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Cai Q, Jing C, Wang X, Xing X, Liu W. STEAP proteins: Roles in disease biology and potential for therapeutic intervention. Int J Biol Macromol 2025:142797. [PMID: 40185436 DOI: 10.1016/j.ijbiomac.2025.142797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 03/25/2025] [Accepted: 04/01/2025] [Indexed: 04/07/2025]
Abstract
Iron and copper are essential metal ions, and maintaining their metabolic balance is critical for organismal health. The Six-Transmembrane Epithelial Antigen of the Prostate (STEAP) protein family, comprising STEAP1, STEAP2, STEAP3, and STEAP4, plays a vital role in cellular metal homeostasis. These proteins are located on the cell membrane and are characterized by six transmembrane domains. With the exception of STEAP1, the STEAP proteins function as metal oxidoreductases due to their F420H2:NADP+ oxidoreductase (FNO)-like domain. However, STEAP1 contributes to metal metabolism through its heme group and interaction with other STEAP proteins. Beyond metal metabolism, STEAP proteins are involved in critical cellular processes, including the regulation of the cell cycle, proliferation, differentiation, and apoptosis. Notably, STEAP proteins are recognized as potential biomarkers and therapeutic targets in human cancers, particularly prostate cancer. This review outlines the structural features and functional roles of STEAP proteins in various diseases, including cancers, insulin resistance, non-alcoholic fatty liver disease (NAFLD), and benign prostatic hyperplasia, with a focus on their potential for therapeutic intervention.
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Affiliation(s)
- Qiaomei Cai
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin 300060, PR China
| | - Chao Jing
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin 300060, PR China
| | - Xudong Wang
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin 300060, PR China
| | - Xiangling Xing
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, PR China.
| | - Wancheng Liu
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, PR China.
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Kirkutyte I, Latunde-Dada GO. Relationship Between Hepatic Iron Concentration and Glycemic Metabolism, Prediabetes, and Type 2 Diabetes: A Systematic Review. Nutr Rev 2024:nuae197. [PMID: 39724915 DOI: 10.1093/nutrit/nuae197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2024] Open
Abstract
CONTEXT Emerging research has suggested a potential link between high iron levels, indicated by serum ferritin levels, and the development of type 2 diabetes (T2D). However, the role of hepatic iron concentration (HIC) on T2D development and progression is not well understood. OBJECTIVES This study aims to systematically review the literature on HIC and/or the degree of hepatic iron overload (HIO) in individuals with prediabetes and/or diagnosed T2D, and to analyze associations between HIC and markers of glucose metabolism. DATA SOURCES The databases Medline, PubMed, Embase, CINAHL, and Web of Knowledge were searched for studies published in English from 1999 to March 2024. This review followed the Preferred Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. DATA EXTRACTION Data were extracted following the established eligibility criteria. Study characteristics and biomarkers related to prediabetes, T2D, and HIO were extracted. The risk of bias was analyzed using the Newcastle-Ottawa Scale. Data were stratified by the exposure and analyzed in subgroups according to the outcome. Data regarding the HIC values in controls, individuals with prediabetes, and individuals with T2D and the association estimates between HIC or HIO and markers of glycemic metabolism, prediabetes, or T2D were extracted. DATA ANALYSIS A total of 12 studies were identified, and data from 4110 individuals were analyzed. HIO was not consistently observed in prediabetic/T2D populations; however, elevated HIC was frequently observed in prediabetic and T2D individuals, and was associated with the disruption of certain glycemic markers in some cases. CONCLUSION The extent of iron overload, as indicated by hepatic iron load, varied among the prediabetic and T2D populations studied. Further research is needed to understand the distribution and regulation of iron in T2D pathology.
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Affiliation(s)
- Indre Kirkutyte
- Department of Nutritional Sciences, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London SE1 9NH, United Kingdom
| | - Gladys Oluyemisi Latunde-Dada
- Department of Nutritional Sciences, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London SE1 9NH, United Kingdom
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Kumar R, Kulshreshtha D, Aggarwal A, Asthana S, Dinda A, Mukhopadhyay CK. Glucose induced regulation of iron transporters implicates kidney iron accumulation. Biochim Biophys Acta Gen Subj 2024; 1868:130713. [PMID: 39278370 DOI: 10.1016/j.bbagen.2024.130713] [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: 05/23/2024] [Revised: 09/06/2024] [Accepted: 09/11/2024] [Indexed: 09/18/2024]
Abstract
Increased iron level is detected in rat kidney and human urine in diabetic condition and implicated in associated nephropathy. However, the biological cue and mechanism of the iron accumulation remain unclear. Here we reveal that glucose increases iron uptake by promoting transferrin receptor 1 (TFRC) in kidney cells by a translational mechanism but does not alter expression of endosomal iron transporter DMT1. Glucose decreases iron exporter ferroportin (FPN) by a protein degradation mechanism. Hepcidin is known to bind at Cys-326 residue in promoting degradation of human ferroportin. When Cys-326 was mutated to Ser in human-FPN-FLAG and expressed in kidney cells, glucose still could degrade FPN-FLAG implicating involvement of hepcidin independent mechanism in glucose induced ferroportin degradation. Chronic hyperglycemia was generated in rats by administering streptozotocin (STZ) with periodic insulin injection to determine the level of iron homeostasis components. Increased TFRC and decreased ferroportin levels were detected in hyperglycemic rat kidney by Western blot and immunohistochemistry analyses. Hepcidin mRNA was not significantly altered in kidney but was marginally decreased in liver. Perls' staining and non-heme iron estimation showed an elevated iron level in hyperglycemic rat kidney. These results suggest that high glucose dysregulates iron transport components resulting iron accumulation in diabetic kidney.
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Affiliation(s)
- Rajiv Kumar
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India; All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110034, India
| | - Diksha Kulshreshtha
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India
| | - Ayushi Aggarwal
- All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110034, India
| | - Somya Asthana
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India
| | - Amit Dinda
- All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110034, India.
| | - Chinmay K Mukhopadhyay
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
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Duță C, Muscurel C, Dogaru CB, Stoian I. Ferroptosis-A Shared Mechanism for Parkinson's Disease and Type 2 Diabetes. Int J Mol Sci 2024; 25:8838. [PMID: 39201524 PMCID: PMC11354749 DOI: 10.3390/ijms25168838] [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: 06/30/2024] [Revised: 07/31/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Type 2 diabetes (T2D) and Parkinson's disease (PD) are the two most frequent age-related chronic diseases. There are many similarities between the two diseases: both are chronic diseases; both are the result of a decrease in a specific substance-insulin in T2D and dopamine in PD; and both are caused by the destruction of specific cells-beta pancreatic cells in T2D and dopaminergic neurons in PD. Recent epidemiological and experimental studies have found that there are common underlying mechanisms in the pathophysiology of T2D and PD: chronic inflammation, mitochondrial dysfunction, impaired protein handling and ferroptosis. Epidemiological research has indicated that there is a higher risk of PD in individuals with T2D. Moreover, clinical studies have observed that the symptoms of Parkinson's disease worsen significantly after the onset of T2D. This article provides an up-to-date review on the intricate interplay between oxidative stress, reactive oxygen species (ROS) and ferroptosis in PD and T2D. By understanding the shared molecular pathways and how they can be modulated, we can develop more effective therapies, or we can repurpose existing drugs to improve patient outcomes in both disorders.
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Tyczyńska M, Hunek G, Szczasny M, Brachet A, Januszewski J, Forma A, Portincasa P, Flieger J, Baj J. Supplementation of Micro- and Macronutrients-A Role of Nutritional Status in Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2024; 25:4916. [PMID: 38732128 PMCID: PMC11085010 DOI: 10.3390/ijms25094916] [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: 03/19/2024] [Revised: 04/28/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a condition in which the pathological cumulation of fat with coexisting inflammation and damage of hepatic cells leads to progressive dysfunctions of the liver. Except for the commonly well-known major causes of NAFLD such as obesity, dyslipidemia, insulin resistance, or diabetes, an unbalanced diet and imbalanced nutritional status should also be taken into consideration. In this narrative review, we summarized the current knowledge regarding the micro- and macronutrient status of patients suffering from NAFLD considering various diets and supplementation of chosen supplements. We aimed to summarize the knowledge indicating which nutritional impairments may be associated with the onset and progression of NAFLD at the same time evaluating the potential therapy targets that could facilitate the healing process. Except for the above-mentioned objectives, one of the most important aspects of this review was to highlight the possible strategies for taking care of NAFLD patients taking into account the challenges and opportunities associated with the micronutrient status of the patients. The current research indicates that a supplementation of chosen vitamins (e.g., vitamin A, B complex, C, or D) as well as chosen elements such as zinc may alleviate the symptoms of NAFLD. However, there is still a lack of sufficient data regarding healthy ranges of dosages; thus, further research is of high importance in this matter.
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Affiliation(s)
- Magdalena Tyczyńska
- Department of Correct, Clinical and Imaging Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland;
| | - Gabriela Hunek
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (G.H.); (A.B.)
| | - Martyna Szczasny
- Chair and Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (M.S.); (J.J.)
| | - Adam Brachet
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (G.H.); (A.B.)
| | - Jacek Januszewski
- Chair and Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (M.S.); (J.J.)
| | - Alicja Forma
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (G.H.); (A.B.)
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
| | - Jolanta Flieger
- Department of Analytical Chemistry, Medical University of Lublin, Chodźki 4A, 20-093 Lublin, Poland;
| | - Jacek Baj
- Chair and Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (M.S.); (J.J.)
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Mou X, Miao W, Zhang W, Wang W, Ma Q, Du Z, Li X, Huang N, Yang Z. Zwitterionic polymers-armored amyloid-like protein surface combats thrombosis and biofouling. Bioact Mater 2024; 32:37-51. [PMID: 37810990 PMCID: PMC10556425 DOI: 10.1016/j.bioactmat.2023.09.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/06/2023] [Accepted: 09/06/2023] [Indexed: 10/10/2023] Open
Abstract
Proteins, cells and bacteria adhering to the surface of medical devices can lead to thrombosis and infection, resulting in significant clinical mortality. Here, we report a zwitterionic polymers-armored amyloid-like protein surface engineering strategy we called as "armored-tank" strategy for dual functionalization of medical devices. The "armored-tank" strategy is realized by decoration of partially conformational transformed LZM (PCTL) assembly through oxidant-mediated process, followed by armoring with super-hydrophilic poly-2-methacryloyloxyethyl phosphorylcholine (pMPC). The outer armor of the "armored-tank" shows potent and durable zone defense against fibrinogen, platelet and bacteria adhesion, leading to long-term antithrombogenic properties over 14 days in vivo without anticoagulation. Additionally, the "fired" PCTL from "armored-tank" actively and effectively kills both Gram-positive and Gram-negative bacterial over 30 days as a supplement to the lacking bactericidal functions of passive outer armor. Overall, this "armored-tank" surface engineering strategy serves as a promising solution for preventing biofouling and thrombotic occlusion of medical devices.
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Affiliation(s)
- Xiaohui Mou
- School of Materials Science and Engineering, Key Lab of Advanced Technology of Materials of Education Ministry, Southwest Jiaotong University, Chengdu, 610031, China
- Dongguan Key Laboratory of Smart Biomaterials and Regenerative Medicine, The Tenth Affiliated Hospital of Southern Medical University, Dongguan, Guangdong, 523000, China
| | - Wan Miao
- School of Materials Science and Engineering, Key Lab of Advanced Technology of Materials of Education Ministry, Southwest Jiaotong University, Chengdu, 610031, China
| | - Wentai Zhang
- Dongguan Key Laboratory of Smart Biomaterials and Regenerative Medicine, The Tenth Affiliated Hospital of Southern Medical University, Dongguan, Guangdong, 523000, China
| | - Wenxuan Wang
- School of Materials Science and Engineering, Key Lab of Advanced Technology of Materials of Education Ministry, Southwest Jiaotong University, Chengdu, 610031, China
| | - Qing Ma
- School of Materials Science and Engineering, Key Lab of Advanced Technology of Materials of Education Ministry, Southwest Jiaotong University, Chengdu, 610031, China
- Dongguan Key Laboratory of Smart Biomaterials and Regenerative Medicine, The Tenth Affiliated Hospital of Southern Medical University, Dongguan, Guangdong, 523000, China
| | - Zeyu Du
- School of Materials Science and Engineering, Key Lab of Advanced Technology of Materials of Education Ministry, Southwest Jiaotong University, Chengdu, 610031, China
- Dongguan Key Laboratory of Smart Biomaterials and Regenerative Medicine, The Tenth Affiliated Hospital of Southern Medical University, Dongguan, Guangdong, 523000, China
| | - Xin Li
- Department of Cardiology, Third People's Hospital of Chengdu Affiliated to Southwest Jiaotong University, Chengdu, Sichuan 610072, China
| | - Nan Huang
- School of Materials Science and Engineering, Key Lab of Advanced Technology of Materials of Education Ministry, Southwest Jiaotong University, Chengdu, 610031, China
| | - Zhilu Yang
- Dongguan Key Laboratory of Smart Biomaterials and Regenerative Medicine, The Tenth Affiliated Hospital of Southern Medical University, Dongguan, Guangdong, 523000, China
- Department of Cardiology, Third People's Hospital of Chengdu Affiliated to Southwest Jiaotong University, Chengdu, Sichuan 610072, China
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Gensluckner S, Wernly B, Koutny F, Strebinger G, Zandanell S, Stechemesser L, Paulweber B, Iglseder B, Trinka E, Frey V, Langthaler P, Semmler G, Valenti L, Corradini E, Datz C, Aigner E. Prevalence and Characteristics of Metabolic Hyperferritinemia in a Population-Based Central-European Cohort. Biomedicines 2024; 12:207. [PMID: 38255312 PMCID: PMC10813305 DOI: 10.3390/biomedicines12010207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/07/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Hyperferritinemia (HF) is a common finding and can be considered as metabolic HF (MHF) in combination with metabolic diseases. The definition of MHF was heterogenous until a consensus statement was published recently. Our aim was to apply the definition of MHF to provide data on the prevalence and characteristics of MHF in a Central-European cohort. METHODS This study was a retrospective analysis of the Paracelsus 10,000 study, a population-based cohort study from the region of Salzburg, Austria. We included 8408 participants, aged 40-77. Participants with HF were divided into three categories according to their level of HF and evaluated for metabolic co-morbidities defined by the proposed criteria for MHF. RESULTS HF was present in 13% (n = 1111) with a clear male preponderance (n = 771, 69% of HF). Within the HF group, 81% (n = 901) of subjects fulfilled the metabolic criteria and were defined as MHF, of which 75% (n = 674) were characterized by a major criterion. In the remaining HF cohort, 52% (n = 227 of 437) of subjects were classified as MHF after application of the minor criteria. CONCLUSION HF is a common finding in the general middle-aged population and the majority of cases are classified as MHF. The new classification provides useful criteria for defining MHF.
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Affiliation(s)
- Sophie Gensluckner
- Department of Internal Medicine I, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; (S.G.)
- Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - Bernhard Wernly
- Department of Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University, Paracelsusstraße 37, 5110 Oberndorf, Austria
| | - Florian Koutny
- Department of Internal Medicine 2, Gastroenterology and Hepatology and Rheumatology, University Hospital of St. Pölten, Karl Landsteiner University of Health Sciences, Dunant-Platz 1, Kremser Landstraße 40, 3100 St. Pölten, Austria
| | - Georg Strebinger
- Department of Internal Medicine I, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; (S.G.)
- Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - Stephan Zandanell
- Department of Internal Medicine I, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; (S.G.)
- Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - Lars Stechemesser
- Department of Internal Medicine I, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; (S.G.)
- Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - Bernhard Paulweber
- Department of Internal Medicine I, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; (S.G.)
| | - Bernhard Iglseder
- Department of Geriatric Medicine, Christian Doppler University Hospital, Paracelsus Medical University, Ignaz-Harrer-Straße 79, 5020 Salzburg, Austria
| | - Eugen Trinka
- Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University and Centre for Cognitive Neuroscience, Affiliated Member of the European Reference Network EpiCARE, Ignaz-Harrer-Straße 79, 5020 Salzburg, Austria
| | - Vanessa Frey
- Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University and Centre for Cognitive Neuroscience, Affiliated Member of the European Reference Network EpiCARE, Ignaz-Harrer-Straße 79, 5020 Salzburg, Austria
| | - Patrick Langthaler
- Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University and Centre for Cognitive Neuroscience, Affiliated Member of the European Reference Network EpiCARE, Ignaz-Harrer-Straße 79, 5020 Salzburg, Austria
| | - Georg Semmler
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Via Francesco Forza 35, 20122 Milan, Italy;
- Precision Medicine, Biological Resource Center Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Francesco Sforza, 35, 20122 Milan, Italy
| | - Elena Corradini
- Department of Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Via del Pozzo 71, 41124 Modena, Italy;
- Internal Medicine and Centre for Hemochromatosis and Hereditary Liver Diseases, Azienda Ospedaliero-Universitaria di Modena Policlinico, 41124 Modena, Italy
| | - Christian Datz
- Department of Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University, Paracelsusstraße 37, 5110 Oberndorf, Austria
| | - Elmar Aigner
- Department of Internal Medicine I, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; (S.G.)
- Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
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Suwała S, Białczyk A, Koperska K, Rajewska A, Krintus M, Junik R. Prevalence and Crucial Parameters in Diabesity-Related Liver Fibrosis: A Preliminary Study. J Clin Med 2023; 12:7760. [PMID: 38137829 PMCID: PMC10744287 DOI: 10.3390/jcm12247760] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 11/28/2023] [Accepted: 12/16/2023] [Indexed: 12/24/2023] Open
Abstract
Diabetes and obesity have been recognized as confirmed risk factors for the occurrence of liver fibrosis. Despite the long-standing acknowledgment of "diabesity", the simultaneous existence of diabetes and obesity, scholarly literature has shown limited attention to this topic. The aim of this pilot study was to assess the prevalence of liver fibrosis among individuals with diabetes (specifically those who are obese) in order to identify the key factors associated with hepatofibrosis and determine the most important associations and differences between patients with and without liver fibrosis. The research included a total of 164 participants (48.17% had comorbid obesity). Liver elastography (Fibroscan) was performed on these individuals in addition to laboratory tests. Liver fibrosis was found in 34.76% of type 2 diabetes patients; male gender almost doubled the risk of hepatofibrosis (RR 1.81) and diabesity nearly tripled this risk (RR 2.81; however, in degree III of obesity, the risk was elevated to 3.65 times higher). Anisocytosis, thrombocytopenia, or elevated liver enzymes raised the incidence of liver fibrosis by 1.78 to 2.47 times. In these individuals, liver stiffness was negatively correlated with MCV, platelet count, and albumin concentration; GGTP activity and HbA1c percentage were positively correlated. The regression analysis results suggest that the concentration of albumin and the activity of GGTP are likely to have a substantial influence on the future management of liver fibrosis in patients with diabesity. The findings of this study can serve as the basis for subsequent investigations and actions focused on identifying potential therapeutic and diagnostic avenues.
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Affiliation(s)
- Szymon Suwała
- Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland;
| | - Aleksandra Białczyk
- Evidence-Based Medicine Students Scientific Club of Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland; (A.B.); (K.K.); (A.R.)
| | - Kinga Koperska
- Evidence-Based Medicine Students Scientific Club of Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland; (A.B.); (K.K.); (A.R.)
| | - Alicja Rajewska
- Evidence-Based Medicine Students Scientific Club of Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland; (A.B.); (K.K.); (A.R.)
| | - Magdalena Krintus
- Department of Laboratory Medicine, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland;
| | - Roman Junik
- Department of Endocrinology and Diabetology, Nicolaus Copernicus University, Collegium Medicum, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland;
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Khan MZ, Klepper C, Orkin S, Arce-Clachar AC, Bramlage K, Fei L, Miethke A, Kohli R, Xanthakos S, Mouzaki M. Presence of Alpha 1 Antitrypsin Risk Variants is Not Associated With Histologic Severity of Pediatric NAFLD. J Pediatr Gastroenterol Nutr 2023; 77:166-170. [PMID: 37229749 PMCID: PMC10524978 DOI: 10.1097/mpg.0000000000003845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
BACKGROUND Among adults with nonalcoholic fatty liver disease (NAFLD), alpha-1-antitrypsin (A1AT) heterozygosity has been linked to advanced liver disease; pediatric data remain unclear. OBJECTIVE The objective of this study is to determine whether A1AT PiZ or PiS variants are associated with liver disease severity in youth with NAFLD. METHODS Retrospective study of youth with confirmed NAFLD. Multivariable logistic regression used to determine independent associations between A1AT risk variants and histologic severity [NAFLD activity score (NAS) ≥5 and/or significant fibrosis (stage ≥2)]. RESULTS The cohort included 269 patients, mean age 12 [±3] years with NAFLD and A1AT phenotyping (n = 260) and/or A1AT levels (n = 261). The mean NAS of the cohort was 4.2 [±1.5]; 50% had any, and 18% had significant fibrosis. Most (86%) had the MM A1AT phenotype, while 7% had the MS and 3% the MZ phenotype (the rest had other, nonpathogenic variants). Mean A1AT level was 123 mg/dL [±20]. A1AT levels did not differ by low versus high NAS (122 ± 2 vs 126 ± 19 mg/dL, P = 0.12) or by no/mild versus significant fibrosis (123 ± 20 vs 126 ± 20 mg/dL, P = 0.23, respectively). Carriers and noncarriers of the PiS or PiZ variants had similar NAS (mean NAS 3.8 ± 1.6 vs 4.2 ± 1.4; P = 0.25, respectively). Fibrosis severity did not differ by carrier vs noncarrier group: 38% versus 52% had any fibrosis ( P = 0.17) and 14% versus 18% had significant fibrosis ( P = 0.80, respectively). Multivariable modeling showed no association between A1AT risk variants and histologic severity. CONCLUSION While not uncommon, carriage of the A1AT PiZ or PiS risk variants was not associated with histologic severity in children with NAFLD.
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Affiliation(s)
- Maya Zahid Khan
- Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Corie Klepper
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Sarah Orkin
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- University of Cincinnati College of Medicine
| | - Ana Catalina Arce-Clachar
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- University of Cincinnati College of Medicine
| | - Kristen Bramlage
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- University of Cincinnati College of Medicine
| | - Lin Fei
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- University of Cincinnati College of Medicine
| | - Alexander Miethke
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- University of Cincinnati College of Medicine
| | - Rohit Kohli
- Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Los Angeles, Los Angeles, CA, United States
| | - Stavra Xanthakos
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- University of Cincinnati College of Medicine
| | - Marialena Mouzaki
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- University of Cincinnati College of Medicine
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10
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Sun Z, Pan X, Tian A, Surakka I, Wang T, Jiao X, He S, Song J, Tian X, Tong D, Wen J, Zhang Y, Liu W, Chen P. Genetic variants in HFE are associated with non-alcoholic fatty liver disease in lean individuals. JHEP Rep 2023; 5:100744. [PMID: 37235137 PMCID: PMC10206181 DOI: 10.1016/j.jhepr.2023.100744] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 02/13/2023] [Accepted: 03/07/2023] [Indexed: 05/28/2023] Open
Abstract
Background & Aims Around 20% of patients with non-alcoholic fatty liver disease (NAFLD) are lean. Increasing evidence suggests that lean NAFLD is a unique subtype of the disease. We aimed to explore the metabolic profile, genetic basis, causal risk factors, and clinical sequelae underlying lean NAFLD. Methods NAFLD was diagnosed by whole liver proton density fat fraction ≥5%. Whole liver proton density fat fraction and hepatic iron were quantified using magnetic resonance imaging in the UK Biobank. Individuals in this study were stratified according to the World Health Organization criteria of obesity, into lean, overweight, and obese. Mediation analysis, Mendelian randomisation analysis, and Bayesian networks were used to identify a risk factor or a clinical sequela of lean/obese NAFLD. Results Lean NAFLD manifested a distinct metabolic profile, featured by elevated hepatic iron and fasting glucose. Four loci, namely, HFE rs1800562, SLC17A3-SLC17A2-TRIM38 rs9348697, PNPLA3 rs738409, and TM6SF2 rs58542926, were associated with lean NAFLD (p <5 × 10-8). HFE rs1800562 was specifically associated with lean NAFLD and demonstrated a significant mediation effect through elevating hepatic iron. Type 2 diabetes was the most pronounced clinical sequela of lean NAFLD, followed by liver cirrhosis. Conclusions Our study suggested that HFE plays a potential steatogenic role rather than regulating iron homoeostasis in patients with lean NAFLD. The increased liver iron deposition is associated with lean NAFLD, whereas obese NAFLD is not related to hepatic iron. The clinical management of patients with lean NAFLD shall be concerned with the prevention and treatment of type 2 diabetes and liver cirrhosis. Impact and implications Lean NAFLD has a distinct natural history from obese NAFLD. This study underscored liver iron content and the genetic variant of the iron homoeostasis gene HFE as major risks of lean NAFLD, in addition to the unique metabolic profile. The development of type 2 diabetes or liver cirrhosis shall be closely monitored and prevented in patients with lean NAFLD.
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Affiliation(s)
- Zewen Sun
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Xingchen Pan
- Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Aowen Tian
- Department of Pathology, College of Basic Medical Sciences, Jilin University, Changchun, China
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
| | - Ida Surakka
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
| | - Tao Wang
- Software College of Jilin University, Changchun, China
| | - Xu Jiao
- Software College of Jilin University, Changchun, China
| | - Shanshan He
- Software College of Jilin University, Changchun, China
| | - Jinfang Song
- Department of Pediatrics, The Second Hospital of Jilin University, Changchun, China
| | - Xin Tian
- Department of Pediatrics, The Second Hospital of Jilin University, Changchun, China
| | - Dan Tong
- Department of Radiology, The First Hospital of Jilin University, Changchun, China
| | - Jianping Wen
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Yonggang Zhang
- The Key Laboratory of Symbol Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, China
- College of Computer Science and Technology, Jilin University, Changchun, China
| | - Wanqing Liu
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Peng Chen
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
- Department of Pathology, College of Basic Medical Sciences, Jilin University, Changchun, China
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
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11
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Charlebois E, Pantopoulos K. Nutritional Aspects of Iron in Health and Disease. Nutrients 2023; 15:2441. [PMID: 37299408 PMCID: PMC10254751 DOI: 10.3390/nu15112441] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 05/16/2023] [Accepted: 05/17/2023] [Indexed: 06/12/2023] Open
Abstract
Dietary iron assimilation is critical for health and essential to prevent iron-deficient states and related comorbidities, such as anemia. The bioavailability of iron is generally low, while its absorption and metabolism are tightly controlled to satisfy metabolic needs and prevent toxicity of excessive iron accumulation. Iron entry into the bloodstream is limited by hepcidin, the iron regulatory hormone. Hepcidin deficiency due to loss-of-function mutations in upstream gene regulators causes hereditary hemochromatosis, an endocrine disorder of iron overload characterized by chronic hyperabsorption of dietary iron, with deleterious clinical complications if untreated. The impact of high dietary iron intake and elevated body iron stores in the general population is not well understood. Herein, we summarize epidemiological data suggesting that a high intake of heme iron, which is abundant in meat products, poses a risk factor for metabolic syndrome pathologies, cardiovascular diseases, and some cancers. We discuss the clinical relevance and potential limitations of data from cohort studies, as well as the need to establish causality and elucidate molecular mechanisms.
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Affiliation(s)
- Edouard Charlebois
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada;
- Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
| | - Kostas Pantopoulos
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada;
- Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
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12
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Kose T, Sharp PA, Latunde-Dada GO. Phenolic Acids Rescue Iron-Induced Damage in Murine Pancreatic Cells and Tissues. Molecules 2023; 28:molecules28104084. [PMID: 37241825 DOI: 10.3390/molecules28104084] [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: 03/31/2023] [Revised: 05/06/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
Iron is an essential element involved in a variety of physiological functions. However, excess iron catalyzes the generation of reactive oxygen species (ROS) via the Fenton reaction. Oxidative stress, caused by an increase in intracellular ROS production, can be a contributory factor to metabolic syndromes such as dyslipidemia, hypertension, and type 2 diabetes (T2D). Accordingly, interest has grown recently in the role and use of natural antioxidants to prevent iron-induced oxidative damage. This study investigated the protective effect of the phenolic acids; ferulic acid (FA) and its metabolite ferulic acid 4-O-sulfate disodium salt (FAS) against excess iron-related oxidative stress in murine MIN6 cells and the pancreas of BALB/c mice. Rapid iron overload was induced with 50 μmol/L ferric ammonium citrate (FAC) and 20 μmol/L 8-hydroxyquinoline (8HQ) in MIN6 cells, while iron dextran (ID) was used to facilitate iron overload in mice. Cell viability was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay, ROS levels were determined by dihydrodichlorofluorescein (H2DCF) cell-permeant probe, iron levels were measured by inductively coupled plasma mass spectrometry (ICP-MS), glutathione, SOD (superoxide dismutase) and lipid peroxidation, and mRNA were assayed with commercially available kits. The phenolic acids enhanced cell viability in iron-overloaded MIN6 cells in a dose-dependent manner. Furthermore, MIN6 cells exposed to iron showed elevated levels of ROS, glutathione (GSH) depletion and lipid peroxidation (p < 0.05) compared to cells that were protected by treatment with FA or FAS. The treatment of BALB/c mice with FA or FAS following exposure to ID increased the nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) gene levels in the pancreas. Consequently, levels of its downstream antioxidant genes, HO-1, NQO1, GCLC and GPX4, increased in the pancreas. In conclusion, this study shows that FA and FAS protect pancreatic cells and liver tissue from iron-induced damage via the Nrf2 antioxidant activation mechanism.
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Affiliation(s)
- Tugba Kose
- Department of Nutritional Sciences, School of Life Course and Population Sciences, King's College London, Franklin-Wilkins-Building, 150 Stamford Street, London SE1 9NH, UK
| | - Paul A Sharp
- Department of Nutritional Sciences, School of Life Course and Population Sciences, King's College London, Franklin-Wilkins-Building, 150 Stamford Street, London SE1 9NH, UK
| | - Gladys O Latunde-Dada
- Department of Nutritional Sciences, School of Life Course and Population Sciences, King's College London, Franklin-Wilkins-Building, 150 Stamford Street, London SE1 9NH, UK
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13
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Valenti L, Corradini E, Adams LA, Aigner E, Alqahtani S, Arrese M, Bardou-Jacquet E, Bugianesi E, Fernandez-Real JM, Girelli D, Hagström H, Henninger B, Kowdley K, Ligabue G, McClain D, Lainé F, Miyanishi K, Muckenthaler MU, Pagani A, Pedrotti P, Pietrangelo A, Prati D, Ryan JD, Silvestri L, Spearman CW, Stål P, Tsochatzis EA, Vinchi F, Zheng MH, Zoller H. Consensus Statement on the definition and classification of metabolic hyperferritinaemia. Nat Rev Endocrinol 2023; 19:299-310. [PMID: 36805052 PMCID: PMC9936492 DOI: 10.1038/s41574-023-00807-6] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/19/2023] [Indexed: 02/19/2023]
Abstract
Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes.
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Affiliation(s)
- Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
- Biological Resource Center and Precision Medicine Lab, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy.
- Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy.
| | - Elena Corradini
- Department of Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Modena, Italy.
- Internal Medicine and Centre for Hemochromatosis and Hereditary Liver Diseases, Azienda Ospedaliero-Universitaria di Modena-Policlinico, Modena, Italy.
| | - Leon A Adams
- Medical School, University of Western Australia, Perth, Australia
| | - Elmar Aigner
- First Department of Medicine, University Clinic Salzburg, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Saleh Alqahtani
- Royal Clinics and Gastroenterology and Hepatology, King Faisal Specialist Hospital & Research Centre, Riyadh, Kingdom of Saudi Arabia
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Marco Arrese
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Edouard Bardou-Jacquet
- University of Rennes, UMR1241, CHU Rennes, National Reference Center for Hemochromatosis and iron metabolism disorder, INSERM CIC1414, Rennes, France
| | - Elisabetta Bugianesi
- Department of Medical Sciences, Division of Gastroenterology, University of Turin, Turin, Italy
| | - Jose-Manuel Fernandez-Real
- Department of Diabetes, Endocrinology and Nutrition, Dr Josep Trueta University Hospital, Girona, Spain
- Department of Medical Sciences, Faculty of Medicine, Girona University, Girona, Spain
- Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IdibGi), Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Domenico Girelli
- Section of Internal Medicine, Department of Medicine, University of Verona, Policlinico Giambattista Rossi, Verona, Italy
| | - Hannes Hagström
- Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Benjamin Henninger
- Department of Radiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Kris Kowdley
- Liver Institute Northwest, Seattle, WA, USA
- Elson S. Floyd College of Medicine, Washington State University, Seattle, WA, USA
| | - Guido Ligabue
- Department of Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Modena, Italy
- Division of Radiology, Ospedale di Sassuolo S.p.A, Sassuolo, Modena, Italy
| | - Donald McClain
- Wake Forest School of Medicine, Winston Salem, NC, USA
- Department of Veterans Affairs, Salisbury, NC, USA
| | - Fabrice Lainé
- INSERM CIC1414, Liver Unit, CHU Rennes, Rennes, France
| | - Koji Miyanishi
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Martina U Muckenthaler
- Department of Paediatric Hematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany
- Center for Molecular Translational Iron Research, Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
- German Centre for Cardiovascular Research, Partner Site Heidelberg, Heidelberg, Germany
| | - Alessia Pagani
- Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Patrizia Pedrotti
- Laboratorio di RM Cardiaca Cardiologia 4, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Antonello Pietrangelo
- Department of Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Modena, Italy
- Internal Medicine and Centre for Hemochromatosis and Hereditary Liver Diseases, Azienda Ospedaliero-Universitaria di Modena-Policlinico, Modena, Italy
| | - Daniele Prati
- Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - John D Ryan
- Hepatology Unit, Beaumont Hospital, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Laura Silvestri
- Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy
| | - C Wendy Spearman
- Division of Hepatology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Per Stål
- Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Emmanuel A Tsochatzis
- UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK
| | - Francesca Vinchi
- Iron Research Laboratory, Lindsley F.Kimball Research Institute, New York Blood Center, New York, NY, USA
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Heinz Zoller
- Department of Medicine I, Medical University of Innsbruck, Innsbruck, Austria
- Doppler Laboratory on Iron and Phosphate Biology, Innsbruck, Austria
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14
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Abstract
High iron is a risk factor for type 2 diabetes mellitus (T2DM) and affects most of its cardinal features: decreased insulin secretion, insulin resistance, and increased hepatic gluconeogenesis. This is true across the normal range of tissue iron levels and in pathologic iron overload. Because of iron's central role in metabolic processes (e.g., fuel oxidation) and metabolic regulation (e.g., hypoxia sensing), iron levels participate in determining metabolic rates, gluconeogenesis, fuel choice, insulin action, and adipocyte phenotype. The risk of diabetes related to iron is evident in most or all tissues that determine diabetes phenotypes, with the adipocyte, beta cell, and liver playing central roles. Molecular mechanisms for these effects are diverse, although there may be integrative pathways at play. Elucidating these pathways has implications not only for diabetes prevention and treatment, but also for the pathogenesis of other diseases that are, like T2DM, associated with aging, nutrition, and iron.
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Affiliation(s)
- Alexandria V Harrison
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA;
| | - Felipe Ramos Lorenzo
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA;
- Department of Veterans Affairs, W.G. (Bill) Hefner Veterans Affairs Medical Center, Salisbury, North Carolina, USA
| | - Donald A McClain
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA;
- Department of Veterans Affairs, W.G. (Bill) Hefner Veterans Affairs Medical Center, Salisbury, North Carolina, USA
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15
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Hereditary Hyperferritinemia. Int J Mol Sci 2023; 24:ijms24032560. [PMID: 36768886 PMCID: PMC9917042 DOI: 10.3390/ijms24032560] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/26/2023] [Accepted: 01/26/2023] [Indexed: 02/03/2023] Open
Abstract
Ferritin is a ubiquitous protein that is present in most tissues as a cytosolic protein. The major and common role of ferritin is to bind Fe2+, oxidize it and sequester it in a safe form in the cell, and to release iron according to cellular needs. Ferritin is also present at a considerably low proportion in normal mammalian sera and is relatively iron poor compared to tissues. Serum ferritin might provide a useful and convenient method of assessing the status of iron storage, and its measurement has become a routine laboratory test. However, many additional factors, including inflammation, infection, metabolic abnormalities, and malignancy-all of which may elevate serum ferritin-complicate interpretation of this value. Despite this long history of clinical use, fundamental aspects of the biology of serum ferritin are still unclear. According to the high number of factors involved in regulation of ferritin synthesis, secretion, and uptake, and in its central role in iron metabolism, hyperferritinemia is a relatively common finding in clinical practice and is found in a large spectrum of conditions, both genetic and acquired, associated or not with iron overload. The diagnostic strategy to reveal the cause of hyperferritinemia includes family and personal medical history, biochemical and genetic tests, and evaluation of liver iron by direct or indirect methods. This review is focused on the forms of inherited hyperferritinemia with or without iron overload presenting with normal transferrin saturation, as well as a step-by-step approach to distinguish these forms to the acquired forms, common and rare, of isolated hyperferritinemia.
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16
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Barbalho SM, Laurindo LF, Tofano RJ, Flato UAP, Mendes CG, de Alvares Goulart R, Briguezi AMGM, Bechara MD. Dysmetabolic Iron Overload Syndrome: Going beyond the Traditional Risk Factors Associated with Metabolic Syndrome. ENDOCRINES 2023; 4:18-37. [DOI: 10.3390/endocrines4010002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Dysmetabolic iron overload syndrome (DIOS) corresponds to the increase in iron stores associated with components of metabolic syndrome (MtS) and in the absence of an identifiable cause of iron excess. The objective of this work was to review the main aspects of DIOS. PUBMED and EMBASE were consulted, and PRISMA guidelines were followed. DIOS is usually asymptomatic and can be diagnosed by investigating MtS and steatosis. About 50% of the patients present altered hepatic biochemical tests (increased levels of γ-glutamyl transpeptidase itself or associated with increased levels of alanine aminotransferase). The liver may present parenchymal and mesenchymal iron overload, but the excess of iron is commonly mild. Steatosis or steatohepatitis is observed in half of the patients. Fibrosis is observed in about 15% of patients. Hyperferritinemia may damage the myocardium, liver, and several other tissues, increasing morbidity and mortality. Furthermore, DIOS is closely related to oxidative stress, which is closely associated with several pathological conditions such as inflammatory diseases, hypertension, diabetes, heart failure, and cancer. DIOS is becoming a relevant finding in the general population and can be associated with high morbidity/mortality. For these reasons, investigation of this condition could be an additional requirement for the early prevention of cardiovascular diseases.
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Affiliation(s)
- Sandra Maria Barbalho
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marília (FATEC), Avenida Castro Alves, 62, Marília, São Paulo 17500-000, Brazil
| | - Lucas Fornari Laurindo
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
| | - Ricardo José Tofano
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
- Department of Cardiology, Associação Beneficente Hospital Universitário (ABHU), Rua Dr. Próspero Cecílio Coimbra, 80, Marília, São Paulo 17525-160, Brazil
| | - Uri Adrian Prync Flato
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marília (FATEC), Avenida Castro Alves, 62, Marília, São Paulo 17500-000, Brazil
| | - Claudemir G. Mendes
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
| | - Ricardo de Alvares Goulart
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
| | - Ana Maria Gonçalves Milla Briguezi
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
| | - Marcelo Dib Bechara
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília, São Paulo 17525-902, Brazil
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17
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Prieto Ortíz JE, Sánchez Luque CB, Ortega Quiróz RJ. Hígado graso (parte 1): aspectos generales, epidemiología, fisiopatología e historia natural. REVISTA COLOMBIANA DE GASTROENTEROLOGÍA 2022; 37:420-433. [DOI: 10.22516/25007440.952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
El hígado graso no alcohólico (NAFLD) se define por la presencia de grasa o esteatosis en los hepatocitos y abarca un espectro que va desde la esteatosis simple, pasa por la esteatohepatitis no alcohólica (NASH) con inflamación y fibrosis, y finaliza en la cirrosis. Se considera una prevalencia mundial global cercana al 25% en la población general y se diagnóstica entre los 40 y 50 años, con variaciones respecto al sexo predominante y con diferencias étnicas (la población hispana es la más afectada). El hígado graso está asociado al síndrome metabólico (SM), y la obesidad se considera el principal factor de riesgo con su presencia y con su progresión.
El hígado graso es un trastorno complejo y muy heterogéneo en su fisiopatología, que resulta de la interacción de múltiples elementos: factores genéticos, epigenéticos, ambientales, culturales, entre otros. Todo ello en conjunto lleva a incremento paulatino de grasa hepática, resistencia a la insulina y alteraciones hormonales y de la microbiota intestinal, lo que genera un daño hepatocelular a través de la formación de radicales libres de oxígeno y activación de la fibrogénesis hepática.
La historia natural del hígado graso es dinámica: los pacientes con esteatosis simple tienen bajo riesgo de progresión a cirrosis, mientras que en los pacientes con NASH este riesgo se aumenta; sin embargo, el proceso puede ser reversible y algunas personas tendrán una mejoría espontánea. La fibrosis parece ser el determinante de la mortalidad global y de los desenlaces asociados a la enfermedad hepática; se considera que en todos los pacientes la fibrosis empeora una etapa cada 14 años y en NASH empeora en una etapa cada 7 años. Estudios previos concluyen que aproximadamente 20% de los casos de esteatosis simple progresan a NASH y que, de ellos, aproximadamente el 20% progresan a cirrosis, con presencia de hepatocarcinoma (HCC) en el 5% a 10% de ellos.
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18
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Fatty Liver Disease-Alcoholic and Non-Alcoholic: Similar but Different. Int J Mol Sci 2022; 23:ijms232416226. [PMID: 36555867 PMCID: PMC9783455 DOI: 10.3390/ijms232416226] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
In alcohol-induced liver disease (ALD) and in non-alcoholic fatty liver disease (NAFLD), there are abnormal accumulations of fat in the liver. This phenomenon may be related to excessive alcohol consumption, as well as the combination of alcohol consumption and medications. There is an evolution from simple steatosis to steatohepatitis, fibrosis and cirrhosis leading to hepatocellular carcinoma (HCC). Hepatic pathology is very similar regarding non-alcoholic fatty liver disease (NAFLD) and ALD. Initially, there is lipid accumulation in parenchyma and progression to lobular inflammation. The morphological changes in the liver mitochondria, perivenular and perisinusoidal fibrosis, and hepatocellular ballooning, apoptosis and necrosis and accumulation of fibrosis may lead to the development of cirrhosis and HCC. Medical history of ethanol consumption, laboratory markers of chronic ethanol intake, AST/ALT ratio on the one hand and features of the metabolic syndrome on the other hand, may help in estimating the contribution of alcohol intake and the metabolic syndrome, respectively, to liver steatosis.
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Xiong F, Zhou Q, Huang X, Cao P, Wang Y. Ferroptosis plays a novel role in nonalcoholic steatohepatitis pathogenesis. Front Pharmacol 2022; 13:1055793. [PMID: 36532757 PMCID: PMC9755204 DOI: 10.3389/fphar.2022.1055793] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 11/23/2022] [Indexed: 09/29/2023] Open
Abstract
Ferroptosis relies on iron, and ferroptotic cell death is triggered when the balance of the oxidation-reduction system is disrupted by excessive lipid peroxide accumulation. A close relationship between ferroptosis and nonalcoholic steatohepatitis (NASH) is formed by phospholipid peroxidation substrates, bioactive iron, and reactive oxygen species (ROS) neutralization systems. Recent studies into ferroptosis during NASH development might reveal NASH pathogenesis and drug targets. Our review summarizes NASH pathogenesis from the perspective of ferroptosis mechanisms. Further, we discuss the relationship between mitochondrial dysfunction, ferroptosis, and NASH. Finally, potential pharmacological therapies directed to ferroptosis in NASH are hypothesized.
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Affiliation(s)
- Fei Xiong
- Department of Gastroenterology, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, Chengdu, China
| | - Qiao Zhou
- Department of Rheumatology and Immunology, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, Chengdu, China
| | - Xiaobo Huang
- Department of Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Peng Cao
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Wang
- Department of Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
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20
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Hanna HWZ, Baz HN, Al-Kzayer LFY, El Haddad HE, El-Mougy F. Assessment of plasma catecholamines in patients with dysmetabolic iron overload syndrome. J Appl Biomed 2022; 20:141-145. [PMID: 36708719 DOI: 10.32725/jab.2022.016] [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: 06/21/2022] [Accepted: 11/16/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Dysmetabolic iron overload syndrome (DIOS) is characterized by hyperferritinemia and normal transferrin saturation level with components of metabolic syndrome (MS). Among cases of MS, we determined those with DIOS and their characterizations, then we evaluated the association between plasma catecholamines status and hypertension in DIOS. METHODS We compared 101 hypertensive patients with 50 healthy participants (control group). Iron (iron, transferrin, and ferritin), insulin, and plasma catecholamine (adrenaline, noradrenaline, and dopamine), profiles were measured for both groups. Homeostasis model assessment of insulin resistance index and transferrin saturation were also calculated. RESULTS Out of 101 hypertensive patients, 64 were diagnosed with MS, and 6 of the latter met the DIOS diagnostic criteria. Significantly, DIOS patients were older and had lower body mass index (BMI) compared with hypertensive non-DIOS patients with p-values of (0.026), and (0.033), respectively. Adrenaline, noradrenaline, and dopamine levels did not differ significantly between DIOS and non-DIOS patients. CONCLUSIONS Of the MS patients, 9.3% were diagnosed with DIOS. Accordingly, complete iron profiling should be performed routinely in the cases of MS for early diagnosis of DIOS, to prevent future complications. Further studies are required to test the hypothesis linking older age and lower BMI with the pathogenesis of DIOS.
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Affiliation(s)
| | - Heba N Baz
- Cairo University, Kasr Al Ainy, Faculty of Medicine, Department of Clinical and Chemical Pathology, Cairo, Egypt
| | | | - Hemmat E El Haddad
- Cairo University, Kasr Al Ainy, Faculty of Medicine, Department of Internal Medicine, Cairo, Egypt
| | - Fatma El-Mougy
- Cairo University, Kasr Al Ainy, Faculty of Medicine, Department of Clinical and Chemical Pathology, Cairo, Egypt
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21
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Fernandez M, Lokan J, Leung C, Grigg A. A critical evaluation of the role of iron overload in fatty liver disease. J Gastroenterol Hepatol 2022; 37:1873-1883. [PMID: 35906772 DOI: 10.1111/jgh.15971] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 07/16/2022] [Accepted: 07/27/2022] [Indexed: 12/09/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has been associated with a condition known as the dysmetabolic iron overload syndrome, but the frequency and severity of iron overload in NAFLD is not well described. There is emerging evidence that mild to moderate excess hepatic iron can aggravate the risk of progression of NAFLD to nonalcoholic steatohepatitis and eventually cirrhosis. Mechanisms are postulated to be via reactive oxygen species, inflammatory cytokines, lipid oxidation, and oxidative stress. The aim of this review is to assess the evidence for true hepatic iron overload in NAFLD, to discuss the pathogenesis by which excess iron may be toxic, and to critically evaluate the studies designed to deplete iron by regular venesection. In brief, the studies are inconclusive due to heterogeneity in eligibility criteria, sample size, randomization, hepatic iron measurement, serial histological endpoints, target ferritin levels, length of venesection, and degree of confounding lifestyle intervention. We propose a trial designed to overcome the limitations of these studies.
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Affiliation(s)
- Monique Fernandez
- Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
| | - Julie Lokan
- Department of Anatomical Pathology, Austin Health, Heidelberg, Victoria, Australia
| | - Christopher Leung
- Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.,Departments of Gastroenterology and Hepatology, Austin Health, Heidelberg, Victoria, Australia
| | - Andrew Grigg
- Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.,Department of Clinical Haematology, Austin Health, Heidelberg, Victoria, Australia
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22
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Ameka M, Hasty AH. Paying the Iron Price: Liver Iron Homeostasis and Metabolic Disease. Compr Physiol 2022; 12:3641-3663. [PMID: 35766833 PMCID: PMC10155403 DOI: 10.1002/cphy.c210039] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Iron is an essential metal element whose bioavailability is tightly regulated. Under normal conditions, systemic and cellular iron homeostases are synchronized for optimal function, based on the needs of each system. During metabolic dysfunction, this synchrony is lost, and markers of systemic iron homeostasis are no longer coupled to the iron status of key metabolic organs such as the liver and adipose tissue. The effects of dysmetabolic iron overload syndrome in the liver have been tied to hepatic insulin resistance, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis. While the existence of a relationship between iron dysregulation and metabolic dysfunction has long been acknowledged, identifying correlative relationships is complicated by the prognostic reliance on systemic measures of iron homeostasis. What is lacking and perhaps more informative is an understanding of how cellular iron homeostasis changes with metabolic dysfunction. This article explores bidirectional relationships between different proteins involved in iron homeostasis and metabolic dysfunction in the liver. © 2022 American Physiological Society. Compr Physiol 12:3641-3663, 2022.
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Affiliation(s)
- Magdalene Ameka
- Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA
| | - Alyssa H Hasty
- Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA.,VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA
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23
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Dalbeni A, Castelli M, Zoncapè M, Minuz P, Sacerdoti D. Platelets in Non-alcoholic Fatty Liver Disease. Front Pharmacol 2022; 13:842636. [PMID: 35250588 PMCID: PMC8895200 DOI: 10.3389/fphar.2022.842636] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/03/2022] [Indexed: 12/17/2022] Open
Abstract
Non alcoholic steatohepatitis (NASH) is the inflammatory reaction of the liver to excessive accumulation of lipids in the hepatocytes. NASH can progress to cirrhosis and hepatocellular carcinoma (HCC). Fatty liver is the hepatic manifestation of metabolic syndrome. A subclinical inflammatory state is present in patients with metabolic alterations like insulin resistance, type-2 diabetes, obesity, hyperlipidemia, and hypertension. Platelets participate in immune cells recruitment and cytokines-induced liver damage. It is hypothesized that lipid toxicity cause accumulation of platelets in the liver, platelet adhesion and activation, which primes the immunoinflammatory reaction and activation of stellate cells. Recent data suggest that antiplatelet drugs may interrupt this cascade and prevent/improve NASH. They may also improve some metabolic alterations. The pathophysiology of inflammatory liver disease and the implication of platelets are discussed in details.
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Affiliation(s)
- Andrea Dalbeni
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
- Liver Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Marco Castelli
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Mirko Zoncapè
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
- Liver Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Pietro Minuz
- Division of General Medicine C, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
- *Correspondence: Pietro Minuz,
| | - David Sacerdoti
- Liver Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
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24
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Wang JW, Jin CH, Ke JF, Ma YL, Wang YJ, Lu JX, Li MF, Li LX. Serum iron is closely associated with metabolic dysfunction-associated fatty liver disease in type 2 diabetes: A real-world study. Front Endocrinol (Lausanne) 2022; 13:942412. [PMID: 36133303 PMCID: PMC9484008 DOI: 10.3389/fendo.2022.942412] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 08/16/2022] [Indexed: 11/13/2022] Open
Abstract
AIMS There is still a debate about the relationship between serum iron and metabolic dysfunction-associated fatty liver disease (MAFLD). Furthermore, few relevant studies were conducted in type 2 diabetes mellitus (T2DM). Therefore, this study aimed to explore the association of serum iron levels with MAFLD in Chinese patients with T2DM. METHODS This cross-sectional, real-world study consisted of 1,467 Chinese T2DM patients. MAFLD was diagnosed by abdominal ultrasonography. Based on serum iron quartiles, the patients were classified into four groups. Clinical characteristics were compared among the four groups, and binary logistic analyses were used to assess the associations of serum iron levels and quartiles with the presence of MAFLD in T2DM. RESULTS After adjusting for gender, age, and diabetes duration, significantly higher prevalence of MAFLD was found in the second (45.7%), third (45.2%), and fourth (47.0%) serum iron quartiles than in the first quartiles (26.8%), with the highest MAFLD prevalence in the fourth quartile (p < 0.001 for trend). Moreover, increased HOMA2-IR (p = 0.003 for trend) and decreased HOMA2-S (p = 0.003 for trend) were observed across the serum iron quartiles. Fully adjusted binary logistic regression analyses indicated that both increased serum iron levels (OR: 1.725, 95% CI: 1.427 to 2.085, p < 0.001) and quartiles (p < 0.001 for trend) were still closely associated with the presence of MAFLD in T2DM patients even after controlling for multiple confounding factors. CONCLUSIONS There is a positive correlation between the presence of MAFLD and serum iron levels in T2DM patients, which may be attributed to the close association between serum iron and insulin resistance. Serum iron levels may act as one of the indicators for evaluating the risk of MAFLD in T2DM individuals.
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Affiliation(s)
- Jun-Wei Wang
- 1Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, China
| | - Chun-Hua Jin
- Department of Endocrinology and Metabolism, Shanghai Songjiang District Central Hospital, Songjiang Hospital Affiliated to Shanghai Jiaotong University School of Medicine (Preparatory Stage), Shanghai, China
| | - Jiang-Feng Ke
- 1Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, China
| | - Yi-Lin Ma
- 1Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, China
| | - Yu-Jie Wang
- 1Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, China
| | - Jun-Xi Lu
- 1Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, China
| | - Mei-Fang Li
- Department of Emergency, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Mei-Fang Li, ; Lian-Xi Li,
| | - Lian-Xi Li
- 1Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, China
- *Correspondence: Mei-Fang Li, ; Lian-Xi Li,
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Distribution and Associated Factors of Hepatic Iron-A Population-Based Imaging Study. Metabolites 2021; 11:metabo11120871. [PMID: 34940629 PMCID: PMC8705957 DOI: 10.3390/metabo11120871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/09/2021] [Accepted: 12/11/2021] [Indexed: 11/17/2022] Open
Abstract
Hepatic iron overload can cause severe organ damage; therefore, an early diagnosis and the identification of potential risk factors is crucial. We aimed to investigate the sex-specific distribution of hepatic iron content (HIC) in a population-based cohort and identify relevant associated factors from a panel of markers. We analyzed N = 353 participants from a cross-sectional sample (KORA FF4) who underwent whole-body magnetic resonance imaging. HIC was assessed by single-voxel spectroscopy with a high-speed T2-corrected multi-echo technique. A large panel of markers, including anthropometric, genetic, and laboratory values, as well as behavioral risk factors were assessed. Relevant factors associated with HIC were identified by variable selection based on LASSO regression with bootstrap resampling. HIC in the study sample (mean age at examination: 56.0 years, 58.4% men) was significantly lower in women (mean ± SD: 39.2 ± 4.1 s-1) than in men (41.8 ± 4.7 s-1, p < 0.001). Relevant factors associated with HIC were HbA1c as well as prediabetes for men and visceral adipose tissue as well as age for women. Hepatic fat, alcohol consumption, and genetic risk score for iron levels were associated with HIC in both sexes. In conclusion, there are sex-specific associations of HIC with markers of body composition, glucose metabolism, and alcohol consumption.
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26
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Pădureanu V, Dop D, Drăgoescu AN, Pădureanu R, Mușetescu AE, Nedelcu L. Non-alcoholic fatty liver disease and hematologic manifestations (Review). Exp Ther Med 2021; 22:1355. [PMID: 34659501 PMCID: PMC8515549 DOI: 10.3892/etm.2021.10790] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 08/16/2021] [Indexed: 11/30/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multisystem disease, and it is associated with numerous extra-hepatic manifestations or additional co-occurring diseases. The aim of the present review was the identification and management of the hematologic manifestations of NAFLD. One of the triggers is considered to be iron abnormalities. Increased ferritin levels, hepatic iron deposits and iron overload are associated with NAFLD. The iron overload degree and severity are associated with the level of liver fibrosis and with the risk for hepatocellular carcinoma. Excess iron deposits refers to the dysmetabolic iron overload syndrome (DIOS) and it is characterized by steatosis associated with moderate tissue iron deposition and increased levels of serum ferritin, while the serum transferrin saturation was normal. Further prospective studies are necessary to determine whether NAFLD has an independent risk for hematologic symptoms, besides the known risk factors. Future studies are also needed in order to assess the increasing impact of NAFLD on the micro- and macro-vascular complications of this systemic disease.
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Affiliation(s)
- Vlad Pădureanu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Dalia Dop
- Department of Pediatrics, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Alice Nicoleta Drăgoescu
- Department of Anesthesiology and Intensive Care, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Rodica Pădureanu
- Department of Internal Medicine, Emergency Clinical County Hospital of Craiova, 200642 Craiova, Romania
| | - Anca Emanuela Mușetescu
- Department of Rheumatology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Laurențiu Nedelcu
- Department of Internal Medicine, Faculty of Medicine, Transylvania University Brasov, 500019 Brașov, Romania
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Jia M, Zhang H, Qin Q, Hou Y, Zhang X, Chen D, Zhang H, Chen Y. Ferroptosis as a new therapeutic opportunity for nonviral liver disease. Eur J Pharmacol 2021; 908:174319. [PMID: 34252441 DOI: 10.1016/j.ejphar.2021.174319] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 06/04/2021] [Accepted: 07/07/2021] [Indexed: 12/18/2022]
Abstract
Nonviral liver disease is a global public health problem due to its high mortality and morbidity. However, its underlying mechanism is unclear. Ferroptosis is a novel form of cell death that is involved in a variety of disease processes. Both abnormal iron metabolism (e.g., iron overload) and lipid peroxidation, which is induced by deletion of glutathione (GSH) or glutathione peroxidase 4 (GPX4), and the accumulation of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs) trigger ferroptosis. Recently, ferroptosis has been involved in the pathological process of nonviral liver diseases [including alcohol-related liver disease (ALD); nonalcoholic fatty liver disease (NAFLD); hereditary hemochromatosis (HH); drug-, ischemia/reperfusion- or immune-induced liver injury; liver fibrosis; and liver cancer]. Hepatocyte ferroptosis is activated in ALD; NAFLD; HH; drug-, ischemia/reperfusion- or immune-induced liver injury; and liver fibrosis, whereas hepatic stellate cell and liver cancer cell ferroptosis are inhibited in liver fibrosis and liver cancer, respectively. Thus, ferroptosis is an ideal target for nonviral liver diseases. In the present review, we discuss the latest findings on ferroptosis and potential drugs targeting ferroptosis for nonviral liver diseases. This review will highlight further directions for the treatment and prevention of nonviral liver diseases.
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Affiliation(s)
- Min Jia
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, 710021, China
| | - Hongmei Zhang
- The First Affiliated Hospital of Xi'an Medical University, Xi'an Medical University, Xi'an, Shaanxi, 710077, China
| | - Qiaohong Qin
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, 710021, China
| | - Ying Hou
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, 710021, China
| | - Xin Zhang
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, 710021, China
| | - Di Chen
- School of Basic and Medical Sciences, Xi'an Medical University, Xi'an, Shaanxi, 710021, China
| | - Hong Zhang
- Department of Infectious Diseases, Shaanxi Provincial People's Hospital (the Affiliated Hospital of Xi'an Medical University), Xi'an Medical University, Xi'an, Shaanxi, 710068, China.
| | - Yulong Chen
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, 710021, China.
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Lahaye C, Gladine C, Pereira B, Berger J, Chinetti-Gbaguidi G, Lainé F, Mazur A, Ruivard M. Does iron overload in metabolic syndrome affect macrophage profile? A case control study. J Trace Elem Med Biol 2021; 67:126786. [PMID: 34022567 DOI: 10.1016/j.jtemb.2021.126786] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 04/28/2021] [Accepted: 05/10/2021] [Indexed: 12/31/2022]
Abstract
AIMS Dysmetabolic iron overload syndrome (DIOS) is common but the clinical relevance of iron overload is not understood. Macrophages are central cells in iron homeostasis and inflammation. We hypothesized that iron overload in DIOS could affect the phenotype of monocytes and impair macrophage gene expression. METHODS This study compared 20 subjects with DIOS to 20 subjects with metabolic syndrome (MetS) without iron overload, and 20 healthy controls. Monocytes were phenotyped by Fluorescence-Activated Cell Sorting (FACS) and differentiated into anti-inflammatory M2 macrophages in the presence of IL-4. The expression of 38 genes related to inflammation, iron metabolism and M2 phenotype was assessed by real-time PCR. RESULTS FACS showed no difference between monocytes across the three groups. The macrophagic response to IL-4-driven differentiation was altered in four of the five genes of M2 phenotype (MRC1, F13A1, ABCA1, TGM2 but not FABP4), in DIOS vs Mets and controls demonstrating an impaired M2 polarization. The expression profile of inflammatory genes was not different in DIOS vs MetS. Several genes of iron metabolism presented a higher expression in DIOS vs MetS: SCL11A2 (a free iron transporter, +76 %, p = 0.04), SOD1 (an antioxidant enzyme, +27 %, p = 0.02), and TFRC (the receptor 1 of transferrin, +59 %, p = 0.003). CONCLUSIONS In DIOS, macrophage polarization toward the M2 alternative phenotype is impaired but not associated with a pro-inflammatory profile. The up regulation of transferrin receptor 1 (TFRC) in DIOS macrophages suggests an adaptive role that may limit iron toxicity in DIOS.
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Affiliation(s)
- Clément Lahaye
- Université Clermont Auvergne, CHU Clermont-Ferrand, Service de Médecine interne Hôpital Estaing, INRAE, UNH, Unité de Nutrition Humaine, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
| | - Cécile Gladine
- Université Clermont Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
| | - Bruno Pereira
- Université Clermont Auvergne, CHU Clermont-Ferrand, Unité de biostatistiques, F-63000 Clermont-Ferrand, France.
| | - Juliette Berger
- Université Clermont Auvergne, CHU Clermont-Ferrand, Laboratoire d'Hématologie, Hôpital Estaing, F-63000 Clermont-Ferrand, France.
| | | | - Fabrice Lainé
- INSERM CIC 1414, and Liver Unit, CHU Rennes, 35000 Rennes, France.
| | - Andrzej Mazur
- Université Clermont Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
| | - Marc Ruivard
- Université Clermont Auvergne, CHU Clermont-Ferrand, Service de Médecine interne Hôpital Estaing, F-63000 Clermont-Ferrand, France.
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Pitchika A, Kühn JP, Schipf S, Nauck M, Dörr M, Lerch MM, Kromrey ML, Felix SB, Markus MRP, Rathmann W, Völzke H, Ittermann T. Hepatic steatosis and hepatic iron overload modify the association of iron markers with glucose metabolism disorders and metabolic syndrome. Liver Int 2021; 41:1841-1852. [PMID: 33683798 DOI: 10.1111/liv.14868] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 02/16/2021] [Accepted: 03/04/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Iron status has been linked with impaired glucose metabolism (IGM), type 2 diabetes mellitus (T2DM) and the metabolic syndrome (MetS), but the role of hepatic steatosis or iron overload on these associations remains uncertain. METHODS We analysed data from 2310 participants without known T2DM of the population-based Study of Health in Pomerania (SHIP-TREND, Germany) through logistic regression models. We tested additive and multiplicative interactions between ferritin and hepatic steatosis or iron overload. RESULTS Serum ferritin was positively associated with IGM (OR per 100 µg/L: 1.11 [1.01, 1.23]), T2DM (OR per 100 µg/L: 1.20 [1.06, 1.36]) and MetS (OR per 100 µg/L: 1.11 [1.02, 1.20]) in the total population as well as in participants without hepatic iron overload. However, the synergistic effect of higher ferritin concentrations and hepatic iron overload showed stronger associations with IGM and T2DM. Similarly, while ferritin was positively associated with T2DM and MetS even in the absence of hepatic steatosis, the synergistic effect of higher ferritin concentrations and hepatic steatosis showed stronger associations with IGM, T2DM and MetS. Transferrin was associated with isolated impaired glucose tolerance but not with T2DM and MetS. CONCLUSIONS Our study suggests that ferritin may be associated with glucose metabolism disorders and MetS even in people without hepatic steatosis or iron overload. However, in individuals with higher ferritin concentrations, the presence of hepatic steatosis may indicate stronger risk for glucose metabolism disorders and MetS, while the presence of hepatic iron overload may indicate stronger risk only for glucose metabolism disorders.
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Affiliation(s)
- Anitha Pitchika
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Jens-Peter Kühn
- Institute and Policlinic for Diagnostic and Interventional Radiology, University Hospital, Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - Sabine Schipf
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.,Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Matthias Nauck
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.,German Center for Cardiovascular Research (DZHK e.V.), Partner site Greifswald, Greifswald, Germany
| | - Marcus Dörr
- German Center for Cardiovascular Research (DZHK e.V.), Partner site Greifswald, Greifswald, Germany.,Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany
| | - Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Marie-Luise Kromrey
- Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany
| | - Stephan B Felix
- German Center for Cardiovascular Research (DZHK e.V.), Partner site Greifswald, Greifswald, Germany.,Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany
| | - Marcello R P Markus
- German Center for Cardiovascular Research (DZHK e.V.), Partner site Greifswald, Greifswald, Germany.,Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.,DZD (German Center for Diabetes Research), Site Greifswald, Greifswald, Germany
| | - Wolfgang Rathmann
- DZD (German Center for Diabetes Research), Site Greifswald, Greifswald, Germany.,Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, German Diabetes Center (DDZ), Institute for Biometrics and Epidemiology, Düsseldorf, Germany
| | - Henry Völzke
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.,German Center for Cardiovascular Research (DZHK e.V.), Partner site Greifswald, Greifswald, Germany.,DZD (German Center for Diabetes Research), Site Greifswald, Greifswald, Germany
| | - Till Ittermann
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
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Abbate M, Montemayor S, Mascaró CM, Casares M, Gómez C, Ugarriza L, Tejada S, Abete I, Zulet MÁ, Sureda A, Martínez JA, Tur JA. Albuminuria Is Associated with Hepatic Iron Load in Patients with Non-Alcoholic Fatty Liver Disease and Metabolic Syndrome. J Clin Med 2021; 10:jcm10143187. [PMID: 34300354 PMCID: PMC8305023 DOI: 10.3390/jcm10143187] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/14/2021] [Accepted: 07/15/2021] [Indexed: 12/13/2022] Open
Abstract
Background: Increased albuminuria is associated with increased serum ferritin, insulin resistance, and non-alcoholic fatty liver disease (NAFLD). Liver iron accumulation is also related to hyperferritinemia, insulin resistance, and NAFLD; however, there is no evidence on its relationship with albuminuria. Aims: To assess the relationship between hepatic iron load and urine albumin-to-creatinine ratio (UACR) in patients with metabolic syndrome (MetS) and NAFLD. Methods: In total, 75 MetS and NAFLD patients (aged 40–60 years, BMI 27–40 kg/m2) were selected from a cohort according to available data on hepatic iron load (HepFe) by magnetic resonance imaging (MRI). Subjects underwent anthropometric measurements, biochemistry testing, and liver MRI. Increased albuminuria was defined by UACR. Results: UACR correlated with NAFLD, HepFe, triglycerides, serum ferritin, fasting insulin, insulin resistance (calculated using the homeostatic model assessment for insulin resistance—HOMA-IR- formula), and platelets (p < 0.05). Multiple regression analysis adjusted for gender, age, eGFR, HbA1c, T2DM, and stages of NAFLD, found that HepFe (p = 0.02), serum ferritin (p = 0.04), fasting insulin (p = 0.049), and platelets (p = 0.009) were associated with UACR (R2 = 0.370; p = 0.007). UACR, liver fat accumulation, serum ferritin, and HOMA-IR increased across stages of HepFe (p < 0.05). Patients with severe NAFLD presented higher HepFe, fasting insulin, HOMA-IR, and systolic blood pressure as compared to patients in NAFLD stage 1 (p < 0.05). Conclusion: Hepatic iron load, serum ferritin, fasting insulin, and platelets were independently associated with albuminuria. In the context of MetS, increased stages of NAFLD presented higher levels of HepFe. Higher levels of HepFe were accompanied by increased serum ferritin, insulin resistance, and UACR. The association between iron accumulation, MetS, and NAFLD may represent a risk factor for the development of increased albuminuria.
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Affiliation(s)
- Manuela Abbate
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (M.A.); (S.M.); (C.M.M.); (L.U.); (S.T.); (A.S.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
| | - Sofía Montemayor
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (M.A.); (S.M.); (C.M.M.); (L.U.); (S.T.); (A.S.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
| | - Catalina M. Mascaró
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (M.A.); (S.M.); (C.M.M.); (L.U.); (S.T.); (A.S.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
| | - Miguel Casares
- Radiodiagnosis Service, Red Asistencial Juaneda, 07011 Palma de Mallorca, Spain;
| | - Cristina Gómez
- Clinical Analysis Service, University Hospital Son Espases, 07120 Palma de Mallorca, Spain;
| | - Lucía Ugarriza
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (M.A.); (S.M.); (C.M.M.); (L.U.); (S.T.); (A.S.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
- Camp Redó Primary Health Care Center, 07010 Palma de Mallorca, Spain
| | - Silvia Tejada
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (M.A.); (S.M.); (C.M.M.); (L.U.); (S.T.); (A.S.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (I.A.); (M.Á.Z.); (J.A.M.)
| | - Itziar Abete
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (I.A.); (M.Á.Z.); (J.A.M.)
- Center for Nutrition Research, Department of Nutrition, Food Sciences, and Physiology, University of Navarra, 31008 Pamplona, Spain
| | - M. Ángeles Zulet
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (I.A.); (M.Á.Z.); (J.A.M.)
- Center for Nutrition Research, Department of Nutrition, Food Sciences, and Physiology, University of Navarra, 31008 Pamplona, Spain
| | - Antoni Sureda
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (M.A.); (S.M.); (C.M.M.); (L.U.); (S.T.); (A.S.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (I.A.); (M.Á.Z.); (J.A.M.)
| | - J. Alfredo Martínez
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (I.A.); (M.Á.Z.); (J.A.M.)
- Center for Nutrition Research, Department of Nutrition, Food Sciences, and Physiology, University of Navarra, 31008 Pamplona, Spain
- Cardiometabolics Precision Nutrition Program, IMDEA Food, CEI UAM-CSIC, 28049 Madrid, Spain
| | - Josep A. Tur
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (M.A.); (S.M.); (C.M.M.); (L.U.); (S.T.); (A.S.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (I.A.); (M.Á.Z.); (J.A.M.)
- Correspondence: ; Tel.: +34-971-1731; Fax: +34-9-7117-3184
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Abbasi U, Abbina S, Gill A, Takuechi LE, Kizhakkedathu JN. Role of Iron in the Molecular Pathogenesis of Diseases and Therapeutic Opportunities. ACS Chem Biol 2021; 16:945-972. [PMID: 34102834 DOI: 10.1021/acschembio.1c00122] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Iron is an essential mineral that serves as a prosthetic group for a variety of proteins involved in vital cellular processes. The iron economy within humans is highly conserved in that there is no proper iron excretion pathway. Therefore, iron homeostasis is highly evolved to coordinate iron acquisition, storage, transport, and recycling efficiently. A disturbance in this state can result in excess iron burden in which an ensuing iron-mediated generation of reactive oxygen species imparts widespread oxidative damage to proteins, lipids, and DNA. On the contrary, problems in iron deficiency either due to genetic or nutritional causes can lead to a number of iron deficiency disorders. Iron chelation strategies have been in the works since the early 1900s, and they still remain the most viable therapeutic approach to mitigate the toxic side effects of excess iron. Intense investigations on improving the efficacy of chelation strategies while being well tolerated and accepted by patients have been a particular focus for many researchers over the past 30 years. Moreover, recent advances in our understanding on the role of iron in the pathogenesis of different diseases (both in iron overload and iron deficiency conditions) motivate the need to develop new therapeutics. We summarized recent investigations into the role of iron in health and disease conditions, iron chelation, and iron delivery strategies. Information regarding small molecule as well as macromolecular approaches and how they are employed within different disease pathogenesis such as primary and secondary iron overload diseases, cancer, diabetes, neurodegenerative diseases, infections, and in iron deficiency is provided.
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Affiliation(s)
- Usama Abbasi
- Centre for Blood Research, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3
- Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z7
| | - Srinivas Abbina
- Centre for Blood Research, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3
- Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z7
| | - Arshdeep Gill
- Centre for Blood Research, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3
- Department of Chemistry, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z1
| | - Lily E. Takuechi
- Centre for Blood Research, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3
- Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z7
| | - Jayachandran N. Kizhakkedathu
- Centre for Blood Research, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3
- Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z7
- Department of Chemistry, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z1
- The School of Biomedical Engineering, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3
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Dietary iron to total energy intake ratio and type 2 diabetes incidence in a longitudinal 12-year analysis of the Korean Genome and Epidemiology Cohort Study. Eur J Nutr 2021; 60:4453-4461. [PMID: 34085096 DOI: 10.1007/s00394-021-02596-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 05/21/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE Recent study found iron consumption has been associated with an increased risk of type 2 diabetes (T2DM). Even though, high iron intake is correlated with total caloric intake, most studies have evaluated the individual effect of iron and total caloric intake. The aim of this study was to investigate the effect of iron intake, in conjunction with total energy intake, on developing T2DM. We also investigated the interactions between dietary iron and energy ratios (IERs) and iron-related single nucleotide polymorphisms (SNPs) in the development of T2DM. METHODS The study was carried out in Ansan and Ansung, Korea, between March 2001 and December 2014. A total of 6413 participants (3073 men and 3340 women), aged 40-69 years, were enrolled in this study. The mean follow-up period was 8.4 years. The study population was divided into quartiles based on IERs with cut-off points at 4.54, 5.41, and 6.29. The odds ratios (ORs) for new-onset T2DM were calculated across each quartile of IERs and a random forest model was constructed using the default settings to predict new-onset T2DM. To confirm the interaction among IERs, SNPs, and the incidence of T2DM, we measured the predictive power of new-onset T2DM using IER and six SNPs in genes related to iron metabolism [rs855791 (TPMRSS6), rs38116479 (TF), rs1799852 (TF), rs2280673, rs1799945 (HFT), rs180562 (HFE)]. RESULTS The prevalence of T2DM was 762 (11.8%). IERs showed a positive association with T2DM. The ORs were 1.30 (95% CI 1.02-1.67), 1.20 (95% CI 0.94-1.56), and 1.43 (95% CI 1.11-1.86) across the IER quartiles after adjusting for non-dietary and dietary metabolic risk factors. When the IER was 1.89-fold higher than the reference group, the risk of developing T2DM increased by 43% (OR 1.43; 95% CI 1.11-1.86). CONCLUSION A higher IER was positively associated with developing T2DM independent of dietary or non-dietary risk factors. We also found the possible interactions between the identified SNPs and iron intake in relations to T2DM.
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Botta A, Barra NG, Lam NH, Chow S, Pantopoulos K, Schertzer JD, Sweeney G. Iron Reshapes the Gut Microbiome and Host Metabolism. J Lipid Atheroscler 2021; 10:160-183. [PMID: 34095010 PMCID: PMC8159756 DOI: 10.12997/jla.2021.10.2.160] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/12/2021] [Accepted: 02/21/2021] [Indexed: 12/12/2022] Open
Abstract
Compelling studies have established that the gut microbiome is a modifier of metabolic health. Changes in the composition of the gut microbiome are influenced by genetics and the environment, including diet. Iron is a potential node of crosstalk between the host-microbe relationship and metabolic disease. Although iron is well characterized as a frequent traveling companion of metabolic disease, the role of iron is underappreciated because the mechanisms of iron's influence on host metabolism are poorly characterized. Both iron deficiency and excessive amounts leading to iron overload can have detrimental effects on cardiometabolic health. Optimal iron homeostasis is critical for regulation of host immunity and metabolism in addition to regulation of commensal and pathogenic enteric bacteria. In this article we review evidence to support the notion that altering composition of the gut microbiome may be an important route via which iron impacts cardiometabolic health. We discuss reshaping of the microbiome by iron, the physiological significance and the potential for therapeutic interventions.
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Affiliation(s)
- Amy Botta
- Department of Biology, York University, Toronto, ON, Canada
| | - Nicole G. Barra
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada
| | - Nhat Hung Lam
- Department of Biology, York University, Toronto, ON, Canada
| | - Samantha Chow
- Department of Biology, York University, Toronto, ON, Canada
| | - Kostas Pantopoulos
- Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, QC, Canada
| | - Jonathan D. Schertzer
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada
| | - Gary Sweeney
- Department of Biology, York University, Toronto, ON, Canada
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Jichitu A, Bungau S, Stanescu AMA, Vesa CM, Toma MM, Bustea C, Iurciuc S, Rus M, Bacalbasa N, Diaconu CC. Non-Alcoholic Fatty Liver Disease and Cardiovascular Comorbidities: Pathophysiological Links, Diagnosis, and Therapeutic Management. Diagnostics (Basel) 2021; 11:689. [PMID: 33921359 PMCID: PMC8069361 DOI: 10.3390/diagnostics11040689] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/09/2021] [Accepted: 04/11/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has a growing prevalence in recent years. Its association with cardiovascular disease has been intensively studied, and certain correlations have been identified. The connection between these two entities has lately aroused interest regarding therapeutic management. In order to find the best therapeutic options, a detailed understanding of the pathophysiology that links (NAFLD) to cardiovascular comorbidities is needed. This review focuses on the pathogenic mechanisms that are behind these two diseases and on the therapeutic management available at this time.
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Affiliation(s)
- Alexandra Jichitu
- Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania; (A.J.); (C.C.D.)
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania;
| | - Ana Maria Alexandra Stanescu
- Department 5, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Cosmin Mihai Vesa
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania; (C.M.V.); (C.B.)
| | - Mirela Marioara Toma
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania;
| | - Cristiana Bustea
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania; (C.M.V.); (C.B.)
| | - Stela Iurciuc
- Department of Cardiology, Faculty of Medicine, “Victor Babeş” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Marius Rus
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania;
| | - Nicolae Bacalbasa
- Department 13, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Department of Surgery, “Ion Cantacuzino” Clinical Hospital, 030167 Bucharest, Romania
| | - Camelia Cristina Diaconu
- Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania; (A.J.); (C.C.D.)
- Department 5, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
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35
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Pauk M, Kufner V, Rumenovic V, Dumic-Cule I, Farkas V, Milosevic M, Bordukalo-Niksic T, Vukicevic S. Iron overload in aging Bmp6‑/‑ mice induces exocrine pancreatic injury and fibrosis due to acinar cell loss. Int J Mol Med 2021; 47:60. [PMID: 33649802 PMCID: PMC7910010 DOI: 10.3892/ijmm.2021.4893] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 01/19/2021] [Indexed: 11/27/2022] Open
Abstract
The relationship between hemochromatosis and diabetes has been well established, as excessive iron deposition has been reported to result in impaired function of the endocrine and exocrine pancreas. Therefore, the objective of the present study was to analyze the effects of iron accumulation on the pancreata and glucose homeostasis in a bone morphogenetic protein 6-knockout (Bmp6−/−) mouse model of hemochromatosis. The sera and pancreatic tissues of wild-type (WT) and Bmp6−/− mice (age, 3 and 10 months) were subjected to biochemical and histological analyses. In addition, 18F-fluorodeoxyglucose biodistribution was evaluated in the liver, muscle, heart, kidney and adipose tissue of both animal groups. The results demonstrated that 3-month-old Bmp6−/− mice exhibited iron accumulation preferentially in the exocrine pancreas, with no signs of pancreatic injury or fibrosis. No changes were observed in the glucose metabolism, as pancreatic islet diameter, insulin and glucagon secretion, blood glucose levels and glucose uptake in the liver, muscle and adipose tissue remained comparable with those in the WT mice. Aging Bmp6−/− mice presented with progressive iron deposits in the exocrine pancreas, leading to pancreatic degeneration and injury that was characterized by acinar atrophy, fibrosis and the infiltration of inflammatory cells. However, the aging mice exhibited unaltered blood glucose levels and islet structure, normal insulin secretion and moderately increased α-cell mass compared with those in the age-matched WT mice. Additionally, iron overload and pancreatic damage were not observed in the aging WT mice. These results supported a pathogenic role of iron overload in aging Bmp6−/− mice leading to iron-induced exocrine pancreatic deficiency, whereas the endocrine pancreas retained normal function.
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Affiliation(s)
- Martina Pauk
- Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, School of Medicine, University of Zagreb, HR‑10000 Zagreb, Croatia
| | - Vera Kufner
- Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, School of Medicine, University of Zagreb, HR‑10000 Zagreb, Croatia
| | - Viktorija Rumenovic
- Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, School of Medicine, University of Zagreb, HR‑10000 Zagreb, Croatia
| | - Ivo Dumic-Cule
- Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, School of Medicine, University of Zagreb, HR‑10000 Zagreb, Croatia
| | - Vladimir Farkas
- Molecular Biology Department, Rudjer Boskovic Institute, HR‑10000 Zagreb, Croatia
| | - Milan Milosevic
- Andrija Stampar School of Public Health, School of Medicine, University of Zagreb, HR‑10000 Zagreb, Croatia
| | - Tatjana Bordukalo-Niksic
- Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, School of Medicine, University of Zagreb, HR‑10000 Zagreb, Croatia
| | - Slobodan Vukicevic
- Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, School of Medicine, University of Zagreb, HR‑10000 Zagreb, Croatia
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Rossi EM, Ávila RA, Carneiro MTWD, Almenara CCP, Dos Santos L. Chronic Iron Overload Restrains the Benefits of Aerobic Exercise to the Vasculature. Biol Trace Elem Res 2020; 198:521-534. [PMID: 32124228 DOI: 10.1007/s12011-020-02078-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 02/11/2020] [Indexed: 02/07/2023]
Abstract
Physical exercise is a well-recognized effective non-pharmacological therapy for cardiovascular diseases. However, because iron is essential element in many physiological processes including hemoglobin and myoglobin synthesis, thereby playing a role on oxygen transport, many athletes use iron supplement to improve physical performance. Regarding this, iron overload is associated with oxidative stress and damage to various systems, including cardiovascular. Thus, we aimed to identify the vascular effects of aerobic exercise in a rat model of iron overload. Male Wistar rats were treated with 100 mg/kg/day iron-dextran, i.p., 5 days a week for 4 weeks, and then underwent aerobic exercise protocol on a treadmill at moderate intensity, 60 min/day, 5 days a week for 8 weeks. Exercise reduced vasoconstrictor response of isolated aortic rings by increasing participation of nitric oxide (NO) and reducing oxidative stress, but these benefits to the vasculature were not observed in rats previously subjected to iron overload. The reduced vasoconstriction in the exercised group was reversed by incubation with superoxide dismutase (SOD) inhibitor, suggesting that increased SOD activity by exercise was lost in iron overload rats. Iron overload groups increased serum levels of iron, transferrin saturation, and iron deposition in the liver, gastrocnemius muscle, and aorta, and the catalase was overexpressed in the aorta probably as a compensatory mechanism to the increased oxidative stress. In conclusion, despite the known beneficial effects of aerobic exercise on vasculature, our results indicate that previous iron overload impeded the anticontractile effect mediated by increased NO bioavailability and endogenous antioxidant response due to exercise protocol.
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Affiliation(s)
- Emilly Martinelli Rossi
- Department of Physiological Sciences, Federal University of Espirito Santo, Av. Marechal Campos, 1468, Vitoria, ES, 29040-091, Brazil
| | - Renata Andrade Ávila
- Department of Physiological Sciences, Federal University of Espirito Santo, Av. Marechal Campos, 1468, Vitoria, ES, 29040-091, Brazil
- Faculdades Integradas São Pedro (FAESA), Av. Vitória, 2220, Vitoria, ES, 29053-360, Brazil
| | - Maria Tereza W D Carneiro
- Department of Chemistry, Federal University of Espirito Santo, Av. Fernando Ferrari, 514, Vitoria, ES, 29075-910, Brazil
| | - Camila C P Almenara
- Department of Physiological Sciences, Federal University of Espirito Santo, Av. Marechal Campos, 1468, Vitoria, ES, 29040-091, Brazil
| | - Leonardo Dos Santos
- Department of Physiological Sciences, Federal University of Espirito Santo, Av. Marechal Campos, 1468, Vitoria, ES, 29040-091, Brazil.
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Fillebeen C, Lam NH, Chow S, Botta A, Sweeney G, Pantopoulos K. Regulatory Connections between Iron and Glucose Metabolism. Int J Mol Sci 2020; 21:ijms21207773. [PMID: 33096618 PMCID: PMC7589414 DOI: 10.3390/ijms21207773] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 10/07/2020] [Accepted: 10/16/2020] [Indexed: 02/06/2023] Open
Abstract
Iron is essential for energy metabolism, and states of iron deficiency or excess are detrimental for organisms and cells. Therefore, iron and carbohydrate metabolism are tightly regulated. Serum iron and glucose levels are subjected to hormonal regulation by hepcidin and insulin, respectively. Hepcidin is a liver-derived peptide hormone that inactivates the iron exporter ferroportin in target cells, thereby limiting iron efflux to the bloodstream. Insulin is a protein hormone secreted from pancreatic β-cells that stimulates glucose uptake and metabolism via insulin receptor signaling. There is increasing evidence that systemic, but also cellular iron and glucose metabolic pathways are interconnected. This review article presents relevant data derived primarily from mouse models and biochemical studies. In addition, it discusses iron and glucose metabolism in the context of human disease.
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Affiliation(s)
- Carine Fillebeen
- Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, QC H3Y 1P3, Canada;
| | - Nhat Hung Lam
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (N.H.L.); (S.C.); (A.B.); (G.S.)
| | - Samantha Chow
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (N.H.L.); (S.C.); (A.B.); (G.S.)
| | - Amy Botta
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (N.H.L.); (S.C.); (A.B.); (G.S.)
| | - Gary Sweeney
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (N.H.L.); (S.C.); (A.B.); (G.S.)
| | - Kostas Pantopoulos
- Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, QC H3Y 1P3, Canada;
- Correspondence: ; Tel.: +1-514-340-8260 (ext. 25293)
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Lonardo A, Leoni S, Alswat KA, Fouad Y. History of Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2020; 21:E5888. [PMID: 32824337 PMCID: PMC7460697 DOI: 10.3390/ijms21165888] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/10/2020] [Accepted: 08/12/2020] [Indexed: 12/15/2022] Open
Abstract
Based on the assumption that characterizing the history of a disease will help in improving practice while offering a clue to research, this article aims at reviewing the history of nonalcoholic fatty liver disease (NAFLD) in adults and children. To this end, we address the history of NAFLD histopathology, which begins in 1980 with Ludwig's seminal studies, although previous studies date back to the 19th century. Moreover, the principal milestones in the definition of genetic NAFLD are summarized. Next, a specific account is given of the evolution, over time, of our understanding of the association of NAFLD with metabolic syndrome, spanning from the outdated concept of "NAFLD as a manifestation of the Metabolic Syndrome", to the more appropriate consideration that NAFLD has, with metabolic syndrome, a mutual and bi-directional relationship. In addition, we also report on the evolution from first intuitions to more recent studies, supporting NAFLD as an independent risk factor for cardiovascular disease. This association probably has deep roots, going back to ancient Middle Eastern cultures, wherein the liver had a significance similar to that which the heart holds in contemporary society. Conversely, the notions that NAFLD is a forerunner of hepatocellular carcinoma and extra-hepatic cancers is definitely more modern. Interestingly, guidelines issued by hepatological societies have lagged behind the identification of NAFLD by decades. A comparative analysis of these documents defines both shared attitudes (e.g., ultrasonography and lifestyle changes as the first approaches) and diverging key points (e.g., the threshold of alcohol consumption, screening methods, optimal non-invasive assessment of liver fibrosis and drug treatment options). Finally, the principal historical steps in the general, cellular and molecular pathogenesis of NAFLD are reviewed. We conclude that an in-depth understanding of the history of the disease permits us to better comprehend the disease itself, as well as to anticipate the lines of development of future NAFLD research.
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Affiliation(s)
- Amedeo Lonardo
- Ospedale Civile di Baggiovara, UOC Medicina Metabolica, Dipartimento di Medicina Interna Generale, d’Urgenza e post Acuzie, Azienda Ospedaliero-Universitaria di Modena, Via Giardini 1135, 41125 Modena, Italy
| | - Simona Leoni
- Internal Medicine Unit, Department of Digestive Diseases, S.Orsola-Malpighi Hospital, Via Massarenti 9, 40136 Bologna, Italy;
| | - Khalid A. Alswat
- Liver Research Center, Department of Medicine, College of Medicine, King Saud University, Riyadh 11322, Saudi Arabia;
| | - Yasser Fouad
- Department of Gastroenterology, Hepatology and Endemic Medicine, Faculty of Medicine, Minia University, Minya 19111, Egypt;
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Castiella A, Urreta I, Zapata E, Zubiaurre L, Alústiza JM, Otazua P, Salvador E, Letamendi G, Arrizabalaga B, Rincón ML, Emparanza JI. Liver iron concentration in dysmetabolic hyperferritinemia: Results from a prospective cohort of 276 patients. Ann Hepatol 2020; 19:31-35. [PMID: 31587985 DOI: 10.1016/j.aohep.2019.07.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 06/30/2019] [Accepted: 07/02/2019] [Indexed: 02/08/2023]
Abstract
INTRODUCTION AND OBJECTIVES We aimed to study the liver iron concentration in patients referred for hyperferritinemia to six hospitals in the Basque Country and to determine if there were differences between patients with or without metabolic syndrome. PATIENTS AND METHODS Metabolic syndrome was defined by accepted criteria. Liver iron concentration was determined by magnetic resonance imaging. RESULTS We obtained the data needed to diagnose metabolic syndrome in 276 patients; a total of 135 patients (49%), 115/240 men (48%), and 20/36 women (55.6%) presented metabolic syndrome. In all 276 patients, an MRI for the determination of liver iron concentration (mean±SD) was performed. The mean liver iron concentration was 30.83±19.38 for women with metabolic syndrome, 38.84±25.50 for men with metabolic syndrome, and 37.66±24.79 (CI 95%; 33.44-41.88) for the whole metabolic syndrome group. In 141 patients (51%), metabolic syndrome was not diagnosed: 125/240 were men (52%) and 16/36 were women (44.4%). The mean liver iron concentration was 34.88±16.18 for women without metabolic syndrome, 44.48±38.16 for men without metabolic syndrome, and 43.39±36.43 (CI 95%, 37.32-49.46) for the whole non-metabolic syndrome group. Comparison of the mean liver iron concentration from both groups (metabolic syndrome vs non-metabolic syndrome) revealed no significant differences (p=0.12). CONCLUSIONS Patients with hyperferritinemia and metabolic syndrome presented a mildly increased mean liver iron concentration that was not significantly different to that of patients with hyperferritinemia and non-metabolic syndrome.
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Affiliation(s)
- Agustin Castiella
- Gastroenterology Service, Mendaro Hospital, Mendaro, Spain; Gastroenterology Service, Donostia University Hospital, Donostia, Spain.
| | - Iratxe Urreta
- Clinical Epidemiology Unit, CASPe, CIBER-ESP, Donostia University Hospital, Donostia, Spain
| | - Eva Zapata
- Gastroenterology Service, Mendaro Hospital, Mendaro, Spain; Gastroenterology Service, Donostia University Hospital, Donostia, Spain
| | | | | | - Pedro Otazua
- Gastroenterology Service, Mondragon Hospital, Mondragon, Spain
| | | | | | | | | | - José I Emparanza
- Clinical Epidemiology Unit, CASPe, CIBER-ESP, Donostia University Hospital, Donostia, Spain
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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: 23] [Impact Index Per Article: 3.8] [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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Effect of procyanidin on dietary iron absorption in hereditary hemochromatosis and in dysmetabolic iron overload syndrome: A crossover double-blind randomized controlled trial. Clin Nutr 2019; 39:97-103. [PMID: 30792142 DOI: 10.1016/j.clnu.2019.02.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 01/31/2019] [Accepted: 02/01/2019] [Indexed: 01/01/2023]
Abstract
BACKGROUND & AIMS Type I hereditary hemochromatosis (HH) and dysmetabolic iron overload syndrome (DIOS) are the two most prevalent iron overload diseases. Although many food components, particularly polyphenols, reduce iron bioavailability, there is no clinically validated nutritional strategy to reduce food-iron absorption in patients with these diseases. We aimed to determine whether supplementation with 100 mg of procyanidins during a meal reduces dietary iron absorption in patients with HH or DIOS. METHODS 20 HH and 20 DIOS patients were enrolled in a double-blind three-period crossover randomized study. Basal serum iron level was measured following an overnight fast. Each patient consumed a standardized test iron-rich meal containing 43 mg of iron with two capsules of placebo or procyanidin supplementation. Each period was separated by a 3-day wash-out period. The primary objective was a reduction of dietary iron absorption, assessed by a reduction of serum-iron area under the curve (AUC) corrected for baseline serum iron. RESULTS All patients completed the study. The meal and the procyanidin supplements were well tolerated. In both HH and DIOS patients, the iron-rich meal induced a significant increase of serum iron compared with baseline at 120, 180, 240 min, from 8 to 9.1% (p = 0.002, 0.001 and 0.003, respectively) in DIOS and from 15.8 to 25.7% (p < 0.001) in HH. Iron absorption was 3.5-fold higher in HH than in DIOS (p < 0.001). Procyanidin supplementation did not significantly modify iron absorption in DIOS (AUC of added iron 332.87 ± 649.55 vs 312.61 ± 678.61 μmol.h/L, p = 0.916) or in HH (1168.62 ± 652.87 vs 1148.54 μmol.h/L ± 1290.05, p = 0.917). CONCLUSIONS An iron-rich test meal led to a marked increase in iron absorption in HH but a mild increase in DIOS. Procyanidin supplementation does not significantly reduce dietary iron absorption in either disease. CLINICAL TRIAL REGISTRY: clinicaltrials.gov (NCT03453918).
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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: 182] [Impact Index Per Article: 30.3] [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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Grancini V, Resi V, Palmieri E, Pugliese G, Orsi E. Management of diabetes mellitus in patients undergoing liver transplantation. Pharmacol Res 2019; 141:556-573. [PMID: 30690071 DOI: 10.1016/j.phrs.2019.01.042] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 01/24/2019] [Accepted: 01/24/2019] [Indexed: 02/07/2023]
Abstract
Diabetes is a common feature in cirrhotic individuals both before and after liver transplantation and negatively affects prognosis. Certain aetiological agents of chronic liver disease and loss of liver function per se favour the occurrence of pre-transplant diabetes in susceptible individuals, whereas immunosuppressant treatment, changes in lifestyle habits, and donor- and procedure-related factors contribute to diabetes development/persistence after transplantation. Challenges in the management of pre-transplant diabetes include the profound nutritional alterations characterizing cirrhotic individuals and the limitations to the use of drugs with liver metabolism. Special issues in the management of post-transplant diabetes include the diabetogenic potential of immunosuppressant drugs and the increased cardiovascular risk characterizing solid organ transplant survivors. Overall, the pharmacological management of cirrhotic patients undergoing liver transplantation is complicated by the lack of specific guidelines reflecting the paucity of data on the impact of glycaemic control and the safety and efficacy of anti-hyperglycaemic agents in these individuals.
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Affiliation(s)
- Valeria Grancini
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Veronica Resi
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Eva Palmieri
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, and Diabetes Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Emanuela Orsi
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
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Current Models of Fatty Liver Disease; New Insights, Therapeutic Targets and Interventions. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1134:33-58. [PMID: 30919331 DOI: 10.1007/978-3-030-12668-1_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disorders ranging from simple steatosis to steatosis with inflammation and fibrosis. NAFLD is currently the most prevalent chronic liver disease worldwide, with a global prevalence of 25%, and is soon projected to be the leading cause for liver transplantation in the US. Alarmingly, few effective pharmacotherapeutic approaches are currently available to block or attenuate development and progression of NAFLD. Preclinical models are critical for unraveling the complex and multi-factorial etiology of NAFLD and for testing potential therapeutics. Here we review preclinical models that have been instrumental in highlighting molecular and cellular mechanisms underlying the pathogenesis of NAFLD and in facilitating early proof-of-concept investigations into novel intervention strategies.
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Measurement of liver iron by magnetic resonance imaging in the UK Biobank population. PLoS One 2018; 13:e0209340. [PMID: 30576354 PMCID: PMC6303057 DOI: 10.1371/journal.pone.0209340] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 12/04/2018] [Indexed: 01/07/2023] Open
Abstract
The burden of liver disease continues to increase in the UK, with liver cirrhosis reported to be the third most common cause of premature death. Iron overload, a condition that impacts liver health, was traditionally associated with genetic disorders such as hereditary haemochromatosis, however, it is now increasingly associated with obesity, type-2 diabetes and non-alcoholic fatty liver disease. The aim of this study was to assess the prevalence of elevated levels of liver iron within the UK Biobank imaging study in a cohort of 9108 individuals. Magnetic resonance imaging (MRI) was undertaken at the UK Biobank imaging centre, acquiring a multi-echo spoiled gradient-echo single-breath-hold MRI sequence from the liver. All images were analysed for liver iron and fat (expressed as proton density fat fraction or PDFF) content using LiverMultiScan. Liver iron was measured in 97.3% of the cohort. The mean liver iron content was 1.32 ± 0.32 mg/g while the median was 1.25 mg/g (min: 0.85 max: 6.44 mg/g). Overall 4.82% of the population were defined as having elevated liver iron, above commonly accepted 1.8 mg/g threshold based on biochemical iron measurements in liver specimens obtained by biopsy. Further analysis using univariate models showed elevated liver iron to be related to male sex (p<10−16, r2 = 0.008), increasing age (p<10−16, r2 = 0.013), and red meat intake (p<10−16, r2 = 0.008). Elevated liver fat (>5.6% PDFF) was associated with a slight increase in prevalence of elevated liver iron (4.4% vs 6.3%, p = 0.0007). This study shows that population studies including measurement of liver iron concentration are feasible, which may in future be used to better inform patient stratification and treatment.
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Park M, Moon WJ, Moon Y, Choi JW, Han SH, Wang Y. Region-specific susceptibility change in cognitively impaired patients with diabetes mellitus. PLoS One 2018; 13:e0205797. [PMID: 30308069 PMCID: PMC6181414 DOI: 10.1371/journal.pone.0205797] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 10/02/2018] [Indexed: 12/22/2022] Open
Abstract
Emerging evidence suggests that diabetes mellitus (DM) is associated with iron and calcium metabolism. However, few studies have investigated the presence of DM in cognitively impaired patients and its effect on brain iron and calcium accumulation. Therefore, we assessed the effects of DM on cognitively impaired patients using quantitative susceptibility mapping (QSM). From June 2012 to Feb 2014, 92 eligible cognitively impaired patients underwent 3T magnetic resonance imaging (MRI). There were 46 patients with DM (DM+) and 46 aged matched patients without DM (DM-). QSM was obtained from gradient echo data and analyzed by drawing regions of interest around relevant anatomical structures. Clinical factors and vascular pathology were also evaluated. Measurement differences between DM+ and DM- patients were assessed by t tests. A multiple regression analysis was performed to identify independent predictors of magnetic susceptibility. DM+ patients showed lower susceptibility values, indicative of lower brain iron content, than DM- patients, which was significant in the hippocampus (4.80 ± 8.31 ppb versus 0.22 ± 10.60 ppb, p = 0.024) and pulvinar of the thalamus (36.30 ± 19.88 ppb versus 45.90 ± 20.02 ppb, p = 0.023). On multiple regression analysis, microbleed number was a predictor of susceptibility change in the hippocampus (F = 4.291, beta = 0.236, p = 0.042) and DM was a predictor of susceptibility change in the pulvinar of the thalamus (F = 4.900, beta = - 0.251, p = 0.030). In cognitively impaired patients, presence of DM was associated with lower susceptibility change in the pulvinar of the thalamus and hippocampus. This suggests that there may be region-specific alterations of calcium deposition in cognitively impaired subjects with DM.
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Affiliation(s)
- Mina Park
- Department of Radiology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - Won-Jin Moon
- Department of Radiology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - Yeonsil Moon
- Department of Neurology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - Jin Woo Choi
- Department of Radiology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - Seol-Heui Han
- Department of Neurology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - Yi Wang
- Department of Radiology, Weill Cornell Medical College, New York, New York, United States of America
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DiNicolantonio JJ, Mangan D, O’Keefe JH. The fructose–copper connection: Added sugars induce fatty liver and insulin resistance via copper deficiency. JOURNAL OF INSULIN RESISTANCE 2018. [DOI: 10.4102/jir.v3i1.43] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
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Chronic liver diseases and the potential use of S-adenosyl-L-methionine as a hepatoprotector. Eur J Gastroenterol Hepatol 2018; 30:893-900. [PMID: 29683981 DOI: 10.1097/meg.0000000000001141] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chronic liver diseases result in overall deterioration of health status and changes in metabolism. The search for strategies to control and combat these hepatic diseases has witnessed a great boom in the last decades. Nutritional therapy for controlling and managing liver diseases may be a positive influence as it improves the function of the liver. In this review, we focus mainly on describing liver conditions such as nonalcoholic fatty liver disease, and intrahepatic cholestasis as well as using S-adenosyl-L-methionine as a dietary supplement and its potential alternative therapeutic effect to correct the hepatic dysfunction associated with these conditions.
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Silva TE, Ronsoni MF, Schiavon LL. Challenges in diagnosing and monitoring diabetes in patients with chronic liver diseases. Diabetes Metab Syndr 2018; 12:431-440. [PMID: 29279271 DOI: 10.1016/j.dsx.2017.12.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 12/19/2017] [Indexed: 02/07/2023]
Abstract
The prevalence and mortality of diabetes mellitus and liver disease have risen in recent years. The liver plays an important role in glucose homeostasis, and various chronic liver diseases have a negative effect on glucose metabolism with the consequent emergence of diabetes. Some aspects related to chronic liver disease can affect diagnostic tools and the monitoring of diabetes and other glucose metabolism disorders, and clinicians must be aware of these limitations in their daily practice. In cirrhotic patients, fasting glucose may be normal in up until 23% of diabetes cases, and glycated hemoglobin provides falsely low results, especially in advanced cirrhosis. Similarly, the performance of alternative glucose monitoring tests, such as fructosamine, glycated albumin and 1,5-anhydroglucitol, also appears to be suboptimal in chronic liver disease. This review will examine the association between changes in glucose metabolism and various liver diseases as well as the particularities associated with the diagnosis and monitoring of diabetes in liver disease patients. Alternatives to routinely recommended tests will be discussed.
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Affiliation(s)
- Telma E Silva
- Division of Gastroenterology, Federal University of Santa Catarina, Campus Universitário Reitor João David Ferreira Lima, Trindade Florianópolis, SC, 88040-970, Brazil.
| | - Marcelo F Ronsoni
- Division of Endocrinology, Federal University of Santa Catarina, Campus Universitário Reitor João David Ferreira Lima, Trindade, Florianópolis, SC, 88040-970, Brazil
| | - Leonardo L Schiavon
- Division of Gastroenterology, Federal University of Santa Catarina, Campus Universitário Reitor João David Ferreira Lima, Trindade Florianópolis, SC, 88040-970, Brazil
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