nakagawa H. Complement complex 1 subunit q-mediated hepatic stellate cell activation with connective tissue growth factor elevation is a prognostic factor for survival in rat and human chronic liver diseases. Hepatol Commun 2022; 6:3515-3527. [PMID: 36199236 PMCID: PMC9701491 DOI: 10.1002/hep4.2097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 08/23/2022] [Accepted: 09/01/2022] [Indexed: 01/21/2023] Open
Abstract
Complement complex 1 subunit q (C1q) has multiple functions, including cell migration, in addition to its traditional complement-activating effect. Research shows C1q is a ligand for frizzled receptors (FZDs). FZD-induced yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) alternate Wnt signaling activation induces connective tissue growth factor (CTGF) production and hepatic stellate cell (HSC) activation. However, no study exists in which C1q directly induces CTGF in HSCs. Here, we investigated the role of C1q in HSC activation. Human HSCs (LX2) were incubated with C1q to assess HSC activation. C1q and fibrotic markers were assessed using immunohistochemistry, immunoblotting, and quantitative reverse-transcription polymerase chain reaction in cirrhotic rats administered CCl4 for 21 weeks. Serum C1q, liver function, and fibrosis score were measured in 91 patients with chronic liver disease. The correlations between serum C1q and liver function, fibrosis score, and survival prognosis were examined. C1q-activated LX2s showed morphologic changes, up-regulation of CTGF, tissue inhibitors of metalloproteinases (TIMP-1), and alternate Wnt signal genes FZD2, TAZ, and cysteine-rich angiogenic inducer 61 (Cyr61). Cirrhotic rat liver C1q expression correlated with the Azan-positive area and expression of CTGF, TIMP-1, hyaluronan synthase (HAS)1, HAS3, and CD44. Expression of C1q protein and C1q, CTGF, and TIMP-1 genes were higher in deceased cirrhotic rat livers compared to surviving rats. Human serum C1q levels increased in liver cirrhosis compared to chronic hepatitis and correlated with liver fibrosis and functional markers. Ten patients suffered liver-related death over a 66-month observation period. The C1q cut-off value (11 mg/dl) showed patients with serum values < 11 mg/dl had longer rates of survival compared to C1q ≥ 11 mg/dl. Conclusion: C1q-mediated HSC activation in liver fibrosis is associated with CTGF elevation. Additionally, serum C1q may be diagnostic for survival in human chronic liver diseases.
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Affiliation(s)
- Akiko Eguchi
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Motoh Iwasa
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Ryosuke Sugimoto
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Mina Tempaku
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Kyoko Yoshikawa
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Naohiko Yoshizawa
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Davide Povero
- Department of Biochemistry and Molecular BiologyMayo ClinicRochesterMinnesotaUSA
| | - Kazushi Sugimoto
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Hiroshi Hasegawa
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Yoshiyuki Takei
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
| | - Hayato Nakagawa
- Department of Gastroenterology and Hepatology, School of MedicineMie UniversityTsuJapan
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18
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Sasaki-Tanaka R, Ray R, Moriyama M, Ray RB, Kanda T. Molecular Changes in Relation to Alcohol Consumption and Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:ijms23179679. [PMID: 36077080 PMCID: PMC9456124 DOI: 10.3390/ijms23179679] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 08/23/2022] [Accepted: 08/24/2022] [Indexed: 12/12/2022] Open
Abstract
Alcohol is the one of the major causes of liver diseases and promotes liver cirrhosis and hepatocellular carcinoma (HCC). In hepatocytes, alcohol is converted to acetaldehyde, which causes hepatic steatosis, cellular apoptosis, endoplasmic reticulum stress, peroxidation, production of cytokines and reduces immune surveillance. Endotoxin and lipopolysaccharide produced from intestinal bacteria also enhance the production of cytokines. The development of hepatic fibrosis and the occurrence of HCC are induced by these alcohol metabolites. Several host genetic factors have recently been identified in this process. Here, we reviewed the molecular mechanism associated with HCC in alcoholic liver disease.
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Affiliation(s)
- Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
- Correspondence: (R.S.-T.); (T.K.); Tel.: +81-3-3972-8111 (R.S.-T. & T.K.)
| | - Ranjit Ray
- Departments of Internal Medicine, and Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, MO 63104, USA
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Ratna B. Ray
- Department of Pathology, Saint Louis University, Saint Louis, MO 63104, USA
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
- Correspondence: (R.S.-T.); (T.K.); Tel.: +81-3-3972-8111 (R.S.-T. & T.K.)
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19
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Schulz K, Trendelenburg M. C1q as a target molecule to treat human disease: What do mouse studies teach us? Front Immunol 2022; 13:958273. [PMID: 35990646 PMCID: PMC9385197 DOI: 10.3389/fimmu.2022.958273] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 06/24/2022] [Indexed: 11/17/2022] Open
Abstract
The complement system is a field of growing interest for pharmacological intervention. Complement protein C1q, the pattern recognition molecule at the start of the classical pathway of the complement cascade, is a versatile molecule with additional non-canonical actions affecting numerous cellular processes. Based on observations made in patients with hereditary C1q deficiency, C1q is protective against systemic autoimmunity and bacterial infections. Accordingly, C1q deficient mice reproduce this phenotype with susceptibility to autoimmunity and infections. At the same time, beneficial effects of C1q deficiency on disease entities such as neurodegenerative diseases have also been described in murine disease models. This systematic review provides an overview of all currently available literature on the C1q knockout mouse in disease models to identify potential target diseases for treatment strategies focusing on C1q, and discusses potential side-effects when depleting and/or inhibiting C1q.
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Affiliation(s)
- Kristina Schulz
- Laboratory of Clinical Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
- Division of Internal Medicine, University Hospital Basel, Basel, Switzerland
- *Correspondence: Kristina Schulz,
| | - Marten Trendelenburg
- Laboratory of Clinical Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
- Division of Internal Medicine, University Hospital Basel, Basel, Switzerland
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20
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Pan XY, Wang L, You HM, Cheng M, Yang Y, Huang C, Li J. Alternative activation of macrophages by prostacyclin synthase ameliorates alcohol induced liver injury. J Transl Med 2021; 101:1210-1224. [PMID: 34112940 PMCID: PMC8367821 DOI: 10.1038/s41374-021-00531-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 12/19/2020] [Accepted: 12/19/2020] [Indexed: 12/13/2022] Open
Abstract
Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide. Macrophages exhibit different functional states and are classified as classically activated (M1) and alternatively activated (M2) macrophages. However, the mechanisms that govern M1/M2 polarization in chronic ALD remain to be elucidated. Prostacyclin (PGI2) synthase (PTGIS) is an enzyme of the prostaglandin pathway which catalyzes the conversion of Prostaglandin H2 (PGH2) to PGI2. PTGIS has anti-inflammatory properties. However, the function of PTGIS in ALD has not yet been determined. In this study, we demonstrated that PTGIS was downregulated in ALD and forced PTGIS expression in vivo using recombinant adeno-associated viral vector-packed PTGIS overexpression plasmid, which alleviated the inflammatory response and suppressed the macrophage M1 phenotype in mice. Loss- and gain-of function-experiments demonstrated that forced PTGIS expression inhibited the macrophage switch to the M1 phenotype and promoted M2 polarization. Furthermore, we identified the genes regulated by PTGIS through RNA-sequencing (RNA-seq) analysis. Gene ontology and KEGG pathway analyses showed that PTGIS regulates many genes involved in the immune response and is enriched in the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signal transduction pathway, which plays an important role in regulating macrophage polarization. The proteins interacting with JAKs were predicted using the STRING database. The overlap between the RNA-seq and the STRING database was interleukin-6; this indicated that it was involved in macrophage polarization regulated by JAK/STAT signaling. We further explored the microRNAs that could regulate the expression of PTGIS through TargetScan. The results of luciferase assay illustrated that the expression of PTGIS was regulated by miR-140-3p.1. These results imply that PTGIS plays a pivotal role in ALD, partly by influencing macrophage polarization.
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Affiliation(s)
- Xue-Yin Pan
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Ling Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Hong-Mei You
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Miao Cheng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Yang Yang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
- The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China.
- Institute for Liver Diseases of Anhui Medical University, Hefei, China.
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21
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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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22
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Schonfeld M, Villar MT, Artigues A, Weinman SA, Tikhanovich I. Arginine Methylation of Hepatic hnRNPH Suppresses Complement Activation and Systemic Inflammation in Alcohol-Fed Mice. Hepatol Commun 2021; 5:812-829. [PMID: 34027271 PMCID: PMC8122385 DOI: 10.1002/hep4.1674] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/29/2020] [Accepted: 12/17/2020] [Indexed: 01/16/2023] Open
Abstract
Protein arginine methyl transferase 1 (PRMT1) is the main enzyme for cellular arginine methylation. It regulates many aspects of liver biology including inflammation, lipid metabolism, and proliferation. Previously we identified that PRMT1 is necessary for protection from alcohol-induced liver injury. However, many PRMT1 targets in the liver after alcohol exposure are not yet identified. We studied the changes in the PRMT1-dependent arginine methylated proteome after alcohol feeding in mouse liver using mass spectrometry. We found that arginine methylation of the RNA-binding protein (heterogeneous nuclear ribonucleoprotein [hnRNP]) H1 is mediated by PRMT1 and is altered in alcohol-fed mice. PRMT1-dependent methylation suppressed hnRNP H1 binding to several messenger RNAs of complement pathway including complement component C3. We found that PRMT1-dependent hnRNP H methylation suppressed complement component expression in vitro, and phosphorylation is required for this function of PRMT1. In agreement with that finding, hepatocyte-specific PRMT1 knockout mice had an increase in complement component expression in the liver. Excessive complement expression in alcohol-fed PRMT1 knockout mice resulted in further complement activation and an increase in serum C3a and C5a levels, which correlated with inflammation in multiple organs including lung and adipose tissue. Using specific inhibitors to block C3aR and C5aR receptors, we were able to prevent lung and adipose tissue inflammation without affecting inflammation in the liver or liver injury. Conclusion: Taken together, these data suggest that PRMT1-dependent suppression of complement production in the liver is necessary for prevention of systemic inflammation in alcohol-fed mice. C3a and C5a play a role in this liver-lung and liver-adipose interaction in alcohol-fed mice deficient in liver arginine methylation.
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Affiliation(s)
- Michael Schonfeld
- Department of Internal MedicineUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Maria T Villar
- Department of BiochemistryUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Antonio Artigues
- Department of BiochemistryUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Steven A Weinman
- Department of Internal MedicineUniversity of Kansas Medical CenterKansas CityKSUSA.,Liver CenterUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Irina Tikhanovich
- Department of Internal MedicineUniversity of Kansas Medical CenterKansas CityKSUSA
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23
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Fan X, McCullough RL, Huang E, Bellar A, Kim A, Poulsen KL, McClain CJ, Mitchell M, McCullough AJ, Radaeva S, Barton B, Szabo G, Dasarathy S, Rotroff DM, Nagy LE. Diagnostic and Prognostic Significance of Complement in Patients With Alcohol-Associated Hepatitis. Hepatology 2021; 73:983-997. [PMID: 32557728 PMCID: PMC8005264 DOI: 10.1002/hep.31419] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/06/2020] [Accepted: 05/26/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Given the lack of effective therapies and high mortality in acute alcohol-associated hepatitis (AH), it is important to develop rationally designed biomarkers for effective disease management. Complement, a critical component of the innate immune system, contributes to uncontrolled inflammatory responses leading to liver injury, but is also involved in hepatic regeneration. Here, we investigated whether a panel of complement proteins and activation products would provide useful biomarkers for severity of AH and aid in predicting 90-day mortality. APPROACH AND RESULTS Plasma samples collected at time of diagnosis from 254 patients with moderate and severe AH recruited from four medical centers and 31 healthy persons were used to quantify complement proteins by enzyme-linked immunosorbent assay and Luminex arrays. Components of the classical and lectin pathways, including complement factors C2, C4b, and C4d, as well as complement factor I (CFI) and C5, were reduced in AH patients compared to healthy persons. In contrast, components of the alternative pathway, including complement factor Ba (CFBa) and factor D (CFD), were increased. Markers of complement activation were also differentially evident, with C5a increased and the soluble terminal complement complex (sC5b9) decreased in AH. Mannose-binding lectin, C4b, CFI, C5, and sC5b9 were negatively correlated with Model for End-Stage Liver Disease score, whereas CFBa and CFD were positively associated with disease severity. Lower CFI and sC5b9 were associated with increased 90-day mortality in AH. CONCLUSIONS Taken together, these data indicate that AH is associated with a profound disruption of complement. Inclusion of complement, especially CFI and sC5b9, along with other laboratory indicators, could improve diagnostic and prognostic indications of disease severity and risk of mortality for AH patients.
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Affiliation(s)
- Xiude Fan
- Department of Inflammation and ImmunityCleveland ClinicClevelandOHUSA
- Department of Infectious DiseasesFirst Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Rebecca L McCullough
- Department of Pharmaceutical SciencesSkaggs School of Pharmacy and Pharmaceutical SciencesUniversity of Colorado Anschutz Medical CampusAuroraCOUSA
| | - Emily Huang
- Department of Inflammation and ImmunityCleveland ClinicClevelandOHUSA
| | - Annette Bellar
- Department of Inflammation and ImmunityCleveland ClinicClevelandOHUSA
| | - Adam Kim
- Department of Inflammation and ImmunityCleveland ClinicClevelandOHUSA
| | - Kyle L Poulsen
- Department of Inflammation and ImmunityCleveland ClinicClevelandOHUSA
| | - Craig J McClain
- Department of MedicineUniversity of LouisvilleLouisvilleKYUSA
| | - Mack Mitchell
- Internal MedicineUniversity of Texas Southwestern Medical CenterDallasTXUSA
| | | | | | - Bruce Barton
- Department of Population and Quantitative Health SciencesUniversity of Massachusetts Medical SchoolWorcesterMAUSA
| | - Gyongyi Szabo
- Department of MedicineBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA
| | - Srinivasan Dasarathy
- Department of Inflammation and ImmunityCleveland ClinicClevelandOHUSA
- Department of Gastroenterology and HepatologyCleveland ClinicClevelandOHUSA
- Department of Molecular MedicineCase Western Reserve UniversityClevelandOHUSA
| | - Daniel M Rotroff
- Department of Quantitative Health SciencesCleveland ClinicClevelandOHUSA
| | - Laura E Nagy
- Department of Inflammation and ImmunityCleveland ClinicClevelandOHUSA
- Department of Gastroenterology and HepatologyCleveland ClinicClevelandOHUSA
- Department of Molecular MedicineCase Western Reserve UniversityClevelandOHUSA
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24
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Immunological mechanisms and therapeutic targets of fatty liver diseases. Cell Mol Immunol 2020; 18:73-91. [PMID: 33268887 PMCID: PMC7852578 DOI: 10.1038/s41423-020-00579-3] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the two major types of chronic liver disease worldwide. Inflammatory processes play key roles in the pathogeneses of fatty liver diseases, and continuous inflammation promotes the progression of alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH). Although both ALD and NAFLD are closely related to inflammation, their respective developmental mechanisms differ to some extent. Here, we review the roles of multiple immunological mechanisms and therapeutic targets related to the inflammation associated with fatty liver diseases and the differences in the progression of ASH and NASH. Multiple cell types in the liver, including macrophages, neutrophils, other immune cell types and hepatocytes, are involved in fatty liver disease inflammation. In addition, microRNAs (miRNAs), extracellular vesicles (EVs), and complement also contribute to the inflammatory process, as does intertissue crosstalk between the liver and the intestine, adipose tissue, and the nervous system. We point out that inflammation also plays important roles in promoting liver repair and controlling bacterial infections. Understanding the complex regulatory process of disrupted homeostasis during the development of fatty liver diseases may lead to the development of improved targeted therapeutic intervention strategies.
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25
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Sun X, Ye C, Deng Q, Chen J, Guo C. Contribution of glutaredoxin-1 to Fas s-glutathionylation and inflammation in ethanol-induced liver injury. Life Sci 2020; 264:118678. [PMID: 33127518 DOI: 10.1016/j.lfs.2020.118678] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/19/2020] [Accepted: 10/26/2020] [Indexed: 11/17/2022]
Abstract
AIMS The reversible protein S-glutathionylation (PSSG) modification of Fas augments apoptosis, which can be reversed by the cytosolic deglutathionylation enzyme glutaredoxin-1 (Grx1), but its roles in alcoholic liver injury remain unknown. Therefore, the objective of this study was to investigate the impact of genetic ablation of Grx1 on Fas S-glutathionylation (Fas-SSG) in regulating ethanol-induced injury. MATERIALS AND METHODS We evaluated the Grx1 activity and oxidative damage, hepatic injury related indicators, Fas-SSG, we also assess the nuclear factor-κB (NF-κB) signaling, its downstream signal, and Akt signaling cascades, Furthermore, the number of Kupffer cells and related proinflammatory cytokines between WT and Grx1- groups after alcohol exposure. KEY FINDINGS Ethanol-fed mice had increased Grx1 activity and oxidative damage in the liver. Grx1-deficient mice had more serious liver damage when exposed to ethanol compared to that of wild-type mice, accompanied by increased alanine aminotransferase and aspartate aminotransferase levels, Fas-SSG, cleaved caspase-3 and hepatocyte apoptosis. Grx1 ablation resulted in the suppression of ethanol-induced NF-κB signaling, its downstream signal, and Akt signaling cascades, which are required for protection against Fas-mediated apoptosis. Accordingly, blocking NK-κB prevented Fas-induced apoptosis in WT mice but not Grx1-/- mice. Furthermore, the number of Kupffer cells and related proinflammatory cytokines, including Akt, were lower in Grx1-/- livers than those of the controls. SIGNIFICANCE Grx1 is essential for adaptation to alcohol exposure-induced oxidative injury by modulating Fas-SSG and Fas-induced apoptosis.
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Affiliation(s)
- Xiaomin Sun
- Laboratory of Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Ultrasound, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Cuilian Ye
- Laboratory of Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China; School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Qin Deng
- Laboratory of Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Jingyu Chen
- Laboratory of Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Ultrasound, Children's Hospital of Chongqing Medical University, Chongqing, China.
| | - Chunbao Guo
- Laboratory of Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
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26
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Zhou Y, Yuan G, Zhong F, He S. Roles of the complement system in alcohol-induced liver disease. Clin Mol Hepatol 2020; 26:677-685. [PMID: 33053939 PMCID: PMC7641541 DOI: 10.3350/cmh.2020.0094] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 08/25/2020] [Indexed: 12/19/2022] Open
Abstract
Alcohol-induced liver disease (ALD) is a complex disorder, with a disease spectrum ranging from steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Although the pathogenesis of ALD is incompletely understood and currently no effective drugs are available for ALD, several lines of evidence suggest that complement activation and oxidative stress play crucial roles in the pathogenesis of ALD. Complement activation can regulate the production of ROS and influence oxidative stress in ALD. Precise regulation of the complement system in ALD may be a rational and novel avenue to postpone and even reverse the progression of disease and simultaneously promote the repair of liver injury. In this mini-review, we briefly summarize the recent research progress, especially focusing on the role of complement and oxidative stress-induced transfer RNA-derived fragments, which might help us to better understand the pathogenesis of ALD and provide aid in the development of novel therapeutic strategies for ALD.
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Affiliation(s)
- Yi Zhou
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Guandou Yuan
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Fudi Zhong
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Songqing He
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
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27
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Yang X, Ma Y, Zhao Z, Zhen S, Wen D. Complement C1q as a Potential Biomarker for Obesity and Metabolic Syndrome in Chinese Adolescents. Front Endocrinol (Lausanne) 2020; 11:586440. [PMID: 33329392 PMCID: PMC7735390 DOI: 10.3389/fendo.2020.586440] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 10/20/2020] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Complement C1q (C1q) has been confirmed to be related to obesity, metabolic syndrome (MetS), and its components. However, human data regarding the associations are relatively scarce. This study aimed to investigate associations of C1q with obesity as well as MetS in Chinese adolescents. METHODS A total of 1,191 Chinese adolescents aged 13-18 years were enrolled in this study. The biochemical and anthropometric variables of all the subjects were evaluated using standardized procedures. C1q was measured using the immunoturbidometric assay. The relationship between C1q and obesity or MetS was analyzed using multiple regression analyses. RESULTS Obesity was more prevalent among participants in the highest tertile than in the lowest tertile of C1q levels. The highest tertile of C1q was related to a greater effect on the risk of MetS, and its trend test was statistically significant. Except for hyperglycemia, the prevalence of other components of MetS significantly increased relative to an increase in C1q tertile. Receiver operating characteristic (ROC) curve analysis of C1q for predicting adolescents with MetS illustrated that the area under the curve (AUC) was 0.82 [95% confidence interval (CI): 0.76, 0.88; P<0.001] in the total population after adjusting for confounders. CONCLUSIONS This study observed a significantly higher prevalence of obesity and MetS features in adolescents with high C1q. The findings of the current study also reported a significant relationship between C1q levels and MetS components [except for fasting plasma glucose (FPG)] in Chinese adolescents. C1q may represent a biomarker for predicting obesity or MetS in adolescents.
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Affiliation(s)
- Xuelian Yang
- Institute of Health Sciences, China Medical University, Shenyang, China
| | - Yanan Ma
- School of Public Health, China Medical University, Shenyang, China
| | - Zhongyi Zhao
- Department of Health Management, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shihan Zhen
- Institute of Health Sciences, China Medical University, Shenyang, China
| | - Deliang Wen
- Institute of Health Sciences, China Medical University, Shenyang, China
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Lung T, Sakem B, Risch L, Würzner R, Colucci G, Cerny A, Nydegger U. The complement system in liver diseases: Evidence-based approach and therapeutic options. J Transl Autoimmun 2019; 2:100017. [PMID: 32743505 PMCID: PMC7388403 DOI: 10.1016/j.jtauto.2019.100017] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 09/05/2019] [Accepted: 09/10/2019] [Indexed: 12/12/2022] Open
Abstract
Complement is usually seen to largely originate from the liver to accomplish its tasks systemically - its return to the production site has long been underestimated. Recent progress in genomics, therapeutic effects on complement, standardised possibilities in medical laboratory tests and involvement of complosome brings the complement system with its three major functions of opsonization, cytolysis and phagocytosis back to liver biology and pathology. The LOINC™ system features 20 entries for the C3 component of complement to anticipate the application of artificial intelligence data banks algorythms of which are fed with patient-specific data connected to standard lab assays for liver function. These advancements now lead to increased vigilance by clinicians. This reassessment article will further elucidate the distribution of synthesis sites to the three germ layer-derived cell systems and the role complement now known to play in embryogenesis, senescence, allotransplantation and autoimmune disease. This establishes the liver as part of the gastro-intestinal system in connection with nosological entities never thought of, such as the microbiota-liver-brain axis. In neurological disease etiology infectious and autoimmune hepatitis play an important role in the context of causative viz reactive complement activation. The mosaic of autoimmunity, i.e. multiple combinations of the many factors producing varying clinical pictures, leads to the manifold facets of liver autoimmunity.
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Affiliation(s)
- Thomas Lung
- Labormedizinisches Zentrum Dr. Risch, Lagerstrasse 30, CH-9470, Buchs, Switzerland
| | - Benjamin Sakem
- Labormedizinisches Zentrum Dr. Risch, Waldeggstrasse 37, CH-3097, Liebefeld bei Bern, Switzerland
| | - Lorenz Risch
- Labormedizinisches Zentrum Dr. Risch, Waldeggstrasse 37, CH-3097, Liebefeld bei Bern, Switzerland
| | - Reinhard Würzner
- Medical University Innsbruck, Division of Hygiene & Medical Microbiology, Department of Hygiene, Microbiology and Public Health, Schöpfstrasse 41, A-6020, Innsbruck, Austria
| | - Giuseppe Colucci
- Clinica Luganese Moncucco, Lugano, Via Moncucco, CH-6900, Lugano, Switzerland
- Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Andreas Cerny
- Epatocentro Ticino, Via Soldino 5, CH-6900, Lugano, Switzerland
| | - Urs Nydegger
- Labormedizinisches Zentrum Dr. Risch, Waldeggstrasse 37, CH-3097, Liebefeld bei Bern, Switzerland
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Kwong EK, Liu R, Zhao D, Li X, Zhu W, Wang X, Gurley EC, Lai G, Liu J, Hylemon PB, Zhou H. The role of sphingosine kinase 2 in alcoholic liver disease. Dig Liver Dis 2019; 51:1154-1163. [PMID: 31003959 PMCID: PMC6682426 DOI: 10.1016/j.dld.2019.03.020] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 03/18/2019] [Accepted: 03/19/2019] [Indexed: 02/08/2023]
Abstract
Alcoholic liver disease (ALD) is one of the most common liver diseases worldwide. However, the exact mechanisms underlying ALD remain unclear. Previous studies reported that sphingosine kinase 2 (SphK2) plays an essential role in regulating hepatic lipid metabolism. In the current study, we demonstrate that compared to wild-type (WT) mice, SphK2 deficient (SphK2-/-) mice exhibited a greater degree of liver injury and hepatic lipid accumulation after feeding with an alcohol diet for 60 days. This is accompanied by a down-regulation of steroid 7-alpha-hydroxylase (Cyp7b1) and an up-regulation of pro-inflammatory mediators (Tnfα, F4/80, Il-1β). In vitro experiments showed that alcohol induced SphK2 expression in mouse primary hepatocytes and cultured mouse macrophages. Furthermore, alcohol feeding induced a more severe intestinal barrier dysfunction in SphK2-/- mice than WT mice. Deficiency of SphK2 impaired the growth of intestinal organoids. Finally, SphK2 expression levels were down-regulated in the livers of human patients with alcoholic cirrhosis and hepatocellular carcinoma compared to healthy controls. In summary, these findings suggest that SphK2 is a crucial regulator of hepatic lipid metabolism and that modulating the SphK2-mediated signaling pathway may represent a novel therapeutic strategy for the treatment of ALD and other metabolic liver diseases.
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Affiliation(s)
- Eric K. Kwong
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Runping Liu
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Derrick Zhao
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Xiaojiaoyang Li
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Weiwei Zhu
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Xuan Wang
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Emily C. Gurley
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Guanhua Lai
- Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jimin Liu
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Phillip B. Hylemon
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Huiping Zhou
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
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Gao B, Ahmad MF, Nagy LE, Tsukamoto H. Inflammatory pathways in alcoholic steatohepatitis. J Hepatol 2019; 70:249-259. [PMID: 30658726 PMCID: PMC6361545 DOI: 10.1016/j.jhep.2018.10.023] [Citation(s) in RCA: 252] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 10/16/2018] [Accepted: 10/23/2018] [Indexed: 12/12/2022]
Abstract
Inflammatory processes are primary contributors to the development and progression of alcoholic steatohepatitis (ASH), with severe alcoholic hepatitis characterised by non-resolving inflammation. Inflammation in the progression of ASH is a complex response to microbial dysbiosis, loss of barrier integrity in the intestine, hepatocellular stress and death, as well as inter-organ crosstalk. Herein, we review the roles of multiple cell types that are involved in inflammation in ASH, including resident macrophages and infiltrating monocytes, as well as other cell types in the innate and adaptive immune system. In response to chronic, heavy alcohol exposure, hepatocytes themselves also contribute to the inflammatory process; hepatocytes express a large number of chemokines and inflammatory mediators and can also release damage-associated molecular patterns during injury and death. These cellular responses are mediated and accompanied by changes in the expression of pro- and anti-inflammatory cytokines and chemokines, as well as by signals which orchestrate the recruitment of immune cells and activation of the inflammatory process. Additional mechanisms for cell-cell and inter-organ communication in ASH are also reviewed, including the roles of extracellular vesicles and microRNAs, as well as inter-organ crosstalk. We highlight the concept that inflammation also plays an important role in promoting liver repair and controlling bacterial infection. Understanding the complex regulatory processes that are disrupted during the progression of ASH will likely lead to better targeted strategies for therapeutic interventions.
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Affiliation(s)
- Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, United States.
| | - Maleeha F Ahmad
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Laura E Nagy
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States; Northern Ohio Alcohol Center, Departments of Molecular Medicine, Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States.
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, University of Southern California, Greater Los Angeles VA Healthcare System, Los Angeles, CA, United States.
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Lamas-Paz A, Hao F, Nelson LJ, Vázquez MT, Canals S, Gómez del Moral M, Martínez-Naves E, Nevzorova YA, Cubero FJ. Alcoholic liver disease: Utility of animal models. World J Gastroenterol 2018; 24:5063-5075. [PMID: 30568384 PMCID: PMC6288648 DOI: 10.3748/wjg.v24.i45.5063] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 11/08/2018] [Accepted: 11/09/2018] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) is a major cause of acute and chronic liver injury. Extensive evidence has been accumulated on the pathological process of ALD during the past decades. However, effective treatment options for ALD are very limited due to the lack of suitable in vivo models that recapitulate the full spectrum of ALD. Experimental animal models of ALD, particularly rodents, have been used extensively to mimic human ALD. An ideal animal model should recapitulate all aspects of the ALD process, including significant steatosis, hepatic neutrophil infiltration, and liver injury. A better strategy against ALD depends on clear diagnostic biomarkers, accurate predictor(s) of its progression and new therapeutic approaches to modulate stop or even reverse the disease. Numerous models employing rodent animals have been established in the last decades to investigate the effects of acute and chronic alcohol exposure on the initiation and progression of ALD. Although significant progress has been made in gaining better knowledge on the mechanisms and pathology of ALD, many features of ALD are unknown, and require further investigation, ideally with improved animal models that more effectively mimic human ALD. Although differences in the degree and stages of alcoholic liver injury inevitably exist between animal models and human ALD, the acquisition and translational relevance will be greatly enhanced with the development of new and improved animal models of ALD.
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Affiliation(s)
- Arantza Lamas-Paz
- Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid 28040, Spain
- Yulia A Nevzovova, Francisco Javier Cubero, 12 de Octubre Health Research Institute (imas12), Madrid 28041, Spain
| | - Fengjie Hao
- Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid 28040, Spain
- Yulia A Nevzovova, Francisco Javier Cubero, 12 de Octubre Health Research Institute (imas12), Madrid 28041, Spain
| | - Leonard J Nelson
- Institute for Bioengineering (IBioE), School of Engineering, Faraday Building, The University of Edinburgh, Edinburgh EH9 3 JL, Scotland, United Kingdom
| | - Maria Teresa Vázquez
- Department of Human Anatomy and Embryology, Complutense University School of Medicine, Madrid 28040, Spain
| | - Santiago Canals
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, San Juan de Alicante 03550, Spain
| | - Manuel Gómez del Moral
- Department of Cell Biology, Complutense University School of Medicine, Madrid 28040, Spain
| | - Eduardo Martínez-Naves
- Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid 28040, Spain
- Yulia A Nevzovova, Francisco Javier Cubero, 12 de Octubre Health Research Institute (imas12), Madrid 28041, Spain
| | - Yulia A Nevzorova
- Department of Genetics, Physiology and Microbiology, Faculty of Biology, Universidad Complutense, Madrid 28040, Spain
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen 52062, Germany
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid 28040, Spain
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DeGroat AR, Fleming CK, Dunlay SM, Hagood KL, Moorman JP, Peterson JM. The sex specific effect of alcohol consumption on circulating levels of CTRP3. PLoS One 2018; 13:e0207011. [PMID: 30403751 PMCID: PMC6221322 DOI: 10.1371/journal.pone.0207011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 10/23/2018] [Indexed: 02/06/2023] Open
Abstract
The goal of this project was to establish the effect of alcohol consumption on the circulating levels of the adipose tissue derived protein C1q TNF Related Protein 3 (CTRP3). Adipose tissue secretes several adipokines, such as adiponectin and leptin, which exert a multitude of biological effects important for human health. However, adipose tissue is extremely sensitive to alcohol consumption, leading not only to disrupted fat storage, but also to disruptions in adipokine production. Changes to adipokine secretion could have widespread biological effects and potentially contribute to alcohol-induced ailments, such as alcoholic fatty liver disease (ALD). CTRP3 has been previously demonstrated to attenuate fatty liver disease, and suppression of CTRP3 with alcohol consumption could contribute to development of and progression to alcoholic fatty liver disease. To examine the effect of ethanol consumption on circulating adipokine levels, male and female mice were fed an ethanol containing diet (Lieber-DeCarli 5% (v/v) ethanol diet) for 10-days followed by a single gavage of 5 g/kg ethanol (the NIAAA model), or for 6-weeks with no binge added (chronic model). In female mice, adiponectin levels increased ~2-fold in both models of ethanol feeding, but in male mice increased adiponectin levels were only observed after chronic ethanol feeding. On the other hand, in female mice, circulating CTRP3 levels decreased by ~75% and ~50% in the NIAAA and chronic model, respectively, with no changes observed in the male mice in either feeding model. Leptin levels were unchanged with ethanol feeding regardless of model or sex of mice. Lastly, chronic ethanol feeding led to a significant increase in mortality (~50%) in female mice, with no difference in relative ethanol consumption. These findings indicate that ethanol consumption can dysregulate adipokine secretion, but that the effects vary by sex of animal, method of ethanol consumption, and adipokine examined. These findings also indicate that female mice are more sensitive to the chronic effects of ethanol than male mice. Notably, this is the first study to document the effects of ethanol consumption on the circulating levels of CTRP3. Understanding the impact of excessive alcohol consumption on adipokine production and secretion could identify novel mechanisms of alcohol-induced human disease. However, the mechanism responsible for the increased sensitivity remains elusive.
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Affiliation(s)
- Ashley R. DeGroat
- Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee, United States of America
| | - Christina K. Fleming
- Department of Health Sciences, College of Public Health, East Tennessee State University, Johnson City, Tennessee, United States of America
| | - Samantha M. Dunlay
- Department of Health Sciences, College of Public Health, East Tennessee State University, Johnson City, Tennessee, United States of America
| | - Kendra L. Hagood
- Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee, United States of America
| | - Jonathan P. Moorman
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America
- Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America
- Department of Veterans Affairs, Hepatitis (HCV/HIV) Program, James H Quillen VA Medical Center, Johnson City, Tennessee, United States of America
| | - Jonathan M. Peterson
- Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee, United States of America
- Department of Health Sciences, College of Public Health, East Tennessee State University, Johnson City, Tennessee, United States of America
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America
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Lin CJ, Hu ZG, Yuan GD, Lei B, He SQ. Complements are involved in alcoholic fatty liver disease, hepatitis and fibrosis. World J Hepatol 2018; 10:662-669. [PMID: 30386459 PMCID: PMC6206158 DOI: 10.4254/wjh.v10.i10.662] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 07/26/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023] Open
Abstract
The complement system is a key component of the body’s immune system. When abnormally activated, this system can induce inflammation and damage to normal tissues and participate in the development and progression of a variety of diseases. In the past, many scholars believed that alcoholic liver disease (ALD) is induced by the stress of ethanol on liver cells, including oxidative stress and dysfunction of mitochondria and protease bodies, causing hepatocyte injury and apoptosis. Recent studies have shown that complement activation is also involved in the genesis and development of ALD. This review focuses on the roles of complement activation in ALD and of therapeutic intervention in complement-activation pathways. We intend to provide new ideas on the diagnosis and treatment of ALD.
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Affiliation(s)
- Cheng-Jie Lin
- Department of Hepatopancreatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zhi-Gao Hu
- Department of Hepatopancreatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Guan-Dou Yuan
- Department of Hepatopancreatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Biao Lei
- Department of Hepatopancreatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Song-Qing He
- Department of Hepatopancreatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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McCullough RL, McMullen MR, Poulsen KL, Kim A, Medof ME, Nagy LE. Anaphylatoxin Receptors C3aR and C5aR1 Are Important Factors That Influence the Impact of Ethanol on the Adipose Secretome. Front Immunol 2018; 9:2133. [PMID: 30294325 PMCID: PMC6158367 DOI: 10.3389/fimmu.2018.02133] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 08/29/2018] [Indexed: 12/11/2022] Open
Abstract
Background and aims: Chronic ethanol exposure results in inflammation in adipose tissue; this response is associated with activation of complement as well as the development of alcohol-related liver disease (ALD). Adipose communicates with other organs, including liver, via the release of soluble mediators, such as adipokines and cytokines, characterized as the "adipose secretome." Here we investigated the role of the anaphaylatoxin receptors C3aR and C5aR1 in the development of adipose tissue inflammation and regulation of the adipose secretome in murine ALD (mALD). Methods: Wild-type C57BL/6 (WT), C3aR -/-, and C5aR1 -/- mice were fed Lieber-DeCarli ethanol diet for 25 days (6% v/v, 32% kcal) or isocaloric control diets; indicators of inflammation and injury were assessed in gonadal adipose tissue. The adipose secretome was characterized in isolated adipocytes and stromal vascular cells. Results: Ethanol feeding increased the expression of adipokines, chemokines and leukocyte markers in gonadal adipose tissue from WT mice; C3aR -/- were partially protected while C5aR1 -/- mice were completely protected. In contrast, induction of CYP2E1 and accumulation of TUNEL-positive cells in adipose in response to ethanol feeding was independent of genotype. Bone marrow chimeras, generated with WT and C5aR1 -/- mice, revealed C5aR1 expression on non-myeloid cells, likely to be adipocytes, contributed to ethanol-induced adipose inflammation. Chronic ethanol feeding regulated both the quantity and distribution of adipokines secreted from adipocytes in a C5aR1-dependent mechanism. In WT mice, chronic ethanol feeding induced a predominant release of pro-inflammatory adipokines from adipocytes, while the adipose secretome from C5aR1 -/- mice was characterized by an anti-inflammatory/protective profile. Further, the cargo of adipocyte-derived extracellular vesicles (EVs) was distinct from the soluble secretome; in WT EVs, ethanol increased the abundance of pro-inflammatory mediators while EV cargo from C5aR1 -/- adipocytes contained a greater diversity and more robust expression of adipokines. Conclusions: C3aR and C5aR1 are potent regulators of ethanol-induced adipose inflammation in mALD. C5aR1 modulated the impact of chronic ethanol on the content of the adipose secretome, as well as influencing the cargo of an extensive array of adipokines from adipocyte-derived EVs. Taken together, our data demonstrate that C5aR1 contributes to ethanol-mediated changes in the adipose secretome, likely contributing to intra-organ injury in ALD.
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Affiliation(s)
- Rebecca L McCullough
- Department of Inflammation and Immunity, Center for Liver Disease Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Megan R McMullen
- Department of Inflammation and Immunity, Center for Liver Disease Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Kyle L Poulsen
- Department of Inflammation and Immunity, Center for Liver Disease Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Adam Kim
- Department of Inflammation and Immunity, Center for Liver Disease Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - M Edward Medof
- Institute of Pathology, Case Western Reserve University, Cleveland, OH, United States
| | - Laura E Nagy
- Department of Inflammation and Immunity, Center for Liver Disease Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States.,Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, United States
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Brown ZJ, Heinrich B, Greten TF. Mouse models of hepatocellular carcinoma: an overview and highlights for immunotherapy research. Nat Rev Gastroenterol Hepatol 2018; 15:536-554. [PMID: 29904153 DOI: 10.1038/s41575-018-0033-6] [Citation(s) in RCA: 164] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Mouse models are the basis of preclinical and translational research in hepatocellular carcinoma (HCC). Multiple methods exist to induce tumour formation in mice, including genetically engineered mouse models, chemotoxic agents, intrahepatic or intrasplenic injection of tumour cells and xenograft approaches. Additionally, as HCC generally develops in the context of diseased liver, methods exist to induce liver disease in mice to mimic viral hepatitis, fatty liver disease, fibrosis, alcohol-induced liver disease and cholestasis. Similar to HCC in humans, response to therapy in mouse models is monitored with imaging modalities such as CT or MRI, as well as additional techniques involving bioluminescence. As immunotherapy is increasingly applied to HCC, mouse models for these approaches are required for preclinical data. In studying cancer immunotherapy, it is important to consider aspects of antitumour immune responses and to produce a model that mimics the complexity of the immune system. This Review provides an overview of the different mouse models of HCC, presenting techniques to prepare an HCC mouse model and discussing different approaches to help researchers choose an appropriate model for a specific hypothesis. Specific aspects of immunotherapy research in HCC and the applied mouse models in this field are also highlighted.
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Affiliation(s)
- Zachary J Brown
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Bernd Heinrich
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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Kermanizadeh A, Jacobsen NR, Roursgaard M, Loft S, Møller P. Hepatic Hazard Assessment of Silver Nanoparticle Exposure in Healthy and Chronically Alcohol Fed Mice. Toxicol Sci 2018; 158:176-187. [PMID: 28453772 DOI: 10.1093/toxsci/kfx080] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Silver (Ag) nanoparticles (NPs) are currently among one of the most widely used nanomaterials. This in turn, implies an increased risk of human and environmental exposure. Alcohol abuse is a global issue with millions of people in the general population affected by the associated adverse effects. The excessive consumption of alcohol is a prominent cause of chronic liver disease which manifest in multiple disorders. In this study, the adverse health effects of Ag NP exposure were investigated in models of alcoholic hepatic disease in vitro and in vivo. The data showed that Ag NP induced hepatic health effects were aggravated in the alcohol pretreated mice in comparison to controls with regards to an organ specific inflammatory response, changes in blood biochemistry, acute phase response and hepatic pathology. In addition, alcoholic disease influenced the organ's ability for recovery post-NP challenge. Additionally, it is demonstrated that the in vivo data correlated well with in vitro findings where ethanol pretreatment of hepatocytes resulted in significantly increased inflammatory response post-Ag NP exposure. To the best of our knowledge this is the first study of its kind to investigate nano-sized material-induced hepatic pathology in models representative of susceptible individuals (those with pre-existing alcohol liver disease) within the population. This is an area of research in the field of nanotoxicology, and in particular with regard to NP risk assessment that is almost entirely overlooked.
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Affiliation(s)
- Ali Kermanizadeh
- Department of Public Health, Section of Environmental Health, University of Copenhagen, Copenhagen, Denmark
| | - Nicklas R Jacobsen
- National Research Centre for the Working Environment, Copenhagen, Denmark
| | - Martin Roursgaard
- Department of Public Health, Section of Environmental Health, University of Copenhagen, Copenhagen, Denmark
| | - Steffen Loft
- Department of Public Health, Section of Environmental Health, University of Copenhagen, Copenhagen, Denmark
| | - Peter Møller
- Department of Public Health, Section of Environmental Health, University of Copenhagen, Copenhagen, Denmark
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McCullough RL, McMullen MR, Sheehan MM, Poulsen KL, Roychowdhury S, Chiang DJ, Pritchard MT, Caballeria J, Nagy LE. Complement Factor D protects mice from ethanol-induced inflammation and liver injury. Am J Physiol Gastrointest Liver Physiol 2018; 315:G66-G79. [PMID: 29597356 PMCID: PMC6109707 DOI: 10.1152/ajpgi.00334.2017] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 01/31/2018] [Accepted: 03/04/2018] [Indexed: 01/31/2023]
Abstract
Complement plays a crucial role in microbial defense and clearance of apoptotic cells. Emerging evidence suggests complement is an important contributor to alcoholic liver disease. While complement component 1, Q subcomponent (C1q)-dependent complement activation contributes to ethanol-induced liver injury, the role of the alternative pathway in ethanol-induced injury is unknown. Activation of complement via the classical and alternative pathways was detected in alcoholic hepatitis patients. Female C57BL/6J [wild type (WT)], C1q-deficient ( C1qa-/-, lacking classical pathway activation), complement protein 4-deficient ( C4-/-, lacking classical and lectin pathway activation), complement factor D-deficient ( FD-/-, lacking alternative pathway activation), and C1qa/FD-/- (lacking classical and alternative pathway activation) mice were fed an ethanol-containing liquid diet or pair-fed control diet for 4 or 25 days. Following chronic ethanol exposure, liver injury, steatosis, and proinflammatory cytokine expression were increased in WT but not C1qa-/-, C4-/-, or C1qa/FD-/- mice. In contrast, liver injury, steatosis, and proinflammatory mediators were robustly increased in ethanol-fed FD-/- mice compared with WT mice. Complement activation, assessed by hepatic accumulation of C1q and complement protein 3 (C3) cleavage products (C3b/iC3b/C3c), was evident in livers of WT mice in response to both short-term and chronic ethanol. While C1q accumulated in ethanol-fed FD-/- mice (short term and chronic), C3 cleavage products were detected after short-term but not chronic ethanol. Consistent with impaired complement activation, chronic ethanol induced the accumulation of apoptotic cells and fibrogenic responses in the liver of FD-/- mice. These data highlight the protective role of complement factor D (FD) and suggest that FD-dependent amplification of complement is an adaptive response that promotes hepatic healing and recovery in response to chronic ethanol. NEW & NOTEWORTHY Complement, a component of the innate immune system, is an important pathophysiological contributor to ethanol-induced liver injury. We have identified a novel role for factor D, a component of the alternative pathway, in protecting the liver from ethanol-induced inflammation, accumulation of apoptotic hepatocytes, and profibrotic responses. These data indicate a dual role of complement with regard to inflammatory and protective responses and suggest that accumulation of apoptotic cells impairs hepatic healing/recovery during alcoholic liver disease.
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Affiliation(s)
- Rebecca L McCullough
- Department of Pathobiology, Center for Liver Disease Research, Lerner Research Institute, Cleveland Clinic , Cleveland, Ohio
| | - Megan R McMullen
- Department of Pathobiology, Center for Liver Disease Research, Lerner Research Institute, Cleveland Clinic , Cleveland, Ohio
| | - Megan M Sheehan
- Department of Pathobiology, Center for Liver Disease Research, Lerner Research Institute, Cleveland Clinic , Cleveland, Ohio
| | - Kyle L Poulsen
- Department of Pathobiology, Center for Liver Disease Research, Lerner Research Institute, Cleveland Clinic , Cleveland, Ohio
| | - Sanjoy Roychowdhury
- Department of Pathobiology, Center for Liver Disease Research, Lerner Research Institute, Cleveland Clinic , Cleveland, Ohio
| | - Dian J Chiang
- Division of Gastroenterology, Swedish Medical Group , Seattle, Washington
| | - Michele T Pritchard
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center , Kansas City, Kansas
| | - Juan Caballeria
- Institut d'Investigacions Biomediques August Pi iSunyer, Hospital Clinic of Barcelona , Barcelona , Spain
| | - Laura E Nagy
- Department of Pathobiology, Center for Liver Disease Research, Lerner Research Institute, Cleveland Clinic , Cleveland, Ohio
- Department of Gastroenterology and Hepatology, Cleveland Clinic , Cleveland, Ohio
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Kalinin S, González-Prieto M, Scheiblich H, Lisi L, Kusumo H, Heneka MT, Madrigal JLM, Pandey SC, Feinstein DL. Transcriptome analysis of alcohol-treated microglia reveals downregulation of beta amyloid phagocytosis. J Neuroinflammation 2018; 15:141. [PMID: 29759078 PMCID: PMC5952855 DOI: 10.1186/s12974-018-1184-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 04/29/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Microglial activation contributes to the neuropathology associated with chronic alcohol exposure and withdrawal, including the expression of inflammatory and anti-inflammatory genes. In the current study, we examined the transcriptome of primary rat microglial cells following incubation with alcohol alone, or alcohol together with a robust inflammatory stimulus. METHODS Primary microglia were prepared from mixed rat glial cultures. Cells were incubated with 75 mM ethanol alone or with proinflammatory cytokines ("TII": IL1β, IFNγ, and TNFα). Isolated mRNA was used for RNAseq analysis and qPCR. Effects of alcohol on phagocytosis were determined by uptake of oligomeric amyloid beta. RESULTS Alcohol induced nitrite production in control cells and increased nitrite production in cells co-treated with TII. RNAseq analysis of microglia exposed for 24 h to alcohol identified 312 differentially expressed mRNAs ("Alc-DEs"), with changes confirmed by qPCR analysis. Gene ontology analysis identified phagosome as one of the highest-ranking KEGG pathways including transcripts regulating phagocytosis. Alcohol also increased several complement-related mRNAs that have roles in phagocytosis, including C1qa, b, and c; C3; and C3aR1. RNAseq analysis identified over 3000 differentially expressed mRNAs in microglia following overnight incubation with TII; and comparison to the group of Alc-DEs revealed 87 mRNAs modulated by alcohol but not by TII, including C1qa, b, and c. Consistent with observed changes in phagocytosis-related mRNAs, the uptake of amyloid beta1-42, by primary microglia, was reduced by alcohol. CONCLUSIONS Our results define alterations that occur to microglial gene expression following alcohol exposure and suggest that alcohol effects on phagocytosis could contribute to the development of Alzheimer's disease.
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Affiliation(s)
- Sergey Kalinin
- Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL 60612 USA
| | - Marta González-Prieto
- Department of Pharmacology, University Complutense, Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Madrid, 28040 Spain
| | - Hannah Scheiblich
- Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn, 53127 Bonn, Germany
| | - Lucia Lisi
- Institute of Pharmacology, Catholic University Medical School, 00168 Rome, Italy
| | - Handojo Kusumo
- Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612 USA
| | - Michael T. Heneka
- Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn, 53127 Bonn, Germany
| | - Jose L. M. Madrigal
- Department of Pharmacology, University Complutense, Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Madrid, 28040 Spain
| | - Subhash C. Pandey
- Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612 USA
- Department of Veterans Affairs, Jesse Brown VA Medical Center, Chicago, IL 60612 USA
| | - Douglas L. Feinstein
- Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL 60612 USA
- Department of Veterans Affairs, Jesse Brown VA Medical Center, Chicago, IL 60612 USA
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Bertola A. WITHDRAWN: Rodent models of fatty liver diseases. LIVER RESEARCH 2018. [DOI: 10.1016/j.livres.2018.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Li Z, Zhao J, Zhang S, Weinman SA. FOXO3-dependent apoptosis limits alcohol-induced liver inflammation by promoting infiltrating macrophage differentiation. Cell Death Discov 2018. [PMID: 29531813 PMCID: PMC5841311 DOI: 10.1038/s41420-017-0020-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Alcohol consumption is generally well tolerated by the liver but in some individuals it results in persistent inflammation and liver disease. The mechanisms that regulate alcohol-induced liver inflammation are poorly understood. The transcription factor FOXO3 has previously been shown to be involved in suppressing alcohol-induced liver injury. In this study we demonstrate that in response to alcohol, approximately 10% of mouse hepatic macrophages undergo FOXO3-dependent apoptosis. By 3 days of alcohol exposure total hepatic macrophage numbers declined by 30% but these were restored to normal after 10 days of continued exposure. Whole body or myeloid specific Foxo3-/- mice failed to show this apoptotic response. After 10 days of alcohol exposure, Foxo3−/− mice had an increased basal inflammatory phenotype and an increase in the proportion of pro-inflammatory CD11b+, Ly6C+ infiltrating macrophages (IMs) infiltrating. This led to marked sensitivity to LPS with a 5-fold ALT elevation and liver injury after LPS challenge in Foxo3−/− but not WT mice. Restoring the early macrophage apoptosis burst with a pulse of intravenous GdCl3 at day 2 had no effect on the day 10 phenotype of WT mice but it corrected the hyper-inflammatory phenotype in Foxo3−/− mice. In conclusion, FOXO3-dependent hepatic macrophage apoptosis in response to ethanol serves to promote differentiation of infiltrating macrophages thus limiting the magnitude of the inflammatory response to ethanol.
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Affiliation(s)
- Zhuan Li
- 1Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS USA
| | - Jie Zhao
- 1Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS USA
| | - Shujun Zhang
- 2Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Steven A Weinman
- 1Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS USA.,3Liver Center, University of Kansas Medical Center, Kansas City, KS USA
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Kim A, McCullough RL, Poulsen KL, Sanz-Garcia C, Sheehan M, Stavitsky AB, Nagy LE. Hepatic Immune System: Adaptations to Alcohol. Handb Exp Pharmacol 2018; 248:347-367. [PMID: 29374837 DOI: 10.1007/164_2017_88] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Both the innate and adaptive immune systems are critical for the maintenance of healthy liver function. Immune activity maintains the tolerogenic capacity of the liver, modulates hepatocellular response to various stresses, and orchestrates appropriate cellular repair and turnover. However, in response to heavy, chronic alcohol exposure, the finely tuned balance of pro- and anti-inflammatory functions in the liver is disrupted, leading to a state of chronic inflammation in the liver. Over time, this non-resolving inflammatory response contributes to the progression of alcoholic liver disease (ALD). Here we review the contributions of the cellular components of the immune system to the progression of ALD, as well as the pathophysiological roles for soluble and circulating mediators of immunity, including cytokines, chemokines, complement, and extracellular vesicles, in ALD. Finally, we compare the role of the innate immune response in health and disease in the liver to our growing understanding of the role of neuroimmunity in the development and maintenance of a healthy central nervous system, as well as the progression of neuroinflammation.
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Affiliation(s)
- Adam Kim
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA
| | - Rebecca L McCullough
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Kyle L Poulsen
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA
| | - Carlos Sanz-Garcia
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA
| | - Megan Sheehan
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Abram B Stavitsky
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA
- Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH, USA
| | - Laura E Nagy
- Department of Pathobiology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA.
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA.
- Department of Gastroenterology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, OH, USA.
- Cleveland Clinic, Lerner Research Institute, Cleveland, OH, USA.
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Kermanizadeh A, Jacobsen NR, Roursgaard M, Loft S, Møller P. Hepatic toxicity assessment of cationic liposome exposure in healthy and chronic alcohol fed mice. Heliyon 2017; 3:e00458. [PMID: 29234737 PMCID: PMC5717320 DOI: 10.1016/j.heliyon.2017.e00458] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 11/02/2017] [Accepted: 11/15/2017] [Indexed: 02/01/2023] Open
Abstract
The utilisation of nanoparticles as the means of targeted delivery of therapeutics and/or imaging agents could greatly enhance the specific transport of biologically active payloads to target tissues while avoiding or reducing undesired side-effects. To allow for this to become a reality, the question of potential toxicological effects needs to be addressed. In the present investigation, a cationic liposome with prospective for medical applications was constructed and thoroughly assessed for any material-induced hepatic adverse effects in vivo − in healthy and alcoholic hepatic disease models and in vitro − (HepG2 cells). The data demonstrated that intravenous injection of liposomes did not cause any significant in vivo hepatic toxicity (inflammation, alterations in blood parameters, anti-oxidant depletion, acute phase response and histopathology) at doses of 200 μg per mouse in either healthy or chronically alcohol fed mice. Additionally, the in vitro material-induced adverse effects (cytotoxicity, inflammation or albumin secretion) were all also minimal. The data from this study demonstrated that the intravenous injection of cationic liposomes does not cause hepatic toxicity. This investigation is important as it investigates the toxicity of a nano-sized material in a model of alcoholic hepatic disease in vitro and in vivo. This is an area of research in the field of nanotoxicology that is currently almost entirely overlooked.
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Affiliation(s)
- Ali Kermanizadeh
- University of Copenhagen, Department of Public Health, Section of Environmental Health, Copenhagen, Denmark
| | - Nicklas R Jacobsen
- National Research Centre for the Working Environment, Copenhagen, Denmark
| | - Martin Roursgaard
- University of Copenhagen, Department of Public Health, Section of Environmental Health, Copenhagen, Denmark
| | - Steffen Loft
- University of Copenhagen, Department of Public Health, Section of Environmental Health, Copenhagen, Denmark
| | - Peter Møller
- University of Copenhagen, Department of Public Health, Section of Environmental Health, Copenhagen, Denmark
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Roychowdhury S, McCullough RL, Sanz-Garcia C, Saikia P, Alkhouri N, Matloob A, Pollard K, McMullen MR, Croniger CM, Nagy LE. Receptor interacting protein 3 protects mice from high-fat diet-induced liver injury. Hepatology 2016; 64:1518-1533. [PMID: 27301788 PMCID: PMC5074889 DOI: 10.1002/hep.28676] [Citation(s) in RCA: 115] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 05/02/2016] [Accepted: 05/16/2016] [Indexed: 12/14/2022]
Abstract
UNLABELLED Multiple pathways of programmed cell death are important in liver homeostasis. Hepatocyte death is associated with progression of nonalcoholic fatty liver disease, and inhibition of apoptosis partially protects against liver injury in response to a high-fat diet (HFD). However, the contribution of necroptosis, a caspase-independent pathway of cell death, to HFD-induced liver injury is not known. Wild-type C57BL/6 and receptor interacting protein (RIP) 3-/- mice were randomized to chow or HFD. HFD-fed C57BL/6 mice increased expression of RIP3, the master regulator of necroptosis, as well as phosphorylated mixed lineage kinase domain-like, an effector of necroptotic cell death, in liver. HFD did not increase phosphorylated mixed lineage kinase domain-like in RIP3-/- mice. HFD increased fasting insulin and glucose, as well as glucose intolerance, in C57BL/6 mice. RIP3-/- mice were glucose-intolerant even on the chow diet; HFD further increased fasting glucose and insulin but not glucose intolerance. HFD also increased hepatic steatosis, plasma alanine aminotransferase activity, inflammation, oxidative stress, and hepatocellular apoptosis in wild-type mice; these responses were exacerbated in RIP3-/- mice. Importantly, increased inflammation and injury were associated with early indicators of fibrosis in RIP3-/- compared to C57BL/6 mice. Culture of AML12 hepatocytes with palmitic acid increased cytotoxicity through apoptosis and necrosis. Inhibition of RIP1 with necrostatin-1 or small interfering RNA knockdown of RIP3 reduced palmitic acid-induced cytotoxicity. CONCLUSION Absence of RIP3, a key mediator of necroptosis, exacerbated HFD-induced liver injury, associated with increased inflammation and hepatocyte apoptosis, as well as early fibrotic responses; these findings indicate that shifts in the mode of hepatocellular death can influence disease progression and have therapeutic implications because manipulation of hepatocyte cell death pathways is being considered as a target for treatment of nonalcoholic fatty liver disease. (Hepatology 2016;64:1518-1533).
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Affiliation(s)
- Sanjoy Roychowdhury
- Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Rebecca L. McCullough
- Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio
| | - Carlos Sanz-Garcia
- Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio
| | - Paramananda Saikia
- Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio
| | - Naim Alkhouri
- Department of Gastroenterology, Cleveland Clinic, Cleveland, Ohio,Department of Pediatric Gastroenterology, Cleveland Clinic, Cleveland, Ohio
| | - Ammar Matloob
- Department of Pediatric Gastroenterology, Cleveland Clinic, Cleveland, Ohio
| | - Katherine Pollard
- Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio
| | - Megan R. McMullen
- Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio
| | | | - Laura E. Nagy
- Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio,Department of Gastroenterology, Cleveland Clinic, Cleveland, Ohio,Department of Nutrition, Case Western Reserve University, Cleveland, Ohio,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
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Fulham MA, Mandrekar P. Sexual Dimorphism in Alcohol Induced Adipose Inflammation Relates to Liver Injury. PLoS One 2016; 11:e0164225. [PMID: 27711160 PMCID: PMC5053524 DOI: 10.1371/journal.pone.0164225] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 09/21/2016] [Indexed: 12/17/2022] Open
Abstract
Alcoholic liver disease occurs due to chronic, heavy drinking and is driven both by metabolic alterations and immune cell activation. Women are at a higher risk than men for developing alcohol induced liver injury and this dimorphism is reflected in animal models of alcoholic liver disease. The importance of adipose tissue in alcoholic liver disease is emerging. Chronic alcohol consumption causes adipose tissue inflammation, which can influence liver injury. Sex differences in body fat composition are well known. However, it is still unclear if alcohol-induced adipose tissue inflammation occurs in a sex-dependent manner. Here we have employed the clinically relevant NIAAA model of chronic-binge alcohol consumption to investigate this sexual dimorphism. We report that female mice have greater liver injury than male mice despite lower alcohol consumption. Chronic-binge alcohol induces adipose tissue inflammation in vivo in female mice, which is illustrated by increased expression of TNFα, IL-6, and CCL2, compared to only IL-6 induction in male adipose tissue. Further, macrophage activation markers such as CD68 as well as the pro-inflammatory activation markers CD11b and CD11c were higher in female adipose tissue. Interestingly, alcohol induced expression of TLR2, 3, 4, and 9 in female but not male adipose tissue, without affecting the TLR adaptor, MyD88. Higher trends of serum endotoxin in female mice may likely contribute to adipose tissue inflammation. In vitro chronic alcohol-mediated sensitization of macrophages to endotoxin is independent of sex. In summary, we demonstrate for the first time that there is a sexual dimorphism in alcohol-induced adipose tissue inflammation and female mice exhibit a higher degree of inflammation than male mice.
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Affiliation(s)
- Melissa A. Fulham
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
- Graduate School of Biomedical Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - Pranoti Mandrekar
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
- * E-mail:
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Mandrekar P, Bataller R, Tsukamoto H, Gao B. Alcoholic hepatitis: Translational approaches to develop targeted therapies. Hepatology 2016; 64:1343-55. [PMID: 26940353 PMCID: PMC5010788 DOI: 10.1002/hep.28530] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 02/10/2016] [Accepted: 02/21/2016] [Indexed: 12/12/2022]
Abstract
UNLABELLED Alcoholic liver disease is a leading cause of liver-related mortality worldwide. In contrast to recent advances in therapeutic strategies for patients with viral hepatitis, there is a significant lack of novel therapeutic options for patients with alcoholic liver disease. In particular, there is an urgent need to focus our efforts on effective therapeutic interventions for alcoholic hepatitis (AH), the most severe form of alcoholic liver disease. AH is characterized by an abrupt development of jaundice and complications related to liver insufficiency and portal hypertension in patients with heavy alcohol intake. The mortality of patients with AH is very high (20%-50% at 3 months). Available therapies are not effective in many patients, and targeted approaches are imminently needed. The development of such therapies requires translational studies in human samples and suitable animal models that reproduce the clinical and histological features of AH. In recent years, new animal models that simulate some of the features of human AH have been developed, and translational studies using human samples have identified potential pathogenic factors and histological parameters that predict survival. CONCLUSION This review summarizes the unmet needs for translational studies on the pathogenesis of AH, preclinical translational tools, and emerging drug targets to benefit the AH patient. (Hepatology 2016;64:1343-1355).
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Affiliation(s)
- Pranoti Mandrekar
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
| | - Ramon Bataller
- Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC.
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, University of Southern California, Greater Los Angeles Department of Veterans Affairs Healthcare System, Los Angeles, CA.
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
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Myeloid Cell-Specific Lipin-1 Deficiency Stimulates Endocrine Adiponectin-FGF15 Axis and Ameliorates Ethanol-Induced Liver Injury in Mice. Sci Rep 2016; 6:34117. [PMID: 27666676 PMCID: PMC5036185 DOI: 10.1038/srep34117] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 09/07/2016] [Indexed: 02/08/2023] Open
Abstract
Lipin-1 is a phosphatidate phosphohydrolase (PAP) required for the generation of diacylglycerol during glycerolipid synthesis, and exhibits dual functions in the regulation of lipid metabolism. Lipin-1 has been implicated in the pathogenesis of alcoholic liver disease (ALD). In the present study, we assessed lipin-1 function in myeloid cells in ALD using a myeloid cell-specific lipin-1 knockout (mLipin-1KO) mouse model. Utilizing the Gao-binge ethanol feeding protocol, matched mLipin-1KO mice and littermate loxP control (WT) mice were pair-fed with either an ethanol-containing diet or an ethanol-free diet (control). Surprisingly, deletion of lipin-1 in myeloid cells dramatically attenuated liver inflammatory responses and ameliorated liver injury that would normally occur following the ethanol feeding protocol, but slightly exacerbated the ethanol-induced steatosis in mice. Mechanistically, myeloid cell-specific lipin-1 deficiency concomitantly increased the fat-derived adiponectin and ileum-derived fibroblast growth factor (FGF) 15. In concordance with concerted elevation of circulating adiponectin and FGF15, myeloid cell-specific lipin-1 deficiency diminished hepatic nuclear factor kappa B (NF-κB) activity, limited liver inflammatory responses, normalized serum levels of bile acids, and protected mice from liver damage after ethanol challenge. Our novel data demonstrate that myeloid cell-specific deletion of lipin-1 ameliorated inflammation and alcoholic hepatitis in mice via activation of endocrine adiponectin-FGF15 signaling.
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Liu L, Zhao X, Wang Q, Sun X, Xia L, Wang Q, Yang B, Zhang Y, Montgomery S, Meng H, Geng T, Gong D. Prosteatotic and Protective Components in a Unique Model of Fatty Liver: Gut Microbiota and Suppressed Complement System. Sci Rep 2016; 6:31763. [PMID: 27550859 PMCID: PMC4994046 DOI: 10.1038/srep31763] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 07/27/2016] [Indexed: 01/07/2023] Open
Abstract
Goose can develop severe hepatic steatosis without overt injury, thus it may serve as a unique model for uncovering how steatosis-related injury is prevented. To identify the markedly prosteatotic and protective mechanisms, we performed an integrated analysis of liver transcriptomes and gut microbial metagenomes using samples collected from overfed and normally-fed geese at different time points. The results indicated that the fatty liver transcriptome, initially featuring a ‘metabolism’ pathway, was later joined by ‘cell growth and death’ and ‘immune diseases’ pathways. Gut microbiota played a synergistic role in the liver response as microbial and hepatic genes affected by overfeeding shared multiple pathways. Remarkably, the complement system, an inflammatory component, was comprehensively suppressed in fatty liver, which was partially due to increased blood lactic acid from enriched Lactobacillus. Data from in vitro studies suggested that lactic acid suppressed TNFα via the HNF1α/C5 pathway. In conclusion, gut microbes and their hosts respond to excess energy influx as an organic whole, severe steatosis and related tolerance of goose liver may be partially attributable to gut microbiotic products and suppressed complement system, and lactic acid from gut microbiota participates in the suppression of hepatic TNFα/inflammation through the HNF1α/C5 pathway.
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Affiliation(s)
- Long Liu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Xing Zhao
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Qian Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Xiaoxian Sun
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Lili Xia
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Qianqian Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Biao Yang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Yihui Zhang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Sean Montgomery
- Department of Botany, University of British Columbia, 6270 University Boulevard, British Columbia, V6T 1Z4, Canada
| | - He Meng
- School of Agriculture and Biology, Shanghai Jiaotong University; Shanghai Key Laboratory of Veterinary Biotechnology, 800 Dongchuan Road, Shanghai 200240, China
| | - Tuoyu Geng
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Daoqing Gong
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
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50
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Differential contribution of complement receptor C5aR in myeloid and non-myeloid cells in chronic ethanol-induced liver injury in mice. Mol Immunol 2016; 75:122-32. [PMID: 27280845 DOI: 10.1016/j.molimm.2016.05.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 05/05/2016] [Accepted: 05/07/2016] [Indexed: 01/06/2023]
Abstract
BACKGROUND Complement is implicated in the development of alcoholic liver disease. C3 and C5 contribute to ethanol-induced liver injury; however, the role of C5a receptor (C5aR) on myeloid and non-myeloid cells to progression of injury is not known. METHODS C57BL/6 (WT), global C5aR-/-, myeloid-specific C5aR-/-, and non-myeloid-specific C5aR-/- mice were fed a Lieber-DeCarli diet (32%kcal EtOH) for 25 days. Cultured hepatocytes were challenged with ethanol, TNFα, and C5a. RESULTS Chronic ethanol feeding increased expression of pro-inflammatory mediators in livers of WT mice; this response was completely blunted in C5aR-/- mice. However, C5aR-/- mice were not protected from other measures of hepatocellular damage, including ethanol-induced increases in hepatic triglycerides, plasma alanine aminotransferase and hepatocyte apoptosis. CYP2E1 and 4-hydroxynonenal protein adducts were induced in WT and C5aR-/- mice. Myeloid-specific C5aR-/- mice were protected from ethanol-induced increases in hepatic TNFα, whereas non-myeloid-specific C5aR-/- displayed increased hepatocyte apoptosis and inflammation after chronic ethanol feeding. In cultured hepatocytes, cytotoxicity induced by challenge with ethanol and TNFα was completely eliminated by treatment with C5a in cells from WT, but not C5aR-/- mice. Further, treatment with C5a enhanced activation of pro-survival signal AKT in hepatocytes challenged with ethanol and TNFα. CONCLUSION Taken together, these data reveal a differential role for C5aR during ethanol-induced liver inflammation and injury, with C5aR on myeloid cells contributing to ethanol-induced inflammatory cytokine expression, while non-myeloid C5aR protects hepatocytes from death after chronic ethanol feeding.
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