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He J, Du C, Li C, Li W, Qiu J, Ma M, Chen Y, Zhang Q. Ferroptosis in acute liver Failure: Unraveling the hepcidin-ferroportin axis and therapeutic interventions. Redox Biol 2025; 84:103657. [PMID: 40393152 DOI: 10.1016/j.redox.2025.103657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 04/10/2025] [Accepted: 04/30/2025] [Indexed: 05/22/2025] Open
Abstract
Acute liver failure (ALF) represents a critical clinical syndrome marked by massive hepatocyte death and severe functional deterioration. While metabolic dysregulation is a recognized hallmark, the pathophysiological implications of iron metabolism disturbance in ALF progression remain poorly understood, which may unveil novel therapeutic targets. Using clinical samples and preclinical murine models, we identified ferroptosis as a predominant pathological feature in ALF-affected livers. Notably, pharmacological inhibition of ferroptosis significantly attenuated disease progression in experimental ALF. Mechanistically, dysregulation of the hepcidin-ferroportin (FPN) axis drives hepatic iron overload, precipitating ferroptotic cell death in ALF. The anti-rheumatoid arthritis drug auranofin restored hepcidin-FPN axis homeostasis and mitigated liver injury, though concomitant upregulation of proinflammatory cytokines limited its therapeutic potential. Strikingly, mesenchymal stromal cells (MSCs) demonstrated superior therapeutic efficacy, coordinately modulating the hepcidin-FPN axis while suppressing ferroptosis through PI3K/Akt/Nrf2 pathway activation. Our findings not only establish the causal relationship between hepcidin-FPN axis dysfunction and ferroptosis-driven liver injury, but also propose MSC-based therapy as a multifaceted strategy targeting both iron homeostasis and ferroptosis for ALF management.
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Affiliation(s)
- Jinyong He
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Cong Du
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Cuiping Li
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wei Li
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jinlan Qiu
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Mingpeng Ma
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yunhao Chen
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Qi Zhang
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
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Kouroumalis E, Tsomidis I, Voumvouraki A. HFE-Related Hemochromatosis May Be a Primary Kupffer Cell Disease. Biomedicines 2025; 13:683. [PMID: 40149659 PMCID: PMC11940282 DOI: 10.3390/biomedicines13030683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/28/2025] [Accepted: 03/08/2025] [Indexed: 03/29/2025] Open
Abstract
Iron overload can lead to increased deposition of iron and cause organ damage in the liver, the pancreas, the heart and the synovium. Iron overload disorders are due to either genetic or acquired abnormalities such as excess transfusions or chronic liver diseases. The most common genetic disease of iron deposition is classic hemochromatosis (HH) type 1, which is caused by mutations of HFE. Other rare forms of HH include type 2A with mutations at the gene hemojuvelin or type 2B with mutations in HAMP that encodes hepcidin. HH type 3, is caused by mutations of the gene that encodes transferrin receptor 2. Mutations of SLC40A1 which encodes ferroportin cause either HH type 4A or HH type 4B. In the present review, an overview of iron metabolism including absorption by enterocytes and regulation of iron by macrophages, liver sinusoidal endothelial cells (LSECs) and hepatocyte production of hepcidin is presented. Hereditary Hemochromatosis and the current pathogenetic model are analyzed. Finally, a new hypothesis based on published data was suggested. The Kupffer cell is the primary defect in HFE hemochromatosis (and possibly in types 2 and 3), while the hepcidin-relative deficiency, which is the common underlying abnormality in the three types of HH, is a secondary consequence.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, PAGNI University Hospital, University of Crete Medical School, 71500 Heraklion, Greece
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece;
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Li C, Pang G, Zhao W, Liu Y, Huang X, Chen W, Zhao X, Liu T, Wang P, Fan X, Gao M, Cong M. Hepcidin inhibits hepatocyte apoptosis through the PERK pathway in acute liver injury and fibrosis. Hepatol Commun 2025; 9:e0604. [PMID: 39699302 PMCID: PMC11661744 DOI: 10.1097/hc9.0000000000000604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 10/01/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Hepcidin, a peptide hormone primarily produced by the liver, regulates iron metabolism by interacting with its receptor, ferroportin. Studies have demonstrated that hepcidin participates in the progression of liver fibrosis by regulating HSC activation, but its regulatory effect on hepatocytes remains largely unknown. METHODS A carbon tetrachloride (CCl4)-induced liver fibrosis model was established in C57BL/6 wild-type (WT) and hepcidin knockout (Hamp-/-) mice. Liver injury and inflammation were assessed in WT and Hamp-/- mice at 24 and 48 hours following acute CCl4 exposure. In addition, transcriptomic sequencing of primary hepatocytes was performed to compare gene expression profiles between WT and Hamp-/- mice 24 hours after liver injury. The function of the identified molecule Eif2ak3/PERK (protein kinase R(PKR)-like endoplasmic reticulum kinase), was evaluated both in vitro and in vivo. RESULTS We found that serum hepcidin significantly increased during the progression of liver fibrosis induced by CCl4 and bile duct ligation. In addition, CCl4-treated Hamp-/- mice developed more severe liver injury, liver fibrosis, and hepatocyte apoptosis, with elevated Bax and decreased Bcl-2 expression, compared to the WT mice. Transcriptomic analysis of primary hepatocytes revealed that PERK was upregulated in Hamp-/- mice after CCl4 treatment, promoting apoptosis by regulating Bax and Bcl-2 expression. Subsequently, we demonstrated that hepcidin prevents hepatocyte apoptosis by inhibiting PERK both in vitro and in vivo. CONCLUSIONS Hepcidin inhibits hepatocyte apoptosis through suppression of the PERK pathway, highlighting its protective role in liver fibrosis and identifying a potential therapeutic target for the treatment of liver fibrosis.
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Affiliation(s)
- Changying Li
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Guojin Pang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
- Emergency Department, The First Affiliated Hospital of Tsinghua University, Beijing, China
| | - Weihua Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yingying Liu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Xiaoli Huang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Wei Chen
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xinyan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Tianhui Liu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Ping Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Xu Fan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Ming Gao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Min Cong
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health and National Clinical Research Center of Digestive Diseases, Beijing, China
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Escuder-Rodríguez JJ, Liang D, Jiang X, Sinicrope FA. Ferroptosis: Biology and Role in Gastrointestinal Disease. Gastroenterology 2024; 167:231-249. [PMID: 38431204 PMCID: PMC11193643 DOI: 10.1053/j.gastro.2024.01.051] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 01/29/2024] [Accepted: 01/30/2024] [Indexed: 03/05/2024]
Abstract
Ferroptosis is a form of nonapoptotic cell death that involves iron-dependent phospholipid peroxidation induced by accumulation of reactive oxygen species, and results in plasma membrane damage and the release of damage-associated molecular patterns. Ferroptosis has been implicated in aging and immunity, as well as disease states including intestinal and liver conditions and cancer. To date, several ferroptosis-associated genes and pathways have been implicated in liver disease. Although ferroptotic cell death is associated with dysfunction of the intestinal epithelium, the underlying molecular basis is poorly understood. As the mechanisms regulating ferroptosis become further elucidated, there is clear potential to use ferroptosis to achieve therapeutic benefit.
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Affiliation(s)
- Juan-José Escuder-Rodríguez
- Department of Medicine, Gastrointestinal Research Unit, Mayo Clinic Alix School of Medicine, Rochester, Minnesota
| | - Deguang Liang
- Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Xuejun Jiang
- Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
| | - Frank A Sinicrope
- Department of Medicine, Gastrointestinal Research Unit, Mayo Clinic Alix School of Medicine, Rochester, Minnesota.
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Ahmadi Badi S, Malek A, Seyedi SA, Bereimipour A, Irian S, Shojaie S, Sohouli MH, Rohani P, Masotti A, Khatami S, Siadat SD. Direct and macrophage stimulation mediated effects of active, inactive, and cell-free supernatant forms of Akkermansia muciniphila and Faecalibacterium duncaniae on hepcidin gene expression in HepG2 cells. Arch Microbiol 2024; 206:287. [PMID: 38833010 DOI: 10.1007/s00203-024-04007-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 05/16/2024] [Indexed: 06/06/2024]
Abstract
Hepcidin is a crucial regulator of iron homeostasis with protective effects on liver fibrosis. Additionally, gut microbiota can also affect liver fibrosis and iron metabolism. Although the hepatoprotective potential of Akkermansia muciniphila and Faecalibacterium duncaniae, formerly known as F. prausnitzii, has been reported, however, their effects on hepcidin expression remain unknown. We investigated the direct and macrophage stimulation-mediated effects of active, heat-inactivated, and cell-free supernatant (CFS) forms of A. muciniphila and F. duncaniae on hepcidin expression in HepG2 cells by RT-qPCR analysis. Following stimulation of phorbol-12-myristate-13-acetate (PMA) -differentiated THP-1 cells with A. muciniphila and F. duncaniae, IL-6 concentration was assessed via ELISA. Additionally, the resulting supernatant was treated with HepG2 cells to evaluate the effect of macrophage stimulation on hepcidin gene expression. The expression of genes mediating iron absorption and export was also examined in HepG2 and Caco-2 cells via RT-qPCR. All forms of F. duncaniae increased hepcidin expression while active and heat-inactivated/CFS forms of A. muciniphila upregulated and downregulated its expression, respectively. Active, heat-inactivated, and CFS forms of A. muciniphila and F. duncaniae upregulated hepcidin expression, consistent with the elevation of IL-6 released from THP-1-stimulated cells as a macrophage stimulation effect in HepG2 cells. A. muciniphila and F. duncaniae in active, inactive, and CFS forms altered the expression of hepatocyte and intestinal iron-mediated absorption /exporter genes, namely dcytb and dmt1, and fpn in HepG2 and Caco-2 cells, respectively. In conclusion, A. muciniphila and F. duncaniae affect not only directly but also through macrophage stimulation the expression of hepcidin gene in HepG2 cells. These findings underscore the potential of A. muciniphila and F. duncaniae as a potential therapeutic target for liver fibrosis by modulating hepcidin and intestinal and hepatocyte iron metabolism mediated gene expression.
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Affiliation(s)
- Sara Ahmadi Badi
- Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran
| | - Amin Malek
- Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran
| | | | - Ahmad Bereimipour
- Department of Biological Sciences and BioDiscovery Institute, University of North Texas, Denton, TX, 76203, USA
| | - Saeed Irian
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Shima Shojaie
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran
| | - Mohammad Hassan Sohouli
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran
| | - Pejman Rohani
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran
| | - Andrea Masotti
- Research Laboratories, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy
| | - Shohreh Khatami
- Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran.
| | - Seyed Davar Siadat
- Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran.
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran.
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Ding Y, Yanagi K, Yang F, Callaway E, Cheng C, Hensel ME, Menon R, Alaniz RC, Lee K, Jayaraman A. Oral supplementation of gut microbial metabolite indole-3-acetate alleviates diet-induced steatosis and inflammation in mice. eLife 2024; 12:RP87458. [PMID: 38412016 PMCID: PMC10942630 DOI: 10.7554/elife.87458] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. There is growing evidence that dysbiosis of the intestinal microbiota and disruption of microbiota-host interactions contribute to the pathology of NAFLD. We previously demonstrated that gut microbiota-derived tryptophan metabolite indole-3-acetate (I3A) was decreased in both cecum and liver of high-fat diet-fed mice and attenuated the expression of inflammatory cytokines in macrophages and Tnfa and fatty acid-induced inflammatory responses in an aryl-hydrocarbon receptor (AhR)-dependent manner in hepatocytes. In this study, we investigated the effect of orally administered I3A in a mouse model of diet-induced NAFLD. Western diet (WD)-fed mice given sugar water (SW) with I3A showed dramatically decreased serum ALT, hepatic triglycerides (TG), liver steatosis, hepatocyte ballooning, lobular inflammation, and hepatic production of inflammatory cytokines, compared to WD-fed mice given only SW. Metagenomic analysis show that I3A administration did not significantly modify the intestinal microbiome, suggesting that I3A's beneficial effects likely reflect the metabolite's direct actions on the liver. Administration of I3A partially reversed WD-induced alterations of liver metabolome and proteome, notably, decreasing expression of several enzymes in hepatic lipogenesis and β-oxidation. Mechanistically, we also show that AMP-activated protein kinase (AMPK) mediates the anti-inflammatory effects of I3A in macrophages. The potency of I3A in alleviating liver steatosis and inflammation clearly demonstrates its potential as a therapeutic modality for preventing the progression of steatosis to non-alcoholic steatohepatitis (NASH).
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Affiliation(s)
- Yufang Ding
- Artie McFerrin Department of Chemical Engineering, Texas A&M UniversityCollege StationUnited States
| | - Karin Yanagi
- Department of Chemical and Biological Engineering, Tufts UniversityMedfordUnited States
| | - Fang Yang
- Artie McFerrin Department of Chemical Engineering, Texas A&M UniversityCollege StationUnited States
| | - Evelyn Callaway
- Artie McFerrin Department of Chemical Engineering, Texas A&M UniversityCollege StationUnited States
| | - Clint Cheng
- Artie McFerrin Department of Chemical Engineering, Texas A&M UniversityCollege StationUnited States
| | - Martha E Hensel
- Department of Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M UniversityCollege StationUnited States
| | - Rani Menon
- Artie McFerrin Department of Chemical Engineering, Texas A&M UniversityCollege StationUnited States
| | - Robert C Alaniz
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas Health Science Center, Texas A&M UniversityBryanUnited States
| | - Kyongbum Lee
- Department of Chemical and Biological Engineering, Tufts UniversityMedfordUnited States
| | - Arul Jayaraman
- Artie McFerrin Department of Chemical Engineering, Texas A&M UniversityCollege StationUnited States
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas Health Science Center, Texas A&M UniversityBryanUnited States
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Ahmadi Badi S, Bereimipour A, Rohani P, Khatami S, Siadat SD. Interplay between gut microbiota and the master iron regulator, hepcidin, in the pathogenesis of liver fibrosis. Pathog Dis 2024; 82:ftae005. [PMID: 38555503 PMCID: PMC10990161 DOI: 10.1093/femspd/ftae005] [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: 10/23/2023] [Revised: 02/12/2024] [Accepted: 03/28/2024] [Indexed: 04/02/2024] Open
Abstract
INTRODUCTION There is a proven role for hepcidin and the composition of gut microbiota and its derivatives in the pathophysiology of liver fibrosis. AREA COVERED This review focuses on the literature search regarding the effect of hepcidin and gut microbiota on regulating liver physiology. We presented the regulating mechanisms of hepcidin expression and discussed the possible interaction between gut microbiota and hepcidin regulation. Furthermore, we investigated the importance of the hepcidin gene in biological processes and bacterial interactions using bioinformatics analysis. EXPERT OPINION One of the main features of liver fibrosis is iron accumulation in hepatic cells, including hepatocytes. This accumulation can induce an oxidative stress response, inflammation, and activation of hepatic stellate cells. Hepcidin is a crucial regulator of iron by targeting ferroportin expressed on hepatocytes, macrophages, and enterocytes. Various stimuli, such as iron load and inflammatory signals, control hepcidin regulation. Furthermore, a bidirectional relationship exists between iron and the composition and metabolic activity of gut microbiota. We explored the potential of gut microbiota to influence hepcidin expression and potentially manage liver fibrosis, as the regulation of iron metabolism plays a crucial role in this context.
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Affiliation(s)
- Sara Ahmadi Badi
- Biochemistry Department, Pasteur Institute of Iran, Tehran, 1963737611, Iran
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, 1416753955, Iran
| | - Ahmad Bereimipour
- Department of Biological Sciences and BioDiscovery Institute, University of North Texas, Denton, TX 76203, USA
| | - Pejman Rohani
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, 1416753955, Iran
| | - Shohreh Khatami
- Biochemistry Department, Pasteur Institute of Iran, Tehran, 1963737611, Iran
| | - Seyed Davar Siadat
- Microbiology Research Center, Pasteur Institute of Iran, Tehran, 1963737611, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran,1963737611, Iran
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Schreiner OD, Schreiner TG. Iron chelators as a therapeutic option for Alzheimer's disease-A mini-review. FRONTIERS IN AGING 2023; 4:1234958. [PMID: 37602277 PMCID: PMC10433644 DOI: 10.3389/fragi.2023.1234958] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 07/17/2023] [Indexed: 08/22/2023]
Abstract
Neurodegenerative disorders, particularly Alzheimer's disease (AD), remain a great challenge regarding the finding of effective treatment, one main reason being the incomplete understanding of their etiology. With many intensely debated hypotheses, a newer approach based on the impact of iron imbalance in sustaining neurodegeneration in the central nervous system becomes increasingly popular. Altered iron homeostasis leads to increased iron accumulation in specific brain areas, explaining the clinical picture of AD patients. Moreover, growing evidence sustains the significant impact of iron metabolism in relationship to other pathological processes encountered in the AD-affected brain, such as the amyloidogenic pathway, chronic inflammation, or oxidative stress. In this context, this mini-review aims to summarize the novel data from the continuously expanding literature on this topic in a didactic manner. Thus, in the first part, the authors briefly highlight the most relevant aspects related to iron absorption, transport, regulation, and elimination at the cerebral level, focusing on the role of the blood-brain barrier and the newer concept of ferroptosis. Subsequently, currently available iron chelation therapies are discussed, including an overview of the most relevant clinical trials on this topic. In the final part, based on the latest results from in vitro and in vivo studies, new research directions are suggested to enhance the development of effective antidementia therapies.
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Affiliation(s)
- Oliver Daniel Schreiner
- Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania
- Medical Oncology Department, Regional Institute of Oncology, Iasi, Romania
| | - Thomas Gabriel Schreiner
- Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania
- Faculty of Electrical Engineering and Information Technology, Gheorghe Asachi Technical University of Iasi, Iasi, Romania
- Faculty of Medicine, University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
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Baratz E, Protchenko O, Jadhav S, Zhang D, Violet PC, Grounds S, Shakoury-Elizeh M, Levine M, Philpott CC. Vitamin E Induces Liver Iron Depletion and Alters Iron Regulation in Mice. J Nutr 2023; 153:1866-1876. [PMID: 37127137 PMCID: PMC10375508 DOI: 10.1016/j.tjnut.2023.04.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/14/2023] [Accepted: 04/27/2023] [Indexed: 05/03/2023] Open
Abstract
BACKGROUND Vitamin E (vit E) is an essential nutrient that functions as a lipophilic antioxidant and is used clinically to treat nonalcoholic fatty liver disease, where it suppresses oxidative damage and impedes the progression of steatosis and fibrosis. Mice lacking a critical liver iron-trafficking protein also manifest steatosis because of iron-mediated oxidative damage and are protected from liver disease by oral vit E supplements. OBJECTIVES We aimed to examine the role of dietary vit E supplementation in modulating iron-sensing regulatory systems and nonheme iron levels in mouse liver. METHODS C57Bl/6 male mice, aged 6 wk, were fed purified diets containing normal amounts of iron and either control (45 mg/kg) or elevated (450 mg/kg) levels of 2R-α-tocopherol (vit E) for 18 d. Mouse plasma and liver were analyzed for nonheme iron, levels and activity of iron homeostatic proteins, and markers of oxidative stress. We compared means ± SD for iron and oxidative stress parameters between mice fed the control diet and those fed the vit E diet. RESULTS The Vit E-fed mice exhibited lower levels of liver nonheme iron (38% reduction, P < 0.0001) and ferritin (74% reduction, P < 0.01) than control-fed mice. The levels of liver mRNA for transferrin receptor 1 and divalent metal transporter 1 were reduced to 42% and 57% of the control, respectively. The mRNA levels for targets of nuclear factor erythroid 2-related factor (Nrf2), a major regulator of the oxidative stress response and iron-responsive genes, were also suppressed in vit E livers. Hepcidin, an iron regulatory hormone, levels were lower in the plasma (P < 0.05), and ferroportin (FPN), the iron exporter regulated by hepcidin, was expressed at higher levels in the liver (P < 0.05). CONCLUSIONS Oral vit E supplementation in mice can lead to depletion of liver iron stores by suppressing the iron- and redox-sensing transcription factor Nrf2, leading to enhanced iron efflux through liver FPN. Iron depletion may indirectly enhance the antioxidative effects of vit E.
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Affiliation(s)
- Ethan Baratz
- Genetics and Metabolism Section, NIDDK, NIH, Bethesda, MD, United States
| | - Olga Protchenko
- Genetics and Metabolism Section, NIDDK, NIH, Bethesda, MD, United States
| | | | - Deliang Zhang
- Section on Human Iron Metabolism, NICHD, NIH, Bethesda, MD, United States
| | | | - Samantha Grounds
- Genetics and Metabolism Section, NIDDK, NIH, Bethesda, MD, United States
| | | | - Mark Levine
- Molecular and Clinical Nutrition Section, NIDDK, NIH, Bethesda, MD, United States
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Kouroumalis E, Tsomidis I, Voumvouraki A. Iron as a therapeutic target in chronic liver disease. World J Gastroenterol 2023; 29:616-655. [PMID: 36742167 PMCID: PMC9896614 DOI: 10.3748/wjg.v29.i4.616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/03/2022] [Accepted: 12/31/2022] [Indexed: 01/20/2023] Open
Abstract
It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71003, Greece
| | - Ioannis Tsomidis
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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11
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Lin F, Tuffour A, Hao G, Peprah FA, Huang A, Zhou Y, Zhang H. Distinctive modulation of hepcidin in cancer and its therapeutic relevance. Front Oncol 2023; 13:1141603. [PMID: 36895478 PMCID: PMC9989193 DOI: 10.3389/fonc.2023.1141603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 02/08/2023] [Indexed: 02/23/2023] Open
Abstract
Hepcidin, a short peptide synthesized primarily by hepatocytes in response to increased body iron and inflammation, is a crucial iron-regulating factor. Hepcidin regulates intestinal iron absorption and releases iron from macrophages into plasma through a negative iron feedback mechanism. The discovery of hepcidin inspired a torrent of research into iron metabolism and related problems, which have radically altered our understanding of human diseases caused by an excess of iron, an iron deficiency, or an iron disparity. It is critical to decipher how tumor cells manage hepcidin expression for their metabolic requirements because iron is necessary for cell survival, particularly for highly active cells like tumor cells. Studies show that tumor and non-tumor cells express and control hepcidin differently. These variations should be explored to produce potential novel cancer treatments. The ability to regulate hepcidin expression to deprive cancer cells of iron may be a new weapon against cancer cells.
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Affiliation(s)
- Feng Lin
- Key Laboratory of Healthy Freshwater Aquaculture, Ministry of Agriculture, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
| | - Alex Tuffour
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China.,State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Guijie Hao
- Key Laboratory of Healthy Freshwater Aquaculture, Ministry of Agriculture, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
| | | | - Aixia Huang
- Key Laboratory of Healthy Freshwater Aquaculture, Ministry of Agriculture, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
| | - Yang Zhou
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Haiqi Zhang
- Key Laboratory of Healthy Freshwater Aquaculture, Ministry of Agriculture, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
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12
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Fujiwara S, Izawa T, Mori M, Atarashi M, Yamate J, Kuwamura M. Dietary iron overload enhances Western diet induced hepatic inflammation and alters lipid metabolism in rats sharing similarity with human DIOS. Sci Rep 2022; 12:21414. [PMID: 36496443 PMCID: PMC9741655 DOI: 10.1038/s41598-022-25838-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022] Open
Abstract
Hepatic iron overload is often concurrent with nonalcoholic fatty liver disease (NAFLD). Dysmetabolic iron overload syndrome (DIOS) is characterized by an increase in the liver and body iron stores and metabolic syndrome components. Increasing evidences suggest an overlap between NAFLD with iron overload and DIOS; however, the mechanism how iron is involved in their pathogenesis remains unclear. Here we investigated the role of iron in the pathology of a rat model of NAFLD with iron overload. Rats fed a Western (high-fat and high-fructose) diet for 26 weeks represented hepatic steatosis with an increased body weight and dyslipidemia. Addition of dietary iron overload to the Western diet feeding further increased serum triglyceride and cholesterol, and enhanced hepatic inflammation; the affected liver had intense iron deposition in the sinusoidal macrophages/Kupffer cells, associated with nuclear translocation of NFκB and upregulation of Th1/M1-related cytokines. The present model would be useful to investigate the mechanism underlying the development and progression of NAFLD as well as DIOS, and to elucidate an important role of iron as one of the "multiple hits" factors.
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Affiliation(s)
- Sakura Fujiwara
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531 Japan
| | - Takeshi Izawa
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531 Japan
| | - Mutsuki Mori
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531 Japan
| | - Machi Atarashi
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531 Japan
| | - Jyoji Yamate
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531 Japan
| | - Mitsuru Kuwamura
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531 Japan
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Ma C, Han L, Zhu Z, Heng Pang C, Pan G. Mineral metabolism and ferroptosis in non-alcoholic fatty liver diseases. Biochem Pharmacol 2022; 205:115242. [PMID: 36084708 DOI: 10.1016/j.bcp.2022.115242] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 08/28/2022] [Accepted: 08/30/2022] [Indexed: 11/02/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease worldwide. Minerals including iron, copper, zinc, and selenium, fulfil an essential role in various biochemical processes. Moreover, the identification of ferroptosis and cuproptosis further underscores the importance of intracellular mineral homeostasis. However, perturbation of minerals has been frequently reported in patients with NAFLD and related diseases. Interestingly, studies have attempted to establish an association between mineral disorders and NAFLD pathological features, including oxidative stress, mitochondrial dysfunction, inflammatory response, and fibrogenesis. In this review, we aim to provide an overview of the current understanding of mineral metabolism (i.e., absorption, utilization, and transport) and mineral interactions in the pathogenesis of NAFLD. More importantly, this review highlights potential therapeutic strategies, challenges, future directions for targeting mineral metabolism in the treatment of NAFLD.
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Affiliation(s)
- Chenhui Ma
- Department of Chemical and Environmental Engineering, University of Nottingham Ningbo China, Ningbo 315100, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Li Han
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zheying Zhu
- Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK.
| | - Cheng Heng Pang
- Department of Chemical and Environmental Engineering, University of Nottingham Ningbo China, Ningbo 315100, China.
| | - Guoyu Pan
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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14
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Chen H, Zhao W, Yan X, Huang T, Yang A. Overexpression of Hepcidin Alleviates Steatohepatitis and Fibrosis in a Diet-induced Nonalcoholic Steatohepatitis. J Clin Transl Hepatol 2022; 10:577-588. [PMID: 36062292 PMCID: PMC9396326 DOI: 10.14218/jcth.2021.00289] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 09/22/2021] [Accepted: 09/28/2021] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND AND AIMS Iron overload can contribute to the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH). Hepcidin (Hamp), which is primarily synthesized in hepatocytes, is a key regulator of iron metabolism. However, the role of Hamp in NASH remains unclear. Therefore, we aimed to elucidate the role of Hamp in the pathophysiology of NASH. METHODS Male mice were fed a choline-deficient L-amino acid-defined (CDAA) diet for 16 weeks to establish the mouse NASH model. A choline-supplemented amino acid-defined (CSAA) diet was used as the control diet. Recombinant adeno-associated virus genome 2 serotype 8 vector expressing Hamp (rAAV2/8-Hamp) or its negative control (rAAV2/8-NC) was administered intravenously at week 8 of either the CDAA or CSAA diet. RESULTS rAAV2/8-Hamp treatment markedly decreased liver weight and improved hepatic steatosis in the CDAA-fed mice, accompanied by changes in lipogenesis-related genes and adiponectin expression. Compared with the control group, rAAV2/8-Hamp therapy attenuated liver damage, with mice exhibiting reduced histological NAFLD inflammation and fibrosis, as well as lower levels of liver enzymes. Moreover, α-smooth muscle actin-positive activated hepatic stellate cells (HSCs) and CD68-postive macrophages increased in number in the CDAA-fed mice, which was reversed by rAAV2/8-Hamp treatment. Consistent with the in vivo findings, overexpression of Hamp increased adiponectin expression in hepatocytes and Hamp treatment inhibited HSC activation. CONCLUSIONS Overexpression of Hamp using rAAV2/8-Hamp robustly attenuated liver steatohepatitis, inflammation, and fibrosis in an animal model of NASH, suggesting a potential therapeutic role for Hamp.
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Affiliation(s)
- Hui Chen
- Digestive Department, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- Correspondence to: Hui Chen, Digestive Department, Beijing Chaoyang Hospital, Capital Medical University, No. 5 Jingyuan Road, Shijingshan District, Beijing 100043, China. Tel: +86-10-51718484, Fax: +86-10-83165944, E-mail: . Aiting Yang, Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China. ORCID: https://orcid.org/0000-0002-5671-696X. Tel: +86-10-63139311, Fax: +86-10-83165944, E-mail:
| | - Wenshan Zhao
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Xuzhen Yan
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Tao Huang
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Aiting Yang
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center of Digestive Diseases, Beijing, China
- Beijing Clinical Medicine Institute, Beijing, China
- Correspondence to: Hui Chen, Digestive Department, Beijing Chaoyang Hospital, Capital Medical University, No. 5 Jingyuan Road, Shijingshan District, Beijing 100043, China. Tel: +86-10-51718484, Fax: +86-10-83165944, E-mail: . Aiting Yang, Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing 100050, China. ORCID: https://orcid.org/0000-0002-5671-696X. Tel: +86-10-63139311, Fax: +86-10-83165944, E-mail:
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15
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Sumaily KM. The Roles and Pathogenesis Mechanisms of a Number of Micronutrients in the Prevention and/or Treatment of Chronic Hepatitis, COVID-19 and Type-2 Diabetes Mellitus. Nutrients 2022; 14:2632. [PMID: 35807813 PMCID: PMC9268086 DOI: 10.3390/nu14132632] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 06/18/2022] [Accepted: 06/21/2022] [Indexed: 02/06/2023] Open
Abstract
A trace element is a chemical element with a concentration (or other measures of an amount) that is very low. The essential TEs, such as copper (Cu), selenium (Se), zinc (Zn), iron (Fe) and the electrolyte magnesium (Mg) are among the most commonly studied micronutrients. Each element has been shown to play a distinctive role in human health, and TEs, such as iron (Fe), zinc (Zn) and copper (Cu), are among the essential elements required for the organisms' well-being as they play crucial roles in several metabolic pathways where they act as enzyme co-factors, anti-inflammatory and antioxidant agents. Epidemics of infectious diseases are becoming more frequent and spread at a faster pace around the world, which has resulted in major impacts on the economy and health systems. Different trace elements have been reported to have substantial roles in the pathogenesis of viral infections. Micronutrients have been proposed in various studies as determinants of liver disorders, COVID-19 and T2DM risks. This review article sheds light on the roles and mechanisms of micronutrients in the pathogenesis and prevention of chronic hepatitis B, C and E, as well as Coronavirus-19 infection and type-2 diabetes mellitus. An update on the status of the aforementioned micronutrients in pre-clinical and clinical settings is also briefly summarized.
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Affiliation(s)
- Khalid M Sumaily
- Clinical Biochemistry Unit, Department of Pathology, College of Medicine, King Saud University, Riyadh P.O. Box 145111, Saudi Arabia
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16
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Hepcidin in hepatocellular carcinoma. Br J Cancer 2022; 127:185-192. [PMID: 35264787 PMCID: PMC9296449 DOI: 10.1038/s41416-022-01753-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 01/26/2022] [Accepted: 02/09/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common reasons for cancer-related deaths. Excess iron increases HCC risk. Inevitably, hepcidin, the iron hormone that maintains systemic iron homoeostasis is involved in HCC pathology. Distinct from other cancers that show high hepcidin expression, HCC patients can show low hepcidin levels. Thus, it is of immense clinical benefit to address the regulation and action of hepcidin in HCC as this may help in identifying molecular targets for diagnosis, prognosis, and therapeutics. Accordingly, this review explores hepcidin in HCC. It presents the levels of tissue and serum hepcidin and explains the mechanisms that contribute to hepcidin reduction in HCC. These include downregulation of HAMP, TfR2, HJV, ALK2 and circular RNA circ_0004913, upregulation of matriptase-2 and GDF15, inactivation of RUNX3 and mutation in TP53. The enigmas around mir-122 and the functionalities of two major hepcidin inducers BMP6 and IL6 in relation to hepcidin in HCC are discussed. Effects of hepcidin downregulation are explained, specifically, increased cancer proliferation via activation of CDK1/STAT3 pathway and increased HCC risk due to reduction in a hepcidin-mediated protective effect against hepatic stellate cell activation. Hepcidin–ferroportin axis in HCC is addressed. Finally, the role of hepcidin in the diagnosis, prognosis and therapeutics of HCC is highlighted.
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T K Y, Manjrekar PA, MS R, Rai S, Sindhu, Arya. Evaluation of hepcidin and its relationship with iron in non-alcoholic fatty liver disease. Biomedicine (Taipei) 2022. [DOI: 10.51248/.v42i1.680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Introduction and Aim: There is an increase in the incidence of non-alcoholic fatty liver disease (NAFLD) in obese people, type 2 diabetes and metabolic syndrome. Iron leads to the development of NAFLD. Hence serum hepcidin played a vital role in the development of liver cirrhosis. This study was undertaken to evaluate the role of hepcidin and iron and their relationship with NAFLD.
Materials and Methods: This cross-sectional hospital-based study involved 50 patients. Plasma was evaluated for hepcidin by ELISA. and iron by semi-autoanalyzer. Hepcidin and iron were correlated using Spearman’s correlation.
Results: There was a positive correlation between hepcidin and iron in NAFLD patients. We observed that patients with lower BMI were prone to develop NAFLD. Positive correlation of hepcidin with iron has led to diminished ability to inhibit iron.
Conclusion: Further studies related to the altered lipid metabolism its link with iron, or change in the genes responsible for maintenance of iron balance, or a blend of both results in overload of iron in NAFLD patients. In the development of NAFLD iron played a vital role hence could be used as a target for treatment. Therefore, this evidence-based study may result in new treatment modalities in NAFLD.
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Raj D, Sharma V, Upadhyaya A, Kumar N, Joshi R, Acharya V, Kumar D, Patial V. Swertia purpurascens Wall ethanolic extract mitigates hepatic fibrosis and restores hepatic hepcidin levels via inhibition of TGFβ/SMAD/NFκB signaling in rats. JOURNAL OF ETHNOPHARMACOLOGY 2022; 284:114741. [PMID: 34699946 DOI: 10.1016/j.jep.2021.114741] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/28/2021] [Accepted: 10/09/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Swertia purpurascens Wall belongs to a well-known genus in traditional systems of medicine worldwide. In folklore, it is used to treat various ailments, including hepatic disorders, as an alternative to the endangered species Swertia chirayita. However, the therapeutic potential of Swertia purpurascens Wall against hepatic fibrosis has not been validated yet. AIM OF THE STUDY The present study was planned to evaluate the efficacy of the Swertia purpurascens Wall extract (SPE) against hepatic fibrosis and elucidate the underlying mechanism of action. MATERIALS AND METHODS The metabolite profiling of the SPE was done using UHPLC-QTOF-MS/MS. The acute oral toxicity study of SPE at 2 g/kg BW dose was done in rats. Further, the liver fibrosis was induced by the CCl4 intoxication, and the efficacy of SPE at three doses (100, 200 and 400 mg/kg BW) was evaluated by studying biochemical parameters, histopathology, immunohistochemistry, qRT-PCR, western blotting and in silico analysis. RESULTS UHPLC-QTOF-MS/MS analysis revealed the presence of a total of 23 compounds in SPE. Acute oral toxicity study of SPE at 2 g/kg BW showed no harmful effects in rats. Further, the liver fibrosis was induced by the CCl4 administration, and the efficacy of SPE was evaluated at three doses (100, 200 and 400 mg/kg BW). SPE treatment significantly improved the body weight gain, the relative liver weight, serum liver injury markers and endogenous antioxidant enzyme levels in the CCl4-treated rats. SPE also recovered the altered liver histology and effectively reduced the fibrotic tissue deposition in the hepatic parenchyma. Further, SPE significantly inhibited the fibrotic (TGFβ, αSMA, SMADs and Col1A), proinflammatory markers (NFκB, TNFα and IL1β) and apoptosis in the liver tissue. Interestingly, SPE treatment also restored the altered hepcidin levels in the liver tissue. In silico study revealed the potential of various metabolites as drug candidates and their interaction with target proteins. CONCLUSION Altogether, SPE showed its therapeutic potential against CCl4-induced hepatic fibrosis by restoring the hepatic hepcidin levels and inhibiting TGFβ/SMAD/NFκB signaling in rats.
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Affiliation(s)
- Desh Raj
- Pharmacology and Toxicology Laboratory, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; PG Department of Dravyaguna, Rajiv Gandhi Govt. Post Graduate Ayurvedic College and Hospital, Paprola, 176115, H.P, India
| | - Vinesh Sharma
- Pharmacology and Toxicology Laboratory, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India
| | - Ashwani Upadhyaya
- PG Department of Dravyaguna, Rajiv Gandhi Govt. Post Graduate Ayurvedic College and Hospital, Paprola, 176115, H.P, India
| | - Neeraj Kumar
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India
| | - Robin Joshi
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India
| | - Vishal Acharya
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India
| | - Dinesh Kumar
- Chemical Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India
| | - Vikram Patial
- Pharmacology and Toxicology Laboratory, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India.
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Kouroumalis E, Voumvouraki A. Hepatitis C virus: A critical approach to who really needs treatment. World J Hepatol 2022; 14:1-44. [PMID: 35126838 PMCID: PMC8790391 DOI: 10.4254/wjh.v14.i1.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/14/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction of effective drugs in the treatment of hepatitis C virus (HCV) infection has prompted the World Health Organization to declare a global eradication target by 2030. Propositions have been made to screen the general population and treat all HCV carriers irrespective of the disease status. A year ago the new severe acute respiratory syndrome coronavirus 2 virus appeared causing a worldwide pandemic of coronavirus disease 2019 disease. Huge financial resources were redirected, and the pandemic became the first priority in every country. In this review, we examined the feasibility of the World Health Organization elimination program and the actual natural course of HCV infection. We also identified and analyzed certain comorbidity factors that may aggravate the progress of HCV and some marginalized subpopulations with characteristics favoring HCV dissemination. Alcohol consumption, HIV coinfection and the presence of components of metabolic syndrome including obesity, hyperuricemia and overt diabetes were comorbidities mostly responsible for increased liver-related morbidity and mortality of HCV. We also examined the significance of special subpopulations like people who inject drugs and males having sex with males. Finally, we proposed a different micro-elimination screening and treatment program that can be implemented in all countries irrespective of income. We suggest that screening and treatment of HCV carriers should be limited only in these particular groups.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, University of Crete Medical School, Heraklion 71500, Crete, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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20
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Manrai M, Dawra S, Kapoor R, Srivastava S, Singh A. Anemia in cirrhosis: An underestimated entity. World J Clin Cases 2022; 10:777-789. [PMID: 35127894 PMCID: PMC8790443 DOI: 10.12998/wjcc.v10.i3.777] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/18/2021] [Accepted: 12/25/2021] [Indexed: 02/06/2023] Open
Abstract
Anemia in a patient with cirrhosis is a clinically pertinent but often overlooked clinical entity. Relevant guidelines highlight the algorithmic approach of managing a patient of cirrhosis presenting with acute variceal hemorrhage but day-to-day management in hospital and out-patient raises multiple dilemmas: Whether anemia is a disease complication or a part of the disease spectrum? Should iron, folic acid, and vitamin B complex supplementation and nutritional advice, suffice in those who can perform tasks of daily living but have persistently low hemoglobin. How does one investigate and manage anemia due to multifactorial etiologies in the same patient: Acute or chronic blood loss because of portal hypertension and bone marrow aplasia secondary to hepatitis B or C viremia? To add to the clinician's woes the prevalence of anemia increases with increasing disease severity. We thus aim to critically analyze the various pathophysiological mechanisms complicating anemia in a patient with cirrhosis with an emphasis on the diagnostic flowchart in such patients and proposed management protocols thereafter.
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Affiliation(s)
- Manish Manrai
- Department of Internal Medicine, Armed Forces Medical College, Pune 411040, India
| | - Saurabh Dawra
- Department of Medicine and Gastroenterology, Command Hospital, Pune 411040, India
| | - Rajan Kapoor
- Department of Medicine, Command Hospital, Kolkata 70027, India
| | - Sharad Srivastava
- Department of Medicine and Gastroenterology, Command Hospital, Pune 411040, India
| | - Anupam Singh
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
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21
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Anti-Oxidant and Anti-Inflammatory Effects of Lipopolysaccharide from Rhodobacter sphaeroides against Ethanol-Induced Liver and Kidney Toxicity in Experimental Rats. Molecules 2021; 26:molecules26247437. [PMID: 34946518 PMCID: PMC8707101 DOI: 10.3390/molecules26247437] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/05/2021] [Accepted: 12/06/2021] [Indexed: 12/20/2022] Open
Abstract
This study aimed to investigate the protective effects of lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) against ethanol-induced hepatotoxicity and nephrotoxicity in experimental rats. The study involved an intact control group, LPS-RS group, two groups were given ethanol (3 and 5 g/kg/day) for 28 days, and two other groups (LPS-RS + 3 g/kg ethanol) and (LPS-RS + 5 g/kg ethanol) received a daily dose of LPS-RS (800 μg/kg) before ethanol. Ethanol significantly increased the expression of nuclear factor kappa B (NF-κB) and levels of malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in the liver tissue and decreased anti-oxidant enzymes. Hepcidin expression was downregulated in the liver, with increased serum levels of ferritin and iron. Prior-administration of LPS-RS alleviated the increase in oxidative stress and inflammatory markers, and preserved iron homeostasis markers. In the kidney, administration of ethanol caused significant increase in the expression of NF-κB and the levels of TNF-α and kidney injury markers; whereas LPS-RS + ethanol groups had significantly lower levels of those parameters. In conclusion; this study reports anti-oxidant, anti-inflammatory and iron homeostasis regulatory effects of the toll-like receptor 4 (TLR4) antagonist LPS-RS against ethanol induced toxicity in both the liver and the kidney of experimental rats.
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Zaman BA, Rasool SO, Merza MA, Abdulah DM. Hepcidin-to-ferritin ratio: A potential novel index to predict iron overload-liver fibrosis in ß-thalassemia major. Transfus Clin Biol 2021; 29:153-160. [PMID: 34856399 DOI: 10.1016/j.tracli.2021.11.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 11/25/2021] [Indexed: 12/15/2022]
Abstract
OBJECTIVES We aimed to determine a threshold cutoff for hepcidin, ferritin, and the hepcidin-to-ferritin ratio in the diagnosis of liver fibrosis caused by iron overload in chronic hepatitis C virus (HCV)-free ß-thalassemia major patients . METHODS This 1:1-matched case-control study included 102 individuals (3-30 yr.); 51 ß-thalassemia major patients with iron overload , and 51 apparently healthy individuals. RESULTS The highest areas under the receiver operating characteristic curves (AUC-ROCs) for the diagnosis of patients vs. controls had overlapping 95% confidence intervals (CIs): serum hepcidin (0.758; 0.64-0.87; P ˂ 0.001), serum ferritin (1.000; 1.00-1.00; P˂0.001), and the hepcidin/ferritin ratio (1.000; 1.00-1.00; P˂0.001). For differentiation of patients with liver fibrosis stages of F0-F1 vs. F2-F4 and F0-F1 vs. F3-F4, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) with P-values˂0.001 were the only statistically significant parameters, while the AUC-ROCs of the hepcidin/ferritin ratio (0.631, P=0.188 and 0.684, P=0.098) exhibited 90% and 89.5% sensitivity, respectively, in staging liver fibrosis. CONCLUSION Our results showed that the hepcidin/ferritin ratio is as effective as the APRI and maybe a better predictor for the diagnosis of liver fibrosis and discriminating its stages, with excellent sensitivity and specificity compared to its components.
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Affiliation(s)
- B A Zaman
- Department of Pharmacology, College of Pharmacy, University of Duhok, Kurdistan region, Iraq.
| | - S O Rasool
- Department of Clinical Pharmacy, College of Pharmacy, University of Duhok, Kurdistan region, Iraq.
| | - M A Merza
- Azadi Teaching Hospital, Department of Internal Medicine, College of Pharmacy, University of Duhok, Kurdistan region, Iraq.
| | - D M Abdulah
- Community Health Unit, College of Nursing, University of Duhok, Kurdistan region, Iraq.
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23
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Viveiros A, Schaefer B, Panzer M, Henninger B, Plaikner M, Kremser C, Franke A, Franzenburg S, Hoeppner MP, Stauder R, Janecke A, Tilg H, Zoller H. MRI-Based Iron Phenotyping and Patient Selection for Next-Generation Sequencing of Non-Homeostatic Iron Regulator Hemochromatosis Genes. Hepatology 2021; 74:2424-2435. [PMID: 34048062 PMCID: PMC8596846 DOI: 10.1002/hep.31982] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 05/13/2021] [Accepted: 05/13/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS High serum ferritin is frequent among patients with chronic liver disease and commonly associated with hepatic iron overload. Genetic causes of high liver iron include homozygosity for the p.Cys282Tyr variant in homeostatic iron regulator (HFE) and rare variants in non-HFE genes. The aims of the present study were to describe the landscape and frequency of mutations in hemochromatosis genes and determine whether patient selection by noninvasive hepatic iron quantification using MRI improves the diagnostic yield of next-generation sequencing (NGS) in patients with hyperferritinemia. APPROACH AND RESULTS A cohort of 410 unselected liver clinic patients with high serum ferritin (defined as ≥200 μg/L for women and ≥300 μg/L for men) was investigated by HFE genotyping and abdominal MRI R2*. Forty-one (10%) patients were homozygous for the p.Cys282Tyr variant in HFE. Of the remaining 369 patients, 256 (69%) had high transferrin saturation (TSAT; ≥45%) and 199 (53%) had confirmed hepatic iron overload (liver R2* ≥70 s-1 ). NGS of hemochromatosis genes was carried out in 180 patients with hepatic iron overload, and likely pathogenic variants were identified in 68 of 180 (38%) patients, mainly in HFE (79%), ceruloplasmin (25%), and transferrin receptor 2 (19%). Low spleen iron (R2* <50 s-1 ), but not TSAT, was significantly associated with the presence of mutations. In 167 patients (93%), no monogenic cause of hepatic iron overload could be identified. CONCLUSIONS In patients without homozygosity for p.Cys282Tyr, coincident pathogenic variants in HFE and non-HFE genes could explain hyperferritinemia with hepatic iron overload in a subset of patients. Unlike HFE hemochromatosis, this type of polygenic hepatic iron overload presents with variable TSAT. High ferritin in blood is an indicator of the iron storage disease, hemochromatosis. A simple genetic test establishes this diagnosis in the majority of patients affected. MRI of the abdomen can guide further genetic testing.
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Affiliation(s)
- André Viveiros
- Department of Medicine I and Christian Doppler Laboratory on Iron and Phosphate BiologyMedical University of InnsbruckInnsbruckAustria
| | - Benedikt Schaefer
- Department of Medicine I and Christian Doppler Laboratory on Iron and Phosphate BiologyMedical University of InnsbruckInnsbruckAustria
| | - Marlene Panzer
- Department of Medicine I and Christian Doppler Laboratory on Iron and Phosphate BiologyMedical University of InnsbruckInnsbruckAustria
| | | | - Michaela Plaikner
- Department of RadiologyMedical University of InnsbruckInnsbruckAustria
| | - Christian Kremser
- Department of RadiologyMedical University of InnsbruckInnsbruckAustria
| | - André Franke
- Institute of Clinical Molecular Biology (IKMB)Kiel UniversityKielGermany
| | - Sören Franzenburg
- Institute of Clinical Molecular Biology (IKMB)Kiel UniversityKielGermany
| | - Marc P. Hoeppner
- Institute of Clinical Molecular Biology (IKMB)Kiel UniversityKielGermany
| | - Reinhard Stauder
- Department of Medicine VMedical University of InnsbruckInnsbruckAustria
| | - Andreas Janecke
- Department of PediatricsMedical University of InnsbruckInnsbruckAustria
- Department of GeneticsMedical University of InnsbruckInnsbruckAustria
| | - Herbert Tilg
- Department of Medicine I and Christian Doppler Laboratory on Iron and Phosphate BiologyMedical University of InnsbruckInnsbruckAustria
| | - Heinz Zoller
- Department of Medicine I and Christian Doppler Laboratory on Iron and Phosphate BiologyMedical University of InnsbruckInnsbruckAustria
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24
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Colucci S, Altamura S, Marques O, Dropmann A, Horvat NK, Müdder K, Hammad S, Dooley S, Muckenthaler MU. Liver Sinusoidal Endothelial Cells Suppress Bone Morphogenetic Protein 2 Production in Response to TGFβ Pathway Activation. Hepatology 2021; 74:2186-2200. [PMID: 33982327 DOI: 10.1002/hep.31900] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 04/15/2021] [Accepted: 05/04/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS TGFβ/bone morphogenetic protein (BMP) signaling in the liver plays a critical role in liver disease. Growth factors, such as BMP2, BMP6, and TGFβ1, are released from LSECs and signal in a paracrine manner to hepatocytes and hepatic stellate cells to control systemic iron homeostasis and fibrotic processes, respectively. The misregulation of the TGFβ/BMP pathway affects expression of the iron-regulated hormone hepcidin, causing frequent iron overload and deficiency diseases. However, whether LSEC-secreted factors can act in an autocrine manner to maintain liver homeostasis has not been addressed so far. APPROACH AND RESULTS We analyzed publicly available RNA-sequencing data of mouse LSECs for ligand-receptor interactions and identified members of the TGFβ family (BMP2, BMP6, and TGFβ1) as ligands with the highest expression levels in LSECs that may signal in an autocrine manner. We next tested the soluble factors identified through in silico analysis in optimized murine LSEC primary cultures and mice. Exposure of murine LSEC primary cultures to these ligands shows that autocrine responses to BMP2 and BMP6 are blocked despite high expression levels of the required receptor complexes partially involving the inhibitor FK-506-binding protein 12. By contrast, LSECs respond efficiently to TGFβ1 treatment, which causes reduced expression of BMP2 through activation of activin receptor-like kinase 5. CONCLUSIONS These findings reveal that TGFβ1 signaling is functionally interlinked with BMP signaling in LSECs, suggesting druggable targets for the treatment of iron overload diseases associated with deficiency of the BMP2-regulated hormone hepcidin, such as hereditary hemochromatosis, β-thalassemia, and chronic liver diseases.
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Affiliation(s)
- Silvia Colucci
- Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany.,Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
| | - Sandro Altamura
- Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany.,Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
| | - Oriana Marques
- Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany.,Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
| | - Anne Dropmann
- Section Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Natalie K Horvat
- Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany.,European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Katja Müdder
- Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany
| | - Seddik Hammad
- Section Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Department of Forensic and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Steven Dooley
- Section Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Martina U Muckenthaler
- Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany.,Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
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25
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Dawood RM, El-Meguid MA, Elrobe W, Salum GM, Zayed N, Mousa S, Medhat E. Significance of Hereditary Hemochromatosis Gene (HFE) Mutations in Chronic Hepatitis C and Hepatocellular Carcinoma Patients in Egypt: A Pilot Study. Asian Pac J Cancer Prev 2021; 22:2837-2845. [PMID: 34582652 PMCID: PMC8850884 DOI: 10.31557/apjcp.2021.22.9.2837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 09/12/2021] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Hereditary hemochromatosis is a genetic disease defined by enhanced overloading of iron and associated with Chronic Hepatitis C (CHC). This study aims to evaluate the correlation of the HFE gene mutations on Egyptian CHC with liver disease progression and the risk of HCC development. METHODS The HFE mutations (C282Y and H63D) were genotyped on 100 CHC patients and 50 healthy individuals by a hybridization assay. The serum iron content was also measured for all subjects. RESULTS A significant elevation of the serum iron, ferritin, and TIBC in HCV-infected patients (p≤0.05). The H63D mutation was detected in 23% of the all studied samples. The serum iron and the H63D heterozygosity were correlated significantly between non-cirrhotic and cirrhotic without HCC patients. CONCLUSION The H63D heterozygosity might have a potential role in iron accumulation. Moreover, HFE mutations did not tend to be associated with an increased risk of HCC in cirrhotic patients.
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Affiliation(s)
- Reham M Dawood
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Center, Giza, Egypt.
| | - Mai Abd El-Meguid
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Center, Giza, Egypt.
| | - Walied Elrobe
- Department of Endemic Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt.
| | - Ghada M Salum
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Center, Giza, Egypt.
| | - Naglaa Zayed
- Department of Endemic Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt.
| | - Sherief Mousa
- Department of Endemic Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt.
| | - Eman Medhat
- Department of Endemic Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt.
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26
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Milman NT. Managing Genetic Hemochromatosis: An Overview of Dietary Measures, Which May Reduce Intestinal Iron Absorption in Persons With Iron Overload. Gastroenterology Res 2021; 14:66-80. [PMID: 34007348 PMCID: PMC8110241 DOI: 10.14740/gr1366] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 02/23/2021] [Indexed: 01/22/2023] Open
Abstract
Genetic hemochromatosis causes iron overload by excess absorption of dietary iron, due to a decreased expression of hepcidin. The objective was to elaborate dietary recommendations that can reduce intestinal iron absorption in hemochromatosis patients, based on our present knowledge of the iron contained in nutrients and the mechanisms of iron uptake. This is a narrative review. Literature search in PubMed and Google Scholar of papers dealing with iron absorption from the diet was conducted. Most important proposed dietary recommendations are: 1) Choose a varied vegetarian, semi-vegetarian or flexitarian diet. A “veggie-lacto-ovo-poultry-pescetarian” diet seems optimal. Avoid iron enriched foods and iron supplements. 2) Eat many vegetables and fruits, at least 600 g per day. Choose protein rich pulses and legumes (e.g., kidney- and soya beans). Fresh fruits should be eaten between meals. 3) Abstain from red meat from mammals and choose the lean, white meat from poultry. Avoid processed meat, offal and blood containing foods. Eat no more than 200 g meat from poultry per week. Choose fish, eggs, vegetables and protein rich legumes the other days. Eat fish two to four times a week as main course, 350 - 500 g fish per week, of which half should be fat fish. 4) Choose whole grain products in cereals and bread. Avoid iron enriched grains. Choose non-sourdough, yeast-fermented bread with at least 50% whole grain. 5) Choose vegetable oils, and low-fat dairy products. 6) Eat less sugar and salt. Choose whole foods and foods with minimal processing and none or little added sugar or salt. 7) Quench your thirst in water. Drink green- or black tea, coffee, or low-fat milk with the meals, alternatively water or non-alcoholic beer. Fruit juices must be consumed between meals. Abstain from alcoholic beverages. Drink soft drinks, non-alcoholic beer, or non-alcoholic wine instead. These advices are close to the official Danish dietary recommendations in 2021. In the management of hemochromatosis, dietary modifications that lower iron intake and decrease iron bioavailability may provide additional measures to reduce iron uptake from the foods and reduce the number of phlebotomies. However, there is a need for large, prospective, randomized studies that specifically evaluate the effect of dietary interventions.
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Affiliation(s)
- Nils Thorm Milman
- Department of Clinical Biochemistry, Naestved Hospital, University College Zealand, DK-4700 Naestved, Denmark.
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27
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Eisenga MF. Iron Deficiency Defined by Hepcidin in Critically Ill Patients. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2021; 25:138. [PMID: 33845879 PMCID: PMC8040202 DOI: 10.1186/s13054-021-03542-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 03/11/2021] [Indexed: 12/15/2022]
Affiliation(s)
- Michele F Eisenga
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.
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28
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Gupta R, Gupta R, Kumar N, Rawat VS, Ulfberg J, Allen RP. Restless legs syndrome among subjects having chronic liver disease: A systematic review and meta-analysis. Sleep Med Rev 2021; 58:101463. [PMID: 33836477 DOI: 10.1016/j.smrv.2021.101463] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/03/2021] [Accepted: 03/03/2021] [Indexed: 12/14/2022]
Abstract
Sleep disturbances are commonly reported in patients with chronic liver disease (CLD). Changes in quality of sleep in patients with CLD could be related to multiple factors viz., elevated levels of tryptophan, histamine, and increased turnover of dopamine in caudate-putamen and cingulate cortex. Also, iron metabolism disturbances are reported in patients with CLD. These changes may result in restless legs syndrome (RLS) that worsens sleep-quality. There have been reports suggesting an increased prevalence of RLS among patients with CLD. Literature was searched in PubMed, EMBASE, and Google Scholar. A total of twenty-two relevant articles were found. Out of these, nine studies have assessed the prevalence of RLS among patients with chronic liver disease or cirrhosis in the clinical population. Population prevalence reported from various studies was used to calculate odds ratio. Having included studies using various methods for diagnosis (clinical as well as questionnaires) pooled odds-ratio for the RLS was 8.62. It remains unaffected by study-method, gender, age, and geographical-area. However, studies using clinical diagnosis for RLS had lower odds compared to questionnaire based diagnosis. Studies varied with regards to diagnostic methods, age, gender, etiology, and severity of liver dysfunction. The severity and etiology of CLD and biochemical correlate of CLD were not found to be associated with RLS. Possible pathophysiological mechanisms are discussed for the occurrence of RLS in this population. In conclusion, the prevalence of RLS is higher among patients with CLD, however, the correlates are unknown.
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Affiliation(s)
- Ravi Gupta
- Department of Pyshciatry, Division of Sleep Medicine, All India Institute of Medical Sciences, Rishikesh, 249203, India
| | - Rohit Gupta
- Department of Gastroenterology, All India Institute of Medical Sciences, Rishikesh, 249203, India.
| | - Niraj Kumar
- Department of Neurology and Division of Sleep Medicine, All India Institute of Medical Sciences, Rishikesh, 249203, India
| | - Vikram Singh Rawat
- Department of Pyshciatry, Division of Sleep Medicine, All India Institute of Medical Sciences, Rishikesh, 249203, India
| | - Jan Ulfberg
- Sleep Clinic, Capio Medical Center, Hamnplan, Örebro, Sweden
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Fierro-Fine A, Guerin L, Hicsasmaz H, Brown KE. Clinical Factors Associated with Hepatocellular Iron Deposition in End-stage Liver Disease. J Clin Transl Hepatol 2020; 8:231-239. [PMID: 33083244 PMCID: PMC7562807 DOI: 10.14218/jcth.2020.00022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/18/2020] [Accepted: 06/19/2020] [Indexed: 02/06/2023] Open
Abstract
Background and Aims: Hepatocellular iron accumulation in patients with chronic liver disease has been linked to adverse outcomes. The objective of this study was to identify clinical factors associated with hemosiderosis. Methods: A total of 103 consecutive liver transplant recipients were identified, in whom liver biopsy had been performed prior to transplantation. Laboratory and clinical data at biopsy and transplant were abstracted from the medical records and hepatocyte iron was graded in the biopsy and explant. The association of change in iron score from biopsy to transplant, with the time interval between these two events, was examined using linear mixed model analysis for repeated measures. Results: Most subjects had advanced fibrosis (F3-F4) at liver biopsy, which was performed on average about 2.5 years before transplant. Over 80% of patients had no or 1+ hepatocyte iron at biopsy; iron increased between biopsy and transplant in about 40%. The only demographic or clinical feature that correlated with increased iron was the presence of a transjugular intrahepatic portosystemic shunt. Increased iron at transplant was associated with higher serum iron and transferrin saturation at biopsy, and with lower hemoglobin level, greater mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration, higher ferritin and model for end-stage liver disease score at transplant. Conclusions: The development of hemosiderosis in end-stage liver disease is associated with lower hemoglobin levels and alterations in red blood cell indices that are suggestive of hemolysis. These observations suggest that extravascular hemolysis may play a role in the development of secondary iron overload.
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Affiliation(s)
- Amelia Fierro-Fine
- Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
| | - Leana Guerin
- Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
| | | | - Kyle E. Brown
- Division of Gastroenterology-Hepatology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
- Program in Free Radical and Radiation Biology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
- Iowa City Veterans Administration Medical Center, Iowa City, IA, USA
- Correspondence to: Kyle E. Brown, Division of Gastroenterology-Hepatology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, 4553 JCP, 200 Hawkins Drive, Iowa City, IA 52242, USA. Tel: +1-319-384-6579, Fax: +1-319-356-7918, E-mail:
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30
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Milman NT. A Review of Nutrients and Compounds, Which Promote or Inhibit Intestinal Iron Absorption: Making a Platform for Dietary Measures That Can Reduce Iron Uptake in Patients with Genetic Haemochromatosis. J Nutr Metab 2020; 2020:7373498. [PMID: 33005455 PMCID: PMC7509542 DOI: 10.1155/2020/7373498] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 08/01/2020] [Accepted: 08/25/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE To provide an overview of nutrients and compounds, which influence human intestinal iron absorption, thereby making a platform for elaboration of dietary recommendations that can reduce iron uptake in patients with genetic haemochromatosis. DESIGN Review. Setting. A literature search in PubMed and Google Scholar of papers dealing with iron absorption. RESULTS The most important promoters of iron absorption in foods are ascorbic acid, lactic acid (produced by fermentation), meat factors in animal meat, the presence of heme iron, and alcohol which stimulate iron uptake by inhibition of hepcidin expression. The most important inhibitors of iron uptake are phytic acid/phytates, polyphenols/tannins, proteins from soya beans, milk, eggs, and calcium. Oxalic acid/oxalate does not seem to influence iron uptake. Turmeric/curcumin may stimulate iron uptake through a decrease in hepcidin expression and inhibit uptake by complex formation with iron, but the net effect has not been clarified. CONCLUSIONS In haemochromatosis, iron absorption is enhanced due to a decreased expression of hepcidin. Dietary modifications that lower iron intake and decrease iron bioavailability may provide additional measures to reduce iron uptake from the foods. This could stimulate the patients' active cooperation in the treatment of their disorder and reduce the number of phlebotomies.
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Affiliation(s)
- Nils Thorm Milman
- Department of Clinical Biochemistry, Næstved Hospital, University College Zealand, DK-4700 Næstved, Denmark
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31
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Kumar A, Gupta R, Gupta R. Prevalence of RLS among subjects with chronic liver disease and its effect on sleep and mood. Sleep Med 2020; 73:144-152. [DOI: 10.1016/j.sleep.2020.05.036] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 05/06/2020] [Accepted: 05/19/2020] [Indexed: 12/16/2022]
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Podzolkov VI, Dragomiretskaya NA, Stolbova SK, Tolmacheva AV. Hepcidin and MELD-XI score as markers of multiple organ failure in patients with heart failure with preserved and reduced ejection fraction. КАРДИОВАСКУЛЯРНАЯ ТЕРАПИЯ И ПРОФИЛАКТИКА 2020. [DOI: 10.15829/1728-8800-2020-2529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Data on the changes in hepcidin levels in heart failure (HF) patients are contradictory and do not give an answer about its effect on the progression of multiple organ failure. Since the model of end-stage liver disease excluding INR (MELD-XI) reflects the severity of liver and kidney dysfunction, these markers have been suggested to be associated with decompensated HF.Aim. To assess the MELD-XI score and serum hepcidin levels in patients with decompensated HF with different values of left ventricular ejection fraction (EF).Material and methods. The study included 68 patients (29 women, 39 men; mean age 72,3±11,7 years) hospitalized due to decompensated HF. Patients were divided into three groups: reduced (HFrEF) (n=20), mid-range (HFmrEF) (n=23), and preserved EF (HFpEF) (n=24)). Upon admission, along with standard diagnostic tests, all patients were examined for hepcidin-25 levels by enzyme-linked immunosorbent assay. MELD-XI score was calculated. Statistical processing was carried out using the software package Statistica 8.0.Results. Hepcidin levels in the HFrEF group (31,63 ng/ml [22,0; 71,6]) were significantly higher than in the HFmrEF (23,89 ng/ml [21,1; 27,9]) (p<0,05) and HFpEF (26,91 ng/ml [18,6; 31,1]) (p<0,05) groups. In HFpEF, there was a correlation of hepcidin level with body mass index (r=0,47, p<0,05) and chronic obstructive airway diseases (r=0,44, p<0,05). A correlation of hepcidin level with significant cardiac arrhythmias (r=0,61, p<0,05) was revealed in HFmrEF patients. MELD-XI score were significantly increased from 9,44±3,96 for HFpEF and 11,53±3,82 for HFmrEF to 14,3±4,3 for HFrEF (p<0,005). We also revealed correlation of MELD-XI score with hepcidin levels (r=0,3, p<0,05) and EF (r=-0,43, p<0,0003). Patients with a MELD-XI score of >10,4 were more likely to have NYHA class III-IV HF, HFrEF and significantly higher levels of hepcidin (p<0,05 for all) These patients were also more likely to have chronic kidney disease (p<0,05).Conclusion. Hepcidin level and MELD-XI score in patients with decompensated HF are inversely related to left ventricular EF. There is a direct relationship between hepcidin levels and other clinical parameters: body mass index, the presence of chronic obstructive airway diseases and cardiac arrhythmias.
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Çam H, Yılmaz N. Serum hepcidin levels are related to serum markers for iron metabolism and fibrosis stage in patients with chronic hepatitis B: A cross-sectional study. Arab J Gastroenterol 2020; 21:85-90. [PMID: 32423859 DOI: 10.1016/j.ajg.2020.04.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 02/16/2020] [Accepted: 04/12/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND STUDY AIMS The clinical significance of serum parameters of iron metabolism and hepcidin in liver disease remains unknown. Therefore, this study aimed to evaluate the association of serum hepcidin levels with fibrosis stage and serum iron parameters in patients with chronic hepatitis B (CHB). PATIENTS AND METHODS This cross-sectional study included 126 treatment-naïve patients with CHB (median age, 39.0 years; 64.3% males) who were positive for hepatitis B surface antigen and 23 healthy controls (median age, 33.0 years; 52.2% males). Data on patient demographics, serum hepcidin levels, liver function tests and serum iron parameters and liver biopsy findings including fibrosis grade, histological activity index (HAI) and liver iron level were recorded. RESULTS The median (minimum-maximum) serum hepcidin levels were significantly lower in the CHB group than in the control group [71.2 (13.3-672.7) vs. 657.5 (201.7-2714.2) pg/mL, p < 0.001]. Higher fibrosis stage was associated with higher transferrin saturation (p = 0.029), serum ferritin level (p < 0.001) and viral load (p < 0.001). Fibrosis stage and HAI were positively correlated with ferritin (r = 0.407, p < 0.001 and r = 0.415, p < 0.001, respectively) and transferrin saturation (r = 0.219, p = 0.026 and r = 0.290, p = 0.003, respectively) levels, whereas hepcidin level was negatively correlated with fibrosis stage (r = -0.175, p = 0.051), viral load (r = -0.209, p = 0.020) and ferritin level (r = -0.244, p = 0.006) level. There were no significant differences in serum iron level, total iron binding capacity and liver iron level among patients with different stages of fibrosis. CONCLUSION Reduced hepcidin levels and elevated transferrin saturation and ferritin levels are linked to fibrosis severity and HAI in patients with CHB.
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Affiliation(s)
- Hakan Çam
- Gaziantep University Medical Faculty 27310 Gastroenterology, Gaziantep, Turkey
| | - Nimet Yılmaz
- Gaziantep University Medical Faculty 27310 Gastroenterology, Gaziantep, Turkey
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Mehta KJ, Busbridge M, Patel VB, Farnaud SJ. Hepcidin secretion was not directly proportional to intracellular iron-loading in recombinant-TfR1 HepG2 cells: short communication. Mol Cell Biochem 2020; 468:121-128. [PMID: 32185675 PMCID: PMC7145775 DOI: 10.1007/s11010-020-03716-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 03/06/2020] [Indexed: 02/08/2023]
Abstract
Hepcidin is the master regulator of systemic iron homeostasis and its dysregulation is observed in several chronic liver diseases. Unlike the extracellular iron-sensing mechanisms, the intracellular iron-sensing mechanisms in the hepatocytes that lead to hepcidin induction and secretion are incompletely understood. Here, we aimed to understand the direct role of intracellular iron-loading on hepcidin mRNA and peptide secretion using our previously characterised recombinant HepG2 cells that over-express the cell-surface iron-importer protein transferrin receptor-1. Gene expression of hepcidin (HAMP) was determined by real-time PCR. Intracellular iron levels and secreted hepcidin peptide levels were measured by ferrozine assay and immunoassay, respectively. These measurements were compared in the recombinant and wild-type HepG2 cells under basal conditions at 30 min, 2 h, 4 h and 24 h. Data showed that in the recombinant cells, intracellular iron content was higher than wild-type cells at 30 min (3.1-fold, p < 0.01), 2 h (4.6-fold, p < 0.01), 4 h (4.6-fold, p < 0.01) and 24 h (1.9-fold, p < 0.01). Hepcidin (HAMP) mRNA expression was higher than wild-type cells at 30 min (5.9-fold; p = 0.05) and 24 h (6.1-fold; p < 0.03), but at 4 h, the expression was lower than that in wild-type cells (p < 0.05). However, hepcidin secretion levels in the recombinant cells were similar to those in wild-type cells at all time-points, except at 4 h, when the level was lower than wild-type cells (p < 0.01). High intracellular iron in recombinant HepG2 cells did not proportionally increase hepcidin peptide secretion. This suggests a limited role of elevated intracellular iron in hepcidin secretion.
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Affiliation(s)
- Kosha J Mehta
- Centre for Education, Faculty of Life Sciences and Medicine, King's College London, London, UK.
- School of Life Sciences, University of Westminster, London, UK.
| | - Mark Busbridge
- Department of Clinical Biochemistry, Northwest London Pathology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Vinood B Patel
- School of Life Sciences, University of Westminster, London, UK
| | - Sebastien Je Farnaud
- Centre for Sport, Exercise and Life Sciences, Faculty of Health & Life Sciences, Coventry University, Coventry, UK
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Liu YT, Lv WL. Research Progress in Astragalus Membranaceus and Its Active Components on Immune Responses in Liver Fibrosis. Chin J Integr Med 2019; 26:794-800. [DOI: 10.1007/s11655-019-3039-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2018] [Indexed: 12/11/2022]
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Czaja AJ. Review article: iron disturbances in chronic liver diseases other than haemochromatosis - pathogenic, prognostic, and therapeutic implications. Aliment Pharmacol Ther 2019; 49:681-701. [PMID: 30761559 DOI: 10.1111/apt.15173] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/08/2019] [Accepted: 01/16/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Disturbances in iron regulation have been described in diverse chronic liver diseases other than hereditary haemochromatosis, and iron toxicity may worsen liver injury and outcome. AIMS To describe manifestations and consequences of iron dysregulation in chronic liver diseases apart from hereditary haemochromatosis and to encourage investigations that clarify pathogenic mechanisms, define risk thresholds for iron toxicity, and direct management METHODS: English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed. RESULTS Hyperferritinemia is present in 4%-65% of patients with non-alcoholic fatty liver disease, autoimmune hepatitis, chronic viral hepatitis, or alcoholic liver disease, and hepatic iron content is increased in 11%-52%. Heterozygosity for the C282Y mutation is present in 17%-48%, but this has not uniformly distinguished patients with adverse outcomes. An inappropriately low serum hepcidin level has characterised most chronic liver diseases with the exception of non-alcoholic fatty liver disease, and the finding has been associated mainly with suppression of transcriptional activity of the hepcidin gene. Iron overload has been associated with oxidative stress, advanced fibrosis and decreased survival, and promising therapies beyond phlebotomy and oral iron chelation have included hepcidin agonists. CONCLUSIONS Iron dysregulation is common in chronic liver diseases other than hereditary haemochromatosis, and has been associated with liver toxicity and poor prognosis. Further evaluation of iron overload as a co-morbid factor should identify the key pathogenic disturbances, establish the risk threshold for iron toxicity, and promote molecular interventions.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
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Papadodima S, Masia R, Stone JR. Cardiac iron overload following liver transplantation in patients without hereditary hemochromatosis or severe hepatic iron deposition. Cardiovasc Pathol 2019; 40:7-11. [PMID: 30763826 DOI: 10.1016/j.carpath.2018.12.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 11/21/2018] [Accepted: 12/21/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Cardiac iron overload following liver transplantation in patients without hemochromatosis but with severe hepatic iron deposition has been reported to result in heart failure and/or death in case reports and small case series. However, the frequency and causes of cardiac iron overload following liver transplantation and its relationship to cardiac dysfunction in patients without severe hepatic iron deposition are unclear. METHODS The primary inclusion criteria for this study were liver transplantation followed by autopsy or cardiac transplantation within 1 year. Cases of known hemochromatosis were excluded. Iron stains were performed on left ventricular myocardium from either the autopsy or surgically resected heart, as well as the surgically resected liver. RESULTS Nineteen cases met the study criteria: 18 autopsies and 1 case of cardiac transplantation. None of the resected livers evaluated showed severe iron deposition. Myocardial iron deposition was identified in 7 (37%) of the cases. The presence of myocardial iron deposition was not significantly associated with the grade of hepatic iron deposition, or the pre-liver transplantation serum iron or ferritin levels. However, in the patients with myocardial iron deposition, there were trends toward higher pretransplant transferrin saturation (TSAT) and more units of red blood cells transfused (uRBC). The product of the TSAT multiplied by the uRBC was significantly greater in the patients with myocardial iron deposition [4700 (3100-9800) vs. 680 (400-2300), median (interquartile range), P=.003]. New reduced left ventricular ejection fraction (<50%) following liver transplantation occurred in four of five patients with myocardial iron deposition, compared with zero of eight patients without myocardial iron deposition (P=.007). CONCLUSIONS In this series of patients without severe hepatic iron deposition, cardiac iron overload was associated with cardiac dysfunction following liver transplantation and was related to the product of the pre-liver transplant TSAT multiplied by the number of uRBC transfused during and following the surgery.
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Affiliation(s)
- Stavroula Papadodima
- Department of Forensic Medicine and Toxicology, National and Kapodistrian University of Athens, Athens, Greece
| | - Ricard Masia
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - James R Stone
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
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Mehta KJ, Farnaud SJ, Sharp PA. Iron and liver fibrosis: Mechanistic and clinical aspects. World J Gastroenterol 2019; 25:521-538. [PMID: 30774269 PMCID: PMC6371002 DOI: 10.3748/wjg.v25.i5.521] [Citation(s) in RCA: 193] [Impact Index Per Article: 32.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/02/2019] [Accepted: 01/10/2019] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is characterised by excessive deposition of extracellular matrix that interrupts normal liver functionality. It is a pathological stage in several untreated chronic liver diseases such as the iron overload syndrome hereditary haemochromatosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and diabetes. Interestingly, regardless of the aetiology, iron-loading is frequently observed in chronic liver diseases. Excess iron can feed the Fenton reaction to generate unquenchable amounts of free radicals that cause grave cellular and tissue damage and thereby contribute to fibrosis. Moreover, excess iron can induce fibrosis-promoting signals in the parenchymal and non-parenchymal cells, which accelerate disease progression and exacerbate liver pathology. Fibrosis regression is achievable following treatment, but if untreated or unsuccessful, it can progress to the irreversible cirrhotic stage leading to organ failure and hepatocellular carcinoma, where resection or transplantation remain the only curative options. Therefore, understanding the role of iron in liver fibrosis is extremely essential as it can help in formulating iron-related diagnostic, prognostic and treatment strategies. These can be implemented in isolation or in combination with the current approaches to prepone detection, and halt or decelerate fibrosis progression before it reaches the irreparable stage. Thus, this review narrates the role of iron in liver fibrosis. It examines the underlying mechanisms by which excess iron can facilitate fibrotic responses. It describes the role of iron in various clinical pathologies and lastly, highlights the significance and potential of iron-related proteins in the diagnosis and therapeutics of liver fibrosis.
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Affiliation(s)
- Kosha J Mehta
- School of Population Health and Environmental Sciences, Faculty of Life Sciences and Medicine, King’s College London, London SE1 1UL, United Kingdom
- Division of Human Sciences, School of Applied Sciences, London South Bank University, London SE1 0AA, United Kingdom
| | - Sebastien Je Farnaud
- Faculty Research Centre for Sport, Exercise and Life Sciences, Coventry University, Coventry CV1 2DS, United Kingdom
| | - Paul A Sharp
- Department of Nutritional Sciences, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 9NH, United Kingdom
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Hepcidin Therapeutics. Pharmaceuticals (Basel) 2018; 11:ph11040127. [PMID: 30469435 PMCID: PMC6316648 DOI: 10.3390/ph11040127] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 11/15/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022] Open
Abstract
Hepcidin is a key hormonal regulator of systemic iron homeostasis and its expression is induced by iron or inflammatory stimuli. Genetic defects in iron signaling to hepcidin lead to “hepcidinopathies” ranging from hereditary hemochromatosis to iron-refractory iron deficiency anemia, which are disorders caused by hepcidin deficiency or excess, respectively. Moreover, dysregulation of hepcidin is a pathogenic cofactor in iron-loading anemias with ineffective erythropoiesis and in anemia of inflammation. Experiments with preclinical animal models provided evidence that restoration of appropriate hepcidin levels can be used for the treatment of these conditions. This fueled the rapidly growing field of hepcidin therapeutics. Several hepcidin agonists and antagonists, as well as inducers and inhibitors of hepcidin expression have been identified to date. Some of them were further developed and are currently being evaluated in clinical trials. This review summarizes the state of the art.
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