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Suárez-Ortegón MF, McLachlan S, Fernández-Real JM, Wilson JF, Wild SH. Both low and high body iron stores relate to metabolic syndrome in postmenopausal women: Findings from the VIKING Health Study-Shetland (VIKING I). Eur J Clin Invest 2024; 54:e14312. [PMID: 39239983 DOI: 10.1111/eci.14312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 08/26/2024] [Indexed: 09/07/2024]
Abstract
BACKGROUND There are conflicting results among studies on the association between serum ferritin (SF) and metabolic syndrome (MetS), and by groups of sex/menopausal status. To date, there are no studies on British populations. The SF-MetS association might be U/J-shaped. We evaluated whether SF was independently associated with MetS (harmonized definition) in people from Shetland, Scotland. METHODS We analysed cross-sectional data from the Viking Health Study-Shetland (589 premenopausal women [PreMW], 625 postmenopausal women [PostW] and 832 men). Logistic regressions using two approaches, one with the lowest sex and menopausal status-specific ferritin quartile (Q) as the reference and other using the middle two quartiles combined (2-3) as the reference, were conducted to estimate the SF-MetS association. The shape of the association was verified via cubic spline analyses. The associations were adjusted for age, inflammatory and hepatic injury markers, alcohol intake, smoking and BMI. RESULTS Prevalence of MetS was 18.3%. Among PostMW both low and high SF were associated with MetS (fully adjusted odds ratios [95% confidence interval] compared to the middle two quartiles combined were: 1.99 [1.17-3.38] p =.011 for Q1 and 2.10 [1.27-3.49] p =.004 for Q4) This U-shaped pattern was confirmed in the cubic spline analysis in PostMW with a ferritin range of 15-200 ug/L. In men, a positive association between ferritin quartiles with Q1 as the reference, did not remain significant after adjustment for BMI. CONCLUSION Extreme quartiles of iron status were positively associated with MetS in PostMW, while no SF-MetS associations were found in men or PreMW. The ferritin-MetS association pattern differs between populations and U/J-shaped associations may exist.
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Affiliation(s)
| | | | - José Manuel Fernández-Real
- Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Girona, Spain
- Nutrition, Eumetabolism and Health Group, Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Girona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain
| | - James F Wilson
- Centre for Global Health Research, Usher Institute, Edinburgh, UK
- Centre for Genomic Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
| | - Sarah H Wild
- Usher Institute, University of Edinburgh, Edinburgh, UK
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Aguree S, Owora A, Hawkins M, Gletsu-Miller N. Obesity modifies the association between diabetes and iron biomarkers and red cell indices in reproductive-aged women in the United States. J Investig Med 2024; 72:425-437. [PMID: 38445643 DOI: 10.1177/10815589241240059] [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] [Indexed: 03/07/2024]
Abstract
Obesity and diabetes are associated with impaired iron metabolism. We aimed to examine the independent relationship between diabetes and iron after controlling for body weight (or obesity) in women aged 20-49 years. The National Health and Nutrition Examination Survey data from 2015 to 2018 were used in this investigation. Body composition data, HbAc1, iron biomarkers (serum ferritin (SF), soluble transferrin receptor (sTfR), and body iron index (BII)), mean corpuscular volume (MCV), mean hemoglobin concentration (MCH), red cell distribution width (RDW), and hemoglobin were used. Linear regression models were used to examine how and to what extent body mass index (BMI) modified the relationship between diabetes and iron status biomarkers. A total of 1834 women aged 20-49 were included in the analysis with a mean (SD) age of 32 .2 ± 6.1 years and BMI of 29.5 ± 6.9 kg/m2. The mean SF (p = 0.014) and BII (p < 0.001) were lower, while sTfR (p < 0.001) was higher in women with diabetes than those with no diabetes. Mean estimates for MCV and MCH were lower, while RDW (p = 0.001) was higher in diabetes patients (all p < 0.001). Women with diabetes were more likely to have iron deficiency, anemia, and iron deficiency anemia than those without diabetes (18.1% vs 8.6%, p < 0.001), (24.4% vs 8.4%, p < 0.001), and (14.8% vs 5.2%, p < 0.001), respectively. Among women with obesity, those with diabetes had lower predicted ferritin (β = -0.19, p = 0.016), BII (β = -0.99, p = 0.016), and hemoglobin (β = -0.27, p = 0.042) than those without diabetes. The study shows that diabetes is linked to lower iron stores; this is exacerbated in those with obesity.
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Affiliation(s)
- Sixtus Aguree
- Department of Applied Health Science, Indiana University School of Public Health-Bloomington, Bloomington, IN, USA
| | - Arthur Owora
- Department of Pediatrics, School of Medicine, Indiana University, Indianapolis, IN, USA
- Department of Epidemiology and Biostatistics, School of Public Health, Indiana University, Bloomington, IN, USA
| | - Misty Hawkins
- Department of Health and Wellness Design, School of Public Health, Indiana University, Bloomington, IN, USA
| | - Nana Gletsu-Miller
- Department of Applied Health Science, Indiana University School of Public Health-Bloomington, Bloomington, IN, USA
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Pierce JL, Lyons JW, Chevalier TB, Lindemann MD. Effects of a second iron-dextran injection administered to piglets during lactation on differential gene expression in liver and duodenum at weaning. J Anim Sci 2024; 102:skae005. [PMID: 38219027 PMCID: PMC10874211 DOI: 10.1093/jas/skae005] [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: 09/23/2023] [Accepted: 01/12/2024] [Indexed: 01/15/2024] Open
Abstract
Six female littermate piglets were used in an experiment to evaluate the mRNA expression in tissues from piglets given one or two 1 mL injections of iron dextran (200 mg Fe/mL). All piglets in the litter were administered the first 1 mL injection < 24 h after birth. On day 7, piglets were paired by weight (mean body weight = 1.72 ± 0.13 kg) and one piglet from each pair was randomly selected as control (CON) and the other received a second injection (+Fe). At weaning on day 22, each piglet was anesthetized, and samples of liver and duodenum were taken from the anesthetized piglets and preserved until mRNA extraction. differential gene expression data were analyzed with a fold change cutoff (FC) of |1.2| P < 0.05. Pathway analysis was conducted with Z-score cutoff of P < 0.05. In the duodenum 435 genes were significantly changed with a FC ≥ |1.2| P < 0.05. In the duodenum, Claudin 1 and Claudin 2 were inversely affected by + Fe. Claudin 1 (CLDN1) plays a key role in cell-to-cell adhesion in the epithelial cell sheets and was upregulated (FC = 4.48, P = 0.0423). Claudin 2 (CLDN2) is expressed in cation leaky epithelia, especially during disease or inflammation and was downregulated (FC = -1.41, P = 0.0097). In the liver, 362 genes were expressed with a FC ≥ |1.2| P < 0.05. The gene most affected by a second dose of 200 mg Fe was hepcidin antimicrobial peptide (HAMP) with a FC of 40.8. HAMP is a liver-produced hormone that is the main circulating regulator of Fe absorption and distribution across tissues. It also controls the major flows of Fe into plasma by promoting endocytosis and degradation of ferroportin (SLC4A1). This leads to the retention of Fe in Fe-exporting cells and decreased flow of Fe into plasma. Gene expression related to metabolic pathway changes in the duodenum and liver provides evidence for the improved feed conversion and growth rates in piglets given two iron injections preweaning with contemporary pigs in a companion study. In the duodenum, there is a downregulation of gene clusters associated with gluconeogenesis (P < 0.05). Concurrently, there was a decrease in the mRNA expression of genes for enzymes required for urea production in the liver (P < 0.05). These observations suggest that there may be less need for gluconeogenesis, and possibly less urea production from deaminated amino acids. The genomic and pathway analyses provided empirical evidence linking gene expression with phenotypic observations of piglet health and growth improvements.
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Affiliation(s)
- James L Pierce
- James Pierce Consulting, Nicholasville, KY 40356, USA
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY 40506, USA
| | | | - Tyler B Chevalier
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY 40506, USA
| | - Merlin D Lindemann
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY 40506, USA
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Kubota N, Hori S, Ishizuka S. Differences in iron balance observed with dietary cholic acid supplementation and marginal iron deficiency in rats. Biosci Biotechnol Biochem 2023; 88:79-85. [PMID: 37813822 DOI: 10.1093/bbb/zbad140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 09/27/2023] [Indexed: 10/11/2023]
Abstract
We investigated whether a cholic acid (CA)-supplemented diet and marginal iron deficiency (MID) diet influence hepatic lipid accumulation and iron balance in rats for 2 weeks. The CA diet enhanced hepatic lipid accumulation and modulated iron metabolism such as enhancement of fecal iron excretion, reduction in iron absorption, and no alteration in plasma iron levels. The MID diet did not alter hepatic lipid concentrations with reduced iron concentration in the liver and plasma. In combination, influence of the CA supplementation on the hepatic iron concentration was opposite between iron-sufficient and MID conditions. In the liver, the CA diet enhanced lipocalin 2 expression, whereas the MID diet enhanced transferrin receptor 1 expression and reduced hepcidin expression. This study revealed an involvement of 12-hydroxylated bile acids in regulation of hepatic iron concentration under MID condition.
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Affiliation(s)
- Natsuki Kubota
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | - Shota Hori
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | - Satoshi Ishizuka
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
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Feng S, Tang D, Wang Y, Li X, Bao H, Tang C, Dong X, Li X, Yang Q, Yan Y, Yin Z, Shang T, Zheng K, Huang X, Wei Z, Wang K, Qi S. The mechanism of ferroptosis and its related diseases. MOLECULAR BIOMEDICINE 2023; 4:33. [PMID: 37840106 PMCID: PMC10577123 DOI: 10.1186/s43556-023-00142-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 08/23/2023] [Indexed: 10/17/2023] Open
Abstract
Ferroptosis, a regulated form of cellular death characterized by the iron-mediated accumulation of lipid peroxides, provides a novel avenue for delving into the intersection of cellular metabolism, oxidative stress, and disease pathology. We have witnessed a mounting fascination with ferroptosis, attributed to its pivotal roles across diverse physiological and pathological conditions including developmental processes, metabolic dynamics, oncogenic pathways, neurodegenerative cascades, and traumatic tissue injuries. By unraveling the intricate underpinnings of the molecular machinery, pivotal contributors, intricate signaling conduits, and regulatory networks governing ferroptosis, researchers aim to bridge the gap between the intricacies of this unique mode of cellular death and its multifaceted implications for health and disease. In light of the rapidly advancing landscape of ferroptosis research, we present a comprehensive review aiming at the extensive implications of ferroptosis in the origins and progress of human diseases. This review concludes with a careful analysis of potential treatment approaches carefully designed to either inhibit or promote ferroptosis. Additionally, we have succinctly summarized the potential therapeutic targets and compounds that hold promise in targeting ferroptosis within various diseases. This pivotal facet underscores the burgeoning possibilities for manipulating ferroptosis as a therapeutic strategy. In summary, this review enriched the insights of both investigators and practitioners, while fostering an elevated comprehension of ferroptosis and its latent translational utilities. By revealing the basic processes and investigating treatment possibilities, this review provides a crucial resource for scientists and medical practitioners, aiding in a deep understanding of ferroptosis and its effects in various disease situations.
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Affiliation(s)
- Shijian Feng
- Department of Urology and Institute of Urology (Laboratory of Reconstructive Urology), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Dan Tang
- Department of Urology and Institute of Urology (Laboratory of Reconstructive Urology), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Yichang Wang
- Department of Urology and Institute of Urology (Laboratory of Reconstructive Urology), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Xiang Li
- Department of Urology and Institute of Urology (Laboratory of Reconstructive Urology), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Hui Bao
- Department of Urology and Institute of Urology (Laboratory of Reconstructive Urology), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Chengbing Tang
- Department of Urology and Institute of Urology (Laboratory of Reconstructive Urology), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Xiuju Dong
- Department of Urology and Institute of Urology (Laboratory of Reconstructive Urology), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Xinna Li
- Department of Urology and Institute of Urology (Laboratory of Reconstructive Urology), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Qinxue Yang
- Department of Urology and Institute of Urology (Laboratory of Reconstructive Urology), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Yun Yan
- Department of Urology and Institute of Urology (Laboratory of Reconstructive Urology), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Zhijie Yin
- Department of Urology and Institute of Urology (Laboratory of Reconstructive Urology), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Tiantian Shang
- Department of Urology and Institute of Urology (Laboratory of Reconstructive Urology), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Kaixuan Zheng
- Department of Urology and Institute of Urology (Laboratory of Reconstructive Urology), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Xiaofang Huang
- Department of Urology and Institute of Urology (Laboratory of Reconstructive Urology), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Zuheng Wei
- Chengdu Jinjiang Jiaxiang Foreign Languages High School, Chengdu, People's Republic of China
| | - Kunjie Wang
- Department of Urology and Institute of Urology (Laboratory of Reconstructive Urology), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
| | - Shiqian Qi
- Department of Urology and Institute of Urology (Laboratory of Reconstructive Urology), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
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Luo G, Xiang L, Xiao L. Acetyl-CoA Deficiency Is Involved in the Regulation of Iron Overload on Lipid Metabolism in Apolipoprotein E Knockout Mice. Molecules 2022; 27:molecules27154966. [PMID: 35956917 PMCID: PMC9370536 DOI: 10.3390/molecules27154966] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 11/16/2022] Open
Abstract
The role of dietary iron supplementation in the development of nonalcoholic fatty liver disease (NAFLD) remains controversial. This study aimed to investigate the effect of excess dietary iron on NAFLD development and the underlying mechanism. Apolipoprotein E knockout mice were fed a chow diet, a high-fat diet (HFD), or an HFD containing 2% carbonyl iron (HFD + Fe) for 16 weeks. The serum and liver samples were acquired for biochemical and histopathological examinations. Isobaric tags for relative and absolute quantitation were performed to identify differentially expressed proteins in different groups. Excess dietary iron alleviated HFD-induced NAFLD, as evidenced by significant decreases in serum/the hepatic accumulation of lipids and the NAFLD scores in HFD + Fe-fed mice compared with those in HFD-fed mice. The hepatic acetyl-CoA level was markedly decreased in the HFD + Fe group compared with that in the HFD group. Important enzymes involved in the source and destination of acetyl-CoA were differentially expressed between the HFD and HFD + Fe groups, including the enzymes associated with cholesterol metabolism, glycolysis, and the tricarboxylic acid cycle. Furthermore, iron overload-induced mitochondrial dysfunction and oxidative stress occurred in mouse liver, as evidenced by decreases in the mitochondrial membrane potential and antioxidant expression. Therefore, iron overload regulates lipid metabolism by leading to an acetyl-CoA shortage that reduces cholesterol biosynthesis and might play a role in NAFLD pathogenesis. Iron overload-induced oxidative stress and mitochondrial dysfunction may impair acetyl-CoA formation from pyruvate and β-oxidation. Our study provides acetyl-CoA as a novel perspective for investigating the pathogenesis of NAFLD.
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Affiliation(s)
- Gang Luo
- Department of Health Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, China
| | - Lu Xiang
- Department of Nutrition Science and Food Hygiene, Xiangya School of Public Health, Central South University, Changsha 410078, China
| | - Lin Xiao
- Department of Nutrition Science and Food Hygiene, Xiangya School of Public Health, Central South University, Changsha 410078, China
- Correspondence: ; Tel.: +86-731-8448-7130
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7
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Zhang S, Xin W, Anderson GJ, Li R, Gao L, Chen S, Zhao J, Liu S. Double-edge sword roles of iron in driving energy production versus instigating ferroptosis. Cell Death Dis 2022; 13:40. [PMID: 35013137 PMCID: PMC8748693 DOI: 10.1038/s41419-021-04490-1] [Citation(s) in RCA: 107] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 12/06/2021] [Accepted: 12/20/2021] [Indexed: 12/13/2022]
Abstract
Iron is vital for many physiological functions, including energy production, and dysregulated iron homeostasis underlies a number of pathologies. Ferroptosis is a recently recognized form of regulated cell death that is characterized by iron dependency and lipid peroxidation, and this process has been reported to be involved in multiple diseases. The mechanisms underlying ferroptosis are complex, and involve both well-described pathways (including the iron-induced Fenton reaction, impaired antioxidant capacity, and mitochondrial dysfunction) and novel interactions linked to cellular energy production. In this review, we examine the contribution of iron to diverse metabolic activities and their relationship to ferroptosis. There is an emphasis on the role of iron in driving energy production and its link to ferroptosis under both physiological and pathological conditions. In conclusion, excess reactive oxygen species production driven by disordered iron metabolism, which induces Fenton reaction and/or impairs mitochondrial function and energy metabolism, is a key inducer of ferroptosis.
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Affiliation(s)
- Shuping Zhang
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
| | - Wei Xin
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
| | - Gregory J Anderson
- Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
| | - Ruibin Li
- School for Radiological and Interdisciplinary Science, Soochow University, Suzhou, Jiangsu, 215123, China
| | - Ling Gao
- Department of Endocrinology, Shandong Provincial Hospital, Shandong First Medical University, Jinan, Shandong, 250031, China
| | - Shuguang Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jiajun Zhao
- Department of Endocrinology, Shandong Provincial Hospital, Shandong First Medical University, Jinan, Shandong, 250031, China.
| | - Sijin Liu
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China.
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8
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Fiddler JL, Clarke SL. Evaluation of candidate reference genes for quantitative real-time PCR analysis in a male rat model of dietary iron deficiency. GENES & NUTRITION 2021; 16:17. [PMID: 34600467 PMCID: PMC8487497 DOI: 10.1186/s12263-021-00698-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 09/15/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Quantitative real-time polymerase chain reaction (qPCR) is a reliable and efficient method for quantitation of gene expression. Due to the increased use of qPCR in examining nutrient-gene interactions, it is important to examine, develop, and utilize standardized approaches for data analyses and interpretation. A common method used to normalize expression data involves the use of reference genes (RG) to determine relative mRNA abundance. When calculating the relative abundance, the selection of RG can influence experimental results and has the potential to skew data interpretation. Although common RG may be used for normalization, often little consideration is given to the suitability of RG selection for an experimental condition or between various tissue or cell types. In the current study, we examined the stability of gene expression using BestKeeper, comparative delta quantitation cycle, NormFinder, and RefFinder in a variety of tissues obtained from iron-deficient and pair-fed iron-replete rats to determine the optimal selection among ten candidate RG. RESULTS Our results suggest that several commonly used RG (e.g., Actb and Gapdh) exhibit less stability compared to other candidate RG (e.g., Rpl19 and Rps29) in both iron-deficient and iron-replete pair-fed conditions. For all evaluated RG, Tfrc expression significantly increased in iron-deficient animal livers compared to the iron-replete pair-fed controls; however, the relative induction varied nearly 4-fold between the most suitable (Rpl19) and least suitable (Gapdh) RG. CONCLUSION These results indicate the selection and use of RG should be empirically determined and RG selection may vary across experimental conditions and biological tissues.
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Affiliation(s)
- Joanna L Fiddler
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, 14850-6301, USA.
- Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, 74078, USA.
| | - Stephen L Clarke
- Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, 74078, USA
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9
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Iron supplementation regulates the progression of high fat diet induced obesity and hepatic steatosis via mitochondrial signaling pathways. Sci Rep 2021; 11:10753. [PMID: 34031430 PMCID: PMC8144192 DOI: 10.1038/s41598-021-89673-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 04/23/2021] [Indexed: 12/04/2022] Open
Abstract
Disruption of iron metabolism is closely related to metabolic diseases. Iron deficiency is frequently associated with obesity and hepatic steatosis. However, the effects of iron supplementation on obesity and energy metabolism remain unclear. Here we show that a high-fat diet supplemented with iron reduces body weight gain and hepatic lipid accumulation in mice. Iron supplementation was found to reduce mitochondrial morphological abnormalities and upregulate gene transcription involved in mitochondrial function and beta oxidation in the liver and skeletal muscle. In both these tissues, iron supplementation increased the expression of genes involved in heme or iron–sulfur (Fe–S) cluster synthesis. Heme and Fe–S cluster, which are iron prosthetic groups contained in electron transport chain complex subunits, are essential for mitochondrial respiration. The findings of this study demonstrated that iron regulates mitochondrial signaling pathways—gene transcription of mitochondrial component molecules synthesis and their energy metabolism. Overall, the study elucidates the molecular basis underlying the relationship between iron supplementation and obesity and hepatic steatosis progression, and the role of iron as a signaling molecule.
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10
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Sarlak S, Tabeidian SA, Toghyani M, Shahraki ADF, Goli M, Habibian M. Effects of Replacing Inorganic with Organic Iron on Performance, Egg Quality, Serum and Egg Yolk Lipids, Antioxidant Status, and Iron Accumulation in Eggs of Laying Hens. Biol Trace Elem Res 2021; 199:1986-1999. [PMID: 32666433 DOI: 10.1007/s12011-020-02284-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 07/10/2020] [Indexed: 01/06/2023]
Abstract
This study compared the effects dietary organic (ferrous glycine [FG]) versus inorganic (ferrous sulfate [FS]) iron in laying hens on performance, egg quality, serum and egg yolk lipids, antioxidant status, and iron enrichment of eggs. A total of 378 Shaver White layers were allotted to 7 treatments with 6 replicates (9 birds each) from 30 to 42 weeks of age. A basal diet (19 mg iron/kg) served as control, while the other six diets were supplemented with either FS or FG to provide 30, 60, and 120 mg/kg of added iron. Dietary FG and FS treatments improved (P < 0.05) laying rate, egg weight, and egg quality of layers, relative to the control, albeit eggshell strength and eggshell calcium also deteriorated with the highest level of FS (P < 0.05). The iron treatment groups exhibited a lower serum and egg yolk levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol that accompanied by higher levels of high-density lipoprotein cholesterol and greater activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) as compared with the control (P < 0.05). The contents of malondialdehyde and protein carbonyl were conversely related to the activities SOD and GPx (P < 0.05). The serum and egg fractions (yolk, albumen, and shell) displayed gradually increases in iron contents as the level of iron increased in the diet (P < 0.05), while FG was superior to FS at all tested levels (P < 0.05). To summary, FS can be replaced by FG, with more favorable impacts on egg quality and iron enrichment.
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Affiliation(s)
- Sima Sarlak
- Department of Animal Science, Faculty of Agriculture, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran
| | - Sayed Ali Tabeidian
- Department of Animal Science, Faculty of Agriculture, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran.
| | - Majid Toghyani
- Department of Animal Science, Faculty of Agriculture, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran
| | | | - Mohammad Goli
- Department of Food Sciences and Technology, Faculty of Agriculture, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran
| | - Mahmood Habibian
- Young Researchers and Elite Club, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan, Iran
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11
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Ortiz-Flores AE, Martínez-García MÁ, Nattero-Chávez L, Álvarez-Blasco F, Fernández-Durán E, Quintero-Tobar A, Escobar-Morreale HF, Luque-Ramírez M. Iron Overload in Functional Hyperandrogenism: In a Randomized Trial, Bloodletting Does Not Improve Metabolic Outcomes. J Clin Endocrinol Metab 2021; 106:e1559-e1573. [PMID: 33462622 DOI: 10.1210/clinem/dgaa978] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Indexed: 12/13/2022]
Abstract
CONTEXT Functional hyperandrogenism may be associated with a mild increase in body iron stores. Iron depletion exerts a beneficial effect on metabolic endpoints in other iron overload states. OBJECTIVES (i) To determine the effect of iron depletion on the insulin sensitivity and frequency of abnormal glucose tolerance in patients with functional hyperandrogenism submitted to standard therapy with combined oral contraceptives (COC). ii) To assess the overall safety of this intervention. DESIGN Randomized, parallel, open-label, clinical trial. SETTING Academic hospital. PATIENTS Adult women with polycystic ovary syndrome or idiopathic hyperandrogenism. INTERVENTION After a 3-month run-in period of treatment with 35 μg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to 3 scheduled bloodlettings or observation for another 9 months. MAIN OUTCOME MEASURES Changes in insulin sensitivity index and frequency of prediabetes/diabetes, and percentage of women in whom bloodletting resulted in plasma hemoglobin <120 g/L and/or hematocrit <0.36. RESULTS From 2015 to 2019, 33 women were included by intention-to-treat. During the follow-up, insulin sensitivity did not change in the whole group of women or between study arms [mean of the differences (MD): 0.0 (95%CI: -1.6 to 1.6)]. Women in the experimental arm showed a similar odds of having prediabetes/diabetes than women submitted to observation [odds ratio: 0.981 (95%CI: 0.712 to 1.351)]. After bloodletting, 4 (21.1%) and 2 women (10.5%) in the experimental arm had hemoglobin (Hb) levels <120 g/L and hematocrit (Hct) values <0.36, respectively, but none showed Hb <110 g/L or Hct <0.34. CONCLUSIONS Scheduled bloodletting does not improve insulin sensitivity in women with functional hyperandrogenism on COC.
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Affiliation(s)
- Andrés E Ortiz-Flores
- Diabetes, Obesity, and Human Reproduction Research Group, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
- Department of Endocrinology and Nutrition. Hospital Universitario de Torrejón, Torrejón de Ardoz, Madrid, Spain
| | - María Ángeles Martínez-García
- Diabetes, Obesity, and Human Reproduction Research Group, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Lía Nattero-Chávez
- Diabetes, Obesity, and Human Reproduction Research Group, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Francisco Álvarez-Blasco
- Diabetes, Obesity, and Human Reproduction Research Group, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Elena Fernández-Durán
- Diabetes, Obesity, and Human Reproduction Research Group, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Alejandra Quintero-Tobar
- Diabetes, Obesity, and Human Reproduction Research Group, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Héctor F Escobar-Morreale
- Diabetes, Obesity, and Human Reproduction Research Group, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Manuel Luque-Ramírez
- Diabetes, Obesity, and Human Reproduction Research Group, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Madrid, Spain
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Iron-rich Kupffer cells exhibit phenotypic changes during the development of liver fibrosis in NASH. iScience 2021; 24:102032. [PMID: 33521599 PMCID: PMC7820131 DOI: 10.1016/j.isci.2020.102032] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 12/07/2020] [Accepted: 12/30/2020] [Indexed: 02/06/2023] Open
Abstract
Although recent evidence suggests the involvement of iron accumulation in the pathogenesis of nonalcoholic steatohepatitis (NASH), the underlying mechanisms remain poorly understood. Previously, we reported a unique histological structure termed "crown-like structure (CLS)," where liver-resident macrophages (Kupffer cells) surround dead hepatocytes, scavenge their debris, and induce inflammation and fibrosis in NASH. In this study, using magnetic column separation, we show that iron-rich Kupffer cells exhibit proinflammatory and profibrotic phenotypic changes during the development of NASH, at least partly, through activation of MiT/TFE transcription factors. Activation of MiT/TFE transcription factors is observed in Kupffer cells forming CLSs in murine and human NASH. Iron chelation effectively attenuates liver fibrosis in a murine NASH model. This study provides insight into the pathophysiologic role of iron in NASH. Our data also shed light on a unique macrophage subset rich in iron that contributes to CLS formation and serves as a driver of liver fibrosis.
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Zhou J, Liu C, Francis M, Sun Y, Ryu MS, Grider A, Ye K. The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study. Nutrients 2020; 12:E3174. [PMID: 33080795 PMCID: PMC7603077 DOI: 10.3390/nu12103174] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/13/2020] [Accepted: 10/14/2020] [Indexed: 02/07/2023] Open
Abstract
Blood levels of iron and copper, even within their normal ranges, have been associated with a wide range of clinical outcomes. The available epidemiological evidence for these associations is often inconsistent and suffers from confounding and reverse causation. This study aims to examine the causal clinical effects of blood iron and copper with Mendelian randomization (MR) analyses. Genetic instruments for the blood levels of iron and copper were curated from existing genome-wide association studies. Candidate clinical outcomes were identified based on a phenome-wide association study (PheWAS) between these genetic instruments and a wide range of phenotypes in 310,999 unrelated individuals of European ancestry from the UK Biobank. All signals passing stringent correction for multiple testing were followed by MR analyses, with replication in independent data sources where possible. We found that genetically predicted higher blood levels of iron and copper are both associated with lower risks of iron deficiency anemia (odds ratio (OR) = 0.75, 95% confidence interval (CI): 0.67-0.85, p = 1.90 × 10-6 for iron; OR = 0.88, 95% CI: 0.78-0.98, p = 0.032 for copper), lipid metabolism disorders, and its two subcategories, hyperlipidemia (OR = 0.90, 95% CI: 0.85-0.96, p = 6.44 × 10-4; OR = 0.92, 95% CI: 0.87-0.98, p = 5.51 × 10-3) and hypercholesterolemia (OR = 0.90, 95% CI: 0.84-0.95, p = 5.34 × 10-4; OR = 0.93, 95% CI: 0.89-0.99, p = 0.022). Consistently, they are also associated with lower blood levels of total cholesterol and low-density lipoprotein cholesterol. Multiple sensitivity tests were applied to assess the presence of pleiotropy and the robustness of causal estimates. Regardless of the approaches, consistent evidence was obtained. Moreover, the unique clinical effects of each blood mineral were identified. Notably, genetically predicated higher blood iron is associated with an enhanced risk of varicose veins (OR = 1.28, 95% CI: 1.15-1.42, p = 4.34 × 10-6), while blood copper is positively associated with the risk of osteoarthrosis (OR = 1.07, 95% CI: 1.02-1.13, p = 0.010). Sex-stratified MR analysis further revealed some degree of sex differences in their clinical effects. Our comparative PheWAS-MR study of iron and copper comprehensively characterized their shared and unique clinical effects, highlighting their potential causal roles in hyperlipidemia and hypercholesterolemia. Given the modifiable nature of blood mineral status and the potential for clinical intervention, these findings warrant further investigation.
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Affiliation(s)
- Jingqi Zhou
- Department of Genetics, University of Georgia, Athens, GA 30602, USA; (J.Z.); (C.L.); (Y.S.)
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Chang Liu
- Department of Genetics, University of Georgia, Athens, GA 30602, USA; (J.Z.); (C.L.); (Y.S.)
- College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Michael Francis
- Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA;
| | - Yitang Sun
- Department of Genetics, University of Georgia, Athens, GA 30602, USA; (J.Z.); (C.L.); (Y.S.)
| | - Moon-Suhn Ryu
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN 55108, USA;
| | - Arthur Grider
- Department of Foods and Nutrition, University of Georgia, Athens, GA 30602, USA;
| | - Kaixiong Ye
- Department of Genetics, University of Georgia, Athens, GA 30602, USA; (J.Z.); (C.L.); (Y.S.)
- Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA;
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da Silva Diniz WJ, Banerjee P, Mazzoni G, Coutinho LL, Cesar ASM, Afonso J, Gromboni CF, Nogueira ARA, Kadarmideen HN, de Almeida Regitano LC. Interplay among miR-29 family, mineral metabolism, and gene regulation in Bos indicus muscle. Mol Genet Genomics 2020; 295:1113-1127. [PMID: 32444960 DOI: 10.1007/s00438-020-01683-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 05/04/2020] [Indexed: 11/26/2022]
Abstract
An interplay between gene expression, mineral concentration, and beef quality traits in Bos indicus muscle has been reported previously under a network approach. However, growing evidence suggested that miRNAs not only modulate gene expression but are also involved with mineral homeostasis. To our knowledge, understanding of the miRNA-gene expression-mineral concentration relationship in mammals is still minimal. Therefore, we carried out a miRNA co-expression and multi-level miRNA-mRNA integration analyses to predict the putative drivers (miRNAs and genes) associated with muscle mineral concentration in Nelore steers. In this study, we identified calcium and iron to be the pivotal minerals associated with miRNAs and gene targets. Furthermore, we identified the miR-29 family (miR-29a, -29b, -29c, -29d-3p, and -29e) as the putative key regulators modulating mineral homeostasis. The miR-29 family targets genes involved with AMPK, insulin, mTOR, and thyroid hormone signaling pathways. Finally, we reported an interplay between miRNAs and minerals acting cooperatively to modulate co-expressed genes and signaling pathways both involved with mineral and energy homeostasis in Nelore muscle. Although we provided some evidence to understand this complex relationship, future work should determine the functional implications of minerals for miRNA levels and their feedback regulation system.\\An interplay between gene expression, mineral concentration, and beef quality traits in Bos indicus muscle has been reported previously under a network approach. However, growing evidence suggested that miRNAs not only modulate gene expression but are also involved with mineral homeostasis. To our knowledge, understanding of the miRNA-gene expression-mineral concentration relationship in mammals is still minimal. Therefore, we carried out a miRNA co-expression and multi-level miRNA-mRNA integration analyses to predict the putative drivers (miRNAs and genes) associated with muscle mineral concentration in Nelore steers. In this study, we identified calcium and iron to be the pivotal minerals associated with miRNAs and gene targets. Furthermore, we identified the miR-29 family (miR-29a, -29b, -29c, -29d-3p, and -29e) as the putative key regulators modulating mineral homeostasis. The miR-29 family targets genes involved with AMPK, insulin, mTOR, and thyroid hormone signaling pathways. Finally, we reported an interplay between miRNAs and minerals acting cooperatively to modulate co-expressed genes and signaling pathways both involved with mineral and energy homeostasis in Nelore muscle. Although we provided some evidence to understand this complex relationship, future work should determine the functional implications of minerals for miRNA levels and their feedback regulation system.
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Affiliation(s)
- Wellison Jarles da Silva Diniz
- Graduate Program in Evolutionary Genetics and Molecular Biology, Center for Biological and Health Sciences (CCBS), Federal University of São Carlos, São Carlos, São Paulo, Brazil
- Department of Applied Mathematics and Computer Science, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Priyanka Banerjee
- Department of Applied Mathematics and Computer Science, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Gianluca Mazzoni
- Department of Health Technology, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Luiz Lehmann Coutinho
- Department of Animal Science, Luiz de Queiroz College of Agriculture, University of São Paulo, Piracicaba, São Paulo, Brazil
| | - Aline Silva Mello Cesar
- Department of Animal Science, Luiz de Queiroz College of Agriculture, University of São Paulo, Piracicaba, São Paulo, Brazil
| | - Juliana Afonso
- Graduate Program in Evolutionary Genetics and Molecular Biology, Center for Biological and Health Sciences (CCBS), Federal University of São Carlos, São Carlos, São Paulo, Brazil
| | - Caio Fernando Gromboni
- IFBA, Bahia Federal Institute of Education Science and Technology, Campus Ilhéus, Ilhéus, Bahia, Brazil
| | - Ana Rita Araújo Nogueira
- Empresa Brasileira de Pesquisa Agropecuária, Embrapa Pecuária Sudeste, São Carlos, São Paulo, Brazil
| | - Haja N Kadarmideen
- Department of Applied Mathematics and Computer Science, Technical University of Denmark, Kgs. Lyngby, Denmark
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Sandri BJ, Lubach GR, Lock EF, Georgieff MK, Kling PJ, Coe CL, Rao RB. Early-Life Iron Deficiency and Its Natural Resolution Are Associated with Altered Serum Metabolomic Profiles in Infant Rhesus Monkeys. J Nutr 2020; 150:685-693. [PMID: 31722400 PMCID: PMC7138653 DOI: 10.1093/jn/nxz274] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 07/23/2019] [Accepted: 10/11/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Iron deficiency is the most common nutrient deficiency in human infants aged 6 to 24 mo, and negatively affects many cellular metabolic processes, including energy production, electron transport, and oxidative degradation of toxins. There can be persistent influences on long-term metabolic health beyond its acute effects. OBJECTIVES The objective was to determine how iron deficiency in infancy alters the serum metabolomic profile and to test whether these effects persist after the resolution of iron deficiency in a nonhuman primate model of spontaneous iron deficiency. METHODS Blood was collected from naturally iron-sufficient (IS; n = 10) and iron-deficient (ID; n = 10) male and female infant rhesus monkeys (Macaca mulatta) at 6 mo of age. Iron deficiency resolved without intervention upon feeding of solid foods, and iron status was re-evaluated at 12 mo of age from the IS and formerly ID monkeys using hematological and other indices; sera were metabolically profiled using HPLC/MS and GC/MS with isobaric standards for identification and quantification at both time points. RESULTS A total of 413 metabolites were measured, with differences in 40 metabolites identified between IS and ID monkeys at 6 mo (P$\le $ 0.05). At 12 mo, iron-related hematological parameters had returned to normal, but the formerly ID infants remained metabolically distinct from the age-matched IS infants, with 48 metabolites differentially expressed between the groups. Metabolomic profiling indicated altered liver metabolites, differential fatty acid production, increased serum uridine release, and atypical bile acid production in the ID monkeys. CONCLUSIONS Pathway analyses of serum metabolites provided evidence of a hypometabolic state, altered liver function, differential essential fatty acid production, irregular uracil metabolism, and atypical bile acid production in ID infants. Many metabolites remained altered after the resolution of ID, suggesting long-term effects on metabolic health.
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Affiliation(s)
- Brian J Sandri
- Division of Neonatology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
| | - Gabriele R Lubach
- Harlow Center for Biological Psychology, University of Wisconsin, Madison, WI, USA
| | - Eric F Lock
- School of Public Health, University of Minnesota, Minneapolis, MN, USA
| | - Michael K Georgieff
- Division of Neonatology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA,Center for Neurobehavioral Development, University of Minnesota, Minneapolis, MN, USA
| | - Pamela J Kling
- Division of Neonatology, Department of Pediatrics, University of Wisconsin, Madison, WI, USA
| | - Christopher L Coe
- Harlow Center for Biological Psychology, University of Wisconsin, Madison, WI, USA
| | - Raghavendra B Rao
- Division of Neonatology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA,Center for Neurobehavioral Development, University of Minnesota, Minneapolis, MN, USA,Address correspondence to RBR (e-mail: )
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Zhu B, Liang C, Xia X, Huang K, Yan S, Hao J, Zhu P, Gao H, Tao F. Iron-Related Factors in Early Pregnancy and Subsequent Risk of Gestational Diabetes Mellitus: the Ma'anshan Birth Cohort (MABC) Study. Biol Trace Elem Res 2019; 191:45-53. [PMID: 30515713 DOI: 10.1007/s12011-018-1595-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 11/28/2018] [Indexed: 12/15/2022]
Abstract
Iron is an essential micronutrient while its excessive load has been related to the etiology of diabetes. We used data of 3289 pregnant women from the Ma'anshan birth cohort (MABC) study in China to examine the associations of three iron-related factors (i.e., serum iron (SI) concentration, hemoglobin level, and use of iron supplements) with risk of gestational diabetes mellitus (GDM). Emphatically explore the potential non-linear relationship between SI concentration and risk of GDM. SI concentration was measured in fasting blood using inductively coupled plasma mass spectrometry (ICP-MS). GDM diagnosis was determined by 75 g oral glucose tolerance test at 24~28 weeks. Restricted cubic splines with three knots were used to examine potential non-linear relationship between SI concentration and GDM risk. We observed a U-shape relation between SI concentration in the first trimester and risk of GDM. In the multivariate-adjusted model, compared with the middle level (ln(SI), 7.1-7.7 μg/L), both the lowest level (ln(SI) ≤ 7.1 μg/L) (odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.04-1.76) and the highest level (ln(SI) > 7.7 μg/L) (OR = 1.63, 95%CI = 1.16-2.28) increased risk of GDM. Associations of hemoglobin level in the first trimester and risk of GDM attenuated to non-significance after adjustment for pre-pregnancy body mass index (BMI) and blood pressure. Pre-pregnancy iron supplement use was associated with an increased risk of GDM (OR = 1.57, 95%CI = 1.06-2.32). In conclusion, the three iron-related factors are all related to GDM risk on some level.
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Affiliation(s)
- Beibei Zhu
- Department of Maternal, Child and Adolescent Health, Anhui Medical University, Hefei, China
- Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, Hefei, China
| | - Chunmei Liang
- Department of Maternal, Child and Adolescent Health, Anhui Medical University, Hefei, China
- Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, Hefei, China
| | - Xun Xia
- Department of Maternal, Child and Adolescent Health, Anhui Medical University, Hefei, China
- Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, Hefei, China
| | - Kun Huang
- Department of Maternal, Child and Adolescent Health, Anhui Medical University, Hefei, China
- Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, Hefei, China
| | - Shuangqin Yan
- Ma'anshan Maternal and Child Health Care Center, Ma'anshan, China
| | - Jiahu Hao
- Department of Maternal, Child and Adolescent Health, Anhui Medical University, Hefei, China
- Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, Hefei, China
| | - Peng Zhu
- Department of Maternal, Child and Adolescent Health, Anhui Medical University, Hefei, China
- Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, Hefei, China
| | - Hui Gao
- Department of Maternal, Child and Adolescent Health, Anhui Medical University, Hefei, China
| | - Fangbiao Tao
- Department of Maternal, Child and Adolescent Health, Anhui Medical University, Hefei, China.
- Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, Hefei, China.
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Ma W, Feng Y, Jia L, Li S, Li J, Wang Z, Chen X, Du H. Dietary Iron Modulates Glucose and Lipid Homeostasis in Diabetic Mice. Biol Trace Elem Res 2019; 189:194-200. [PMID: 30027366 DOI: 10.1007/s12011-018-1446-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2018] [Accepted: 07/12/2018] [Indexed: 12/21/2022]
Abstract
Imbalance of iron homeostasis has been involved in clinical courses of metabolic diseases such as type 2 diabetes mellitus, obesity, and nonalcoholic fatty liver, through mechanisms not yet fully elucidated. Herein, we evaluated the effect of dietary iron on the development of diabetic syndromes in genetically obese db/db mice. Mice (aged 7 weeks) were fed with high-iron (HI) diets (1000 mg/kg chow) or low-iron (LI) diets (12 mg/kg) for 9 weeks. HI diets increased hepatic iron threefold and led to fourfold higher mRNA levels of hepcidin. HI also induced a 60% increase in fasting glucose due to insulin resistance, as confirmed by decreased hepatic glycogen deposition eightfold and a 21% decrease of serum adiponectin level. HI-fed mice had lower visceral adipose tissue mass estimated by epididymal and inguinal fat pad, associated with iron accumulation and smaller size of adipocytes. Gene expression analysis of liver showed that HI diet upregulated gluconeogenesis and downregulated lipogenesis. These results suggested that excess dietary iron leads to reduced mass, increased fasting glucose, decreased adiponectin level, and enhancement of insulin resistance, which indicated a multifactorial role of excess iron in the development of diabetes in the setting of obesity.
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Affiliation(s)
- Wan Ma
- Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture, Zhejiang University, Hangzhou, China
- Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Zhejiang University, Hangzhou, China
- College of Animal Science, Zhejiang University, Hangzhou, China
| | - Yunfei Feng
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, China
| | - Li Jia
- Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture, Zhejiang University, Hangzhou, China
- Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Zhejiang University, Hangzhou, China
- College of Animal Science, Zhejiang University, Hangzhou, China
| | - Shuhui Li
- Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture, Zhejiang University, Hangzhou, China
- Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Zhejiang University, Hangzhou, China
- College of Animal Science, Zhejiang University, Hangzhou, China
| | - Jiahui Li
- Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture, Zhejiang University, Hangzhou, China
- Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Zhejiang University, Hangzhou, China
- College of Animal Science, Zhejiang University, Hangzhou, China
| | - Zhenjie Wang
- Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture, Zhejiang University, Hangzhou, China
- Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Zhejiang University, Hangzhou, China
- College of Animal Science, Zhejiang University, Hangzhou, China
| | - Xiaoyun Chen
- Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture, Zhejiang University, Hangzhou, China
- Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Zhejiang University, Hangzhou, China
- College of Animal Science, Zhejiang University, Hangzhou, China
| | - Huahua Du
- Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture, Zhejiang University, Hangzhou, China.
- Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Zhejiang University, Hangzhou, China.
- College of Animal Science, Zhejiang University, Hangzhou, China.
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Konstorum A, Lynch ML, Torti SV, Torti FM, Laubenbacher RC. A Systems Biology Approach to Understanding the Pathophysiology of High-Grade Serous Ovarian Cancer: Focus on Iron and Fatty Acid Metabolism. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2019; 22:502-513. [PMID: 30004845 PMCID: PMC6059353 DOI: 10.1089/omi.2018.0060] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Ovarian cancer (OVC) is the most lethal of the gynecological malignancies, with diagnosis often occurring during advanced stages of the disease. Moreover, a majority of cases become refractory to chemotherapeutic approaches. Therefore, it is important to improve our understanding of the molecular dependencies underlying the disease to identify novel diagnostic and precision therapeutics for OVC. Cancer cells are known to sequester iron, which can potentiate cancer progression through mechanisms that have not yet been completely elucidated. We developed an algorithm to identify novel links between iron and pathways implicated in high-grade serous ovarian cancer (HGSOC), the most common and deadliest subtype of OVC, using microarray gene expression data from both clinical sources and an experimental model. Using our approach, we identified several links between fatty acid (FA) and iron metabolism, and subsequently developed a network for iron involvement in FA metabolism in HGSOC. FA import and synthesis pathways are upregulated in HGSOC and other cancers, but a link between these processes and iron-related genes has not yet been identified. We used the network to derive hypotheses of specific mechanisms by which iron and iron-related genes impact and interact with FA metabolic pathways to promote tumorigenesis. These results suggest a novel mechanism by which iron sequestration by cancer cells can potentiate cancer progression, and may provide novel targets for use in diagnosis and/or treatment of HGSOC.
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Affiliation(s)
- Anna Konstorum
- 1 Center for Quantitative Medicine, UConn Health , Farmington, Connecticut
| | - Miranda L Lynch
- 2 Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center , Buffalo, New York
| | - Suzy V Torti
- 3 Department of Molecular Biology and Biophysics, UConn Health , Farmington, Connecticut
| | - Frank M Torti
- 3 Department of Molecular Biology and Biophysics, UConn Health , Farmington, Connecticut
| | - Reinhard C Laubenbacher
- 1 Center for Quantitative Medicine, UConn Health , Farmington, Connecticut.,4 Jackson Laboratory for Genomic Medicine , Farmington, Connecticut
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Rees WD. Interactions between nutrients in the maternal diet and the implications for the long-term health of the offspring. Proc Nutr Soc 2019; 78:88-96. [PMID: 30378511 DOI: 10.1017/s0029665118002537] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Nutritional science has traditionally used the reductionist approach to understand the roles of individual nutrients in growth and development. The macronutrient dense but micronutrient poor diets consumed by many in the Western world may not result in an overt deficiency; however, there may be situations where multiple mild deficiencies combine with excess energy to alter cellular metabolism. These interactions are especially important in pregnancy as changes in early development modify the risk of developing non-communicable diseases later in life. Nutrient interactions affect all stages of fetal development, influencing endocrine programming, organ development and the epigenetic programming of gene expression. The rapidly developing field of stem cell metabolism reveals new links between cellular metabolism and differentiation. This review will consider the interactions between nutrients in the maternal diet and their influence on fetal development, with particular reference to energy metabolism, amino acids and the vitamins in the B group.
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Affiliation(s)
- William D Rees
- The Rowett Institute of Nutrition and Health, The University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK
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20
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Dziegala M, Josiak K, Kasztura M, Kobak K, von Haehling S, Banasiak W, Anker SD, Ponikowski P, Jankowska E. Iron deficiency as energetic insult to skeletal muscle in chronic diseases. J Cachexia Sarcopenia Muscle 2018; 9:802-815. [PMID: 30178922 PMCID: PMC6204587 DOI: 10.1002/jcsm.12314] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 04/05/2018] [Accepted: 04/22/2018] [Indexed: 12/19/2022] Open
Abstract
Specific skeletal myopathy constitutes a common feature of heart failure, chronic obstructive pulmonary disease, and type 2 diabetes mellitus, where it can be characterized by the loss of skeletal muscle oxidative capacity. There is evidence from in vitro and animal studies that iron deficiency affects skeletal muscle functioning mainly in the context of its energetics by limiting oxidative metabolism in favour of glycolysis and by alterations in both carbohydrate and fat catabolic processing. In this review, we depict the possible molecular pathomechanisms of skeletal muscle energetic impairment and postulate iron deficiency as an important factor causally linked to loss of muscle oxidative capacity that contributes to skeletal myopathy seen in patients with heart failure, chronic obstructive pulmonary disease, and type 2 diabetes mellitus.
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Affiliation(s)
- Magdalena Dziegala
- Laboratory for Applied Research on Cardiovascular System, Department of Heart DiseasesWroclaw Medical University50‐981WroclawPoland
| | - Krystian Josiak
- Centre for Heart DiseasesMilitary Hospital50‐981WroclawPoland
- Department of Heart DiseasesWroclaw Medical University50‐367WroclawPoland
| | - Monika Kasztura
- Laboratory for Applied Research on Cardiovascular System, Department of Heart DiseasesWroclaw Medical University50‐981WroclawPoland
| | - Kamil Kobak
- Laboratory for Applied Research on Cardiovascular System, Department of Heart DiseasesWroclaw Medical University50‐981WroclawPoland
| | - Stephan von Haehling
- Department of Cardiology and PneumologyUniversity Medicine Göttingen (UMG)37075GöttingenGermany
| | | | - Stefan D. Anker
- Department of Cardiology and PneumologyUniversity Medicine Göttingen (UMG)37075GöttingenGermany
- Division of Cardiology and MetabolismCharité Universitätsmedizin10117BerlinGermany
- Department of Cardiology (CVK)Charité Universitätsmedizin10117BerlinGermany
- Berlin‐Brandenburg Center for Regenerative Therapies (BCRT)Charité Universitätsmedizin10117BerlinGermany
- German Centre for Cardiovascular Research (DZHK) partner site BerlinCharité Universitätsmedizin10117BerlinGermany
| | - Piotr Ponikowski
- Centre for Heart DiseasesMilitary Hospital50‐981WroclawPoland
- Department of Heart DiseasesWroclaw Medical University50‐367WroclawPoland
| | - Ewa Jankowska
- Laboratory for Applied Research on Cardiovascular System, Department of Heart DiseasesWroclaw Medical University50‐981WroclawPoland
- Centre for Heart DiseasesMilitary Hospital50‐981WroclawPoland
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Hori S, Hara H, Ishizuka S. Marginal iron deficiency enhances liver triglyceride accumulation in rats fed a high-sucrose diet. Biosci Biotechnol Biochem 2018; 82:2140-2148. [PMID: 30185127 DOI: 10.1080/09168451.2018.1515616] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
We investigated whether marginal iron-deficiency (MID) without anemia influences liver lipid accumulation in rats. Ingestion of a MID diet in which the iron concentration was half of AIN-93 formulation (iron-adequate, IA) for 3 weeks decreased liver iron concentration without anemia. We then evaluated the influence of the MID diet on liver lipid accumulation in combination with a high-sucrose (HS) diet and confirmed that the HS-MID diet successfully decreased liver iron concentration without anemia. Additionally, a significant increase in liver triglyceride concentration was found, accompanied by upregulation of hepatic fatty acid synthase expression in the rats fed the HS-MID diet compared to those in the rats fed an HS-IA diet, although no difference was observed in plasma transaminase activity and hepatic interleukin-1β expression. These results suggest that MID enhances de novo lipid synthesis via upregulation of lipogenic gene expression in combination with sucrose in the diet. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; HS, high sucrose; IA, iron adequate; ID, iron deficiency; MID, marginal irondeficiency; NAFLD, non-alcoholic fatty liver disease.
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Affiliation(s)
- Shota Hori
- a Division of Fundamental Agriscience Research, Research Faculty of Agriculture , Hokkaido University , Sapporo , Japan
| | - Hiroshi Hara
- a Division of Fundamental Agriscience Research, Research Faculty of Agriculture , Hokkaido University , Sapporo , Japan
| | - Satoshi Ishizuka
- a Division of Fundamental Agriscience Research, Research Faculty of Agriculture , Hokkaido University , Sapporo , Japan
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22
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Deciphering the multicomponent synergy mechanism from a systems pharmacology perspective: Application to Gualou Xiebai Decoction for coronary heart disease. J Funct Foods 2018. [DOI: 10.1016/j.jff.2018.02.030] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Chen GH, Luo Z, Chen F, Shi X, Song YF, You WJ, Liu X. PPARα, PPARγ and SREBP-1 pathways mediated waterborne iron (Fe)-induced reduction in hepatic lipid deposition of javelin goby Synechogobius hasta. Comp Biochem Physiol C Toxicol Pharmacol 2017; 197:8-18. [PMID: 28411055 DOI: 10.1016/j.cbpc.2017.04.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 03/29/2017] [Accepted: 04/09/2017] [Indexed: 01/20/2023]
Abstract
The 42-day experiment was conducted to investigate the effects and mechanism of waterborne Fe exposure influencing hepatic lipid deposition in Synechogobius hasta. For that purpose, S. hasta were exposed to four Fe concentrations (0 (control), 0.36, 0.72 and 1.07μM Fe) for 42days. On days 21 and 42, morphological parameters, hepatic lipid deposition and Fe contents, and activities and mRNA levels of enzymes and genes related to lipid metabolism, including lipogenic enzymes (6PGD, G6PD, ME, ICDH, FAS and ACC) and lipolytic enzymes (CPTI, HSL), were analyzed. With the increase of Fe concentration, hepatic Fe content tended to increase but HSI and lipid content tended to decrease. On day 21, Fe exposure down-regulated the lipogenic activities of 6PGD, G6PD, ICDH and FAS as well as the mRNA levels of G6PD, ACCa, FAS, SREBP-1 and PPARγ, but up-regulated CPT I, HSLa and PPARα mRNA levels. On day 42, Fe exposure down-regulated the lipogenic activities of 6PGD, G6PD, ICDH and FAS as well as the mRNA levels of 6PGD, ACCa, FAS and SREBP-1, but up-regulated CPT I, HSLa, PPARα and PPARγ mRNA levels. Using primary S. hasta hepatocytes, specific pathway inhibitors (GW6471 for PPARα and fatostatin for SREBP-1) and activator (troglitazone for PPARγ) were used to explore the signaling pathways of Fe reducing lipid deposition. The GW6471 attenuated the Fe-induced down-regulation of mRNA levels of 6PGD, G6PD, ME, FAS and ACCa, and attenuated the Fe-induced up-regulation of mRNA levels of CPT I, HSLa and PPARα. Compared with single Fe-incubated group, the mRNA levels of G6PD, ME, FAS, ACCa, ACCb and PPARγ were up-regulated while the CPT I mRNA levels were down-regulated after troglitazone pre-treatment; fatostatin pre-treatment down-regulated the mRNA levels of 6PGD, ME, FAS, ACCa, ACCb and SREBP-1, and increased the CPT I and HSLa mRNA levels. Based on these results above, our study indicated that Fe exposure reduced hepatic lipid deposition by down-regulating lipogenesis and up-regulating lipolysis, and PPARα, PPARγ and SREBP-1 pathways mediated the Fe-induced reduction of hepatic lipid deposition in S. hasta.
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Affiliation(s)
- Guang-Hui Chen
- Hubei Provincial Engineering Laboratory for Pond Aquaculture, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Zhi Luo
- Hubei Provincial Engineering Laboratory for Pond Aquaculture, Fishery College, Huazhong Agricultural University, Wuhan 430070, China; Collaborative Innovation Center for Efficient and Health Production of Fisheries in Hunan Province, Changde 415000, China.
| | - Feng Chen
- Hubei Provincial Engineering Laboratory for Pond Aquaculture, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Xi Shi
- Hubei Provincial Engineering Laboratory for Pond Aquaculture, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Yu-Feng Song
- Hubei Provincial Engineering Laboratory for Pond Aquaculture, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Wen-Jing You
- Hubei Provincial Engineering Laboratory for Pond Aquaculture, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Xu Liu
- Postgraduate Research Base, Panjin Guanghe Fishery Co. Ltd., Panjin 124200, China
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Soliman AT, De Sanctis V, Yassin M, Soliman N. Iron deficiency anemia and glucose metabolism. ACTA BIO-MEDICA : ATENEI PARMENSIS 2017; 88:112-118. [PMID: 28467345 PMCID: PMC6166192 DOI: 10.23750/abm.v88i1.6049] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 12/19/2016] [Indexed: 12/20/2022]
Abstract
Iron deficiency anemia (IDA) is a global public health problem affecting both developing and developed countries with major consequences for human health as well as social and economic development. It occurs at all stages of the life cycle, but is more prevalent in pregnant women and young children. IDA appears to be more common in diabetic patients compared to non-diabetic population. Iron deficiency (ID) and IDA can impair glucose homeostasis in animals and human and may negatively affect glycemic control and predispose to more complications in diabetic patients. On the other hand diabetes and its complications are associated with anemia and its correction improves diabetes control and may prevent or delay the occurrence of complications. Physicians treating this form of anemia should be aware of its negative effect on glycemic control in normal and diabetic patients (both type 1 and type 2). They should prevent ID and treat early all those with IDA.This brief review aims to enlighten the different effects of IDA on glucose metabolism in normal and diabetic patients.
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Affiliation(s)
- Ashraf T Soliman
- Department of Pediatrics, Alexandria University Children Hospital, Elchatby, Alexandria, Egypt.
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25
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Zhuo Z, Fang S, Hu Q, Huang D, Feng J. Digital gene expression profiling analysis of duodenum transcriptomes in SD rats administered ferrous sulfate or ferrous glycine chelate by gavage. Sci Rep 2016; 6:37923. [PMID: 27901057 PMCID: PMC5128800 DOI: 10.1038/srep37923] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 11/02/2016] [Indexed: 12/31/2022] Open
Abstract
The absorption of different iron sources is a trending research topic. Many studies have revealed that organic iron exhibits better bioavailability than inorganic iron, but the concrete underlying mechanism is still unclear. In the present study, we examined the differences in bioavailability of ferrous sulfate and ferrous glycinate in the intestines of SD rats using Illumina sequencing technology. Digital gene expression analysis resulted in the generation of almost 128 million clean reads, with expression data for 17,089 unigenes. A total of 123 differentially expressed genes with a |log2(fold change)| >1 and q-value < 0.05 were identified between the FeSO4 and Fe-Gly groups. Gene Ontology functional analysis revealed that these genes were involved in oxidoreductase activity, iron ion binding, and heme binding. Kyoto Encyclopedia of Genes and Genomes pathway analysis also showed relevant important pathways. In addition, the expression patterns of 9 randomly selected genes were further validated by qRT-PCR, which confirmed the digital gene expression results. Our study showed that the two iron sources might share the same absorption mechanism, and that differences in bioavailability between FeSO4 and Fe-Gly were not only in the absorption process but also during the transport and utilization process.
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Affiliation(s)
- Zhao Zhuo
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Science, Zhejiang University, Hangzhou, 310058, P. R. China
| | - Shenglin Fang
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Science, Zhejiang University, Hangzhou, 310058, P. R. China
| | - Qiaoling Hu
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Science, Zhejiang University, Hangzhou, 310058, P. R. China
| | - Danping Huang
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Science, Zhejiang University, Hangzhou, 310058, P. R. China
| | - Jie Feng
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Science, Zhejiang University, Hangzhou, 310058, P. R. China
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26
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Hay SM, McArdle HJ, Hayes HE, Stevens VJ, Rees WD. The effect of iron deficiency on the temporal changes in the expression of genes associated with fat metabolism in the pregnant rat. Physiol Rep 2016; 4:4/21/e12908. [PMID: 27905292 PMCID: PMC5112487 DOI: 10.14814/phy2.12908] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 07/25/2016] [Accepted: 07/28/2016] [Indexed: 12/22/2022] Open
Abstract
Iron is essential for the oxidative metabolism of lipids. Lipid metabolism changes during gestation to meet the requirements of the growing fetus and to prepare for lactation. The temporal effects of iron deficiency during gestation were studied in female rats fed complete or iron‐deficient diets. Plasma triglycerides were elevated in the iron‐deficient group throughout gestation. There were time‐dependent changes in the triglyceride content of the maternal liver, falling at the midpoint of gestation and then increasing on d21.5. Compared to the control, triglycerides in the maternal liver were not different in the iron‐deficient group prior to pregnancy and on d12.5, but were markedly reduced by d21.5. The abundance of mRNAs in the maternal liver suggests that lipogenesis is unchanged and beta‐oxidation is reduced on d21.5 by iron deficiency. On d21.5 of gestation, the expression of placental lipase was unchanged by iron deficiency, however, the abundance of mRNAs for SREBP‐1c, FABP4 were reduced, suggesting that there were changes in fatty acid handling. In the fetal liver, iron deficiency produced a marked decrease in the abundance of the L‐CPT‐1 mRNA, suggesting that beta‐oxidation is reduced. This study shows that the major effect of iron deficiency on maternal lipid metabolism occurs late in gestation and that perturbed lipid metabolism may be a common feature of models of fetal programming.
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Affiliation(s)
- Susan M Hay
- The Rowett Institute of Nutrition and Health, University of Aberdeen, Foresterhill, Aberdeen, U.K
| | - Harry J McArdle
- The Rowett Institute of Nutrition and Health, University of Aberdeen, Foresterhill, Aberdeen, U.K
| | - Helen E Hayes
- The Rowett Institute of Nutrition and Health, University of Aberdeen, Foresterhill, Aberdeen, U.K
| | - Valerie J Stevens
- The Rowett Institute of Nutrition and Health, University of Aberdeen, Foresterhill, Aberdeen, U.K
| | - William D Rees
- The Rowett Institute of Nutrition and Health, University of Aberdeen, Foresterhill, Aberdeen, U.K.
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27
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Diniz WJDS, Coutinho LL, Tizioto PC, Cesar ASM, Gromboni CF, Nogueira ARA, de Oliveira PSN, de Souza MM, Regitano LCDA. Iron Content Affects Lipogenic Gene Expression in the Muscle of Nelore Beef Cattle. PLoS One 2016; 11:e0161160. [PMID: 27532424 PMCID: PMC4988672 DOI: 10.1371/journal.pone.0161160] [Citation(s) in RCA: 14] [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: 11/03/2015] [Accepted: 08/01/2016] [Indexed: 12/16/2022] Open
Abstract
Iron (Fe) is an essential mineral for metabolism and plays a central role in a range of biochemical processes. Therefore, this study aimed to identify differentially expressed (DE) genes and metabolic pathways in Longissimus dorsi (LD) muscle from cattle with divergent iron content, as well as to investigate the likely role of these DE genes in biological processes underlying beef quality parameters. Samples for RNA extraction for sequencing and iron, copper, manganese, and zinc determination were collected from LD muscles at slaughter. Eight Nelore steers, with extreme genomic estimated breeding values for iron content (Fe-GEBV), were selected from a reference population of 373 animals. From the 49 annotated DE genes (FDR<0.05) found between the two groups, 18 were up-regulated and 31 down-regulated for the animals in the low Fe-GEBV group. The functional enrichment analyses identified several biological processes, such as lipid transport and metabolism, and cell growth. Lipid metabolism was the main pathway observed in the analysis of metabolic and canonical signaling pathways for the genes identified as DE, including the genes FASN, FABP4, and THRSP, which are functional candidates for beef quality, suggesting reduced lipogenic activities with lower iron content. Our results indicate metabolic pathways that are partially influenced by iron, contributing to a better understanding of its participation in skeletal muscle physiology.
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Affiliation(s)
| | | | | | | | | | | | | | - Marcela Maria de Souza
- Department of Genetic and Evolution, Federal University of São Carlos, São Carlos, Brazil
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Meroño T, Dauteuille C, Tetzlaff W, Martín M, Botta E, Lhomme M, Saez MS, Sorroche P, Boero L, Arbelbide J, Chapman MJ, Kontush A, Brites F. Oxidative stress, HDL functionality and effects of intravenous iron administration in women with iron deficiency anemia. Clin Nutr 2016; 36:552-558. [PMID: 26926576 DOI: 10.1016/j.clnu.2016.02.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 01/28/2016] [Accepted: 02/05/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Iron deficiency anemia (IDA) affects around 20-30% of adults worldwide. An association between IDA and cardiovascular disease (CVD) has been reported. Oxidative stress, inflammation and low concentration of high-density lipoproteins (HDL) were implicated on endothelial dysfunction and CVD in IDA. We studied the effects of iron deficiency and of an intravenous iron administration on oxidative stress and HDL characteristics in IDA women. METHODS Two studies in IDA women are presented: a case-control study, including 18 patients and 18 age-matched healthy women, and a follow-up study 72hr after the administration of intravenous iron (n = 16). Lipids, malondialdehyde, cholesteryl ester transfer protein (CETP), paraoxonase-1 (PON-1) and HDL chemical composition and functionality (cholesterol efflux and antioxidative activity) were measured. Cell cholesterol efflux from iron-deficient macrophages to a reference HDL was also evaluated. RESULTS IDA patients showed higher triglycerides and CETP activity and lower HDL-C than controls (all p < 0.001). HDL particles from IDA patients showed higher triglyceride content (+30%,p < 0.05) and lower antioxidative capacity (-23%,p < 0.05). Although HDL-mediated cholesterol efflux was similar between the patients and controls, iron deficiency provoked a significant reduction in macrophage cholesterol efflux (-25%,p < 0.05). Arylesterase activity of PON-1 was significantly lower in IDA patients than controls (-16%,p < 0.05). The intravenous administration of iron was associated with a decrease in malondialdehyde levels and an increase in arylesterase activity of PON-1 (-22% and +18%, respectively, p < 0.05). CONCLUSION IDA is associated with oxidative stress and functionally deficient HDL particles. It remains to be determined if such alterations suffice to impair endothelial function in IDA.
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Affiliation(s)
- Tomás Meroño
- Laboratory of Lipids and Atherosclerosis, School of Pharmacy and Biochemistry, INFIBIOC, University of Buenos Aires, CONICET, Buenos Aires, Argentina.
| | - Carolane Dauteuille
- National Institute for Health and Medical Research (INSERM), UMR ICAN 1166, University of Pierre et Marie Curie - Paris 6, AP-HP, Groupe Hospitalier Pitié-Salpétrière, Paris, F-75013, France
| | - Walter Tetzlaff
- Laboratory of Lipids and Atherosclerosis, School of Pharmacy and Biochemistry, INFIBIOC, University of Buenos Aires, CONICET, Buenos Aires, Argentina
| | - Maximiliano Martín
- Laboratory of Lipids and Atherosclerosis, School of Pharmacy and Biochemistry, INFIBIOC, University of Buenos Aires, CONICET, Buenos Aires, Argentina
| | - Eliana Botta
- Laboratory of Lipids and Atherosclerosis, School of Pharmacy and Biochemistry, INFIBIOC, University of Buenos Aires, CONICET, Buenos Aires, Argentina
| | - Marie Lhomme
- National Institute for Health and Medical Research (INSERM), UMR ICAN 1166, University of Pierre et Marie Curie - Paris 6, AP-HP, Groupe Hospitalier Pitié-Salpétrière, Paris, F-75013, France
| | - María Soledad Saez
- Central Laboratory, Italian Hospital of Buenos Aires, Buenos Aires, Argentina
| | - Patricia Sorroche
- Central Laboratory, Italian Hospital of Buenos Aires, Buenos Aires, Argentina
| | - Laura Boero
- Laboratory of Lipids and Atherosclerosis, School of Pharmacy and Biochemistry, INFIBIOC, University of Buenos Aires, CONICET, Buenos Aires, Argentina
| | - Jorge Arbelbide
- Hematology Division, Italian Hospital of Buenos Aires, Buenos Aires, Argentina
| | - M John Chapman
- National Institute for Health and Medical Research (INSERM), UMR ICAN 1166, University of Pierre et Marie Curie - Paris 6, AP-HP, Groupe Hospitalier Pitié-Salpétrière, Paris, F-75013, France
| | - Anatol Kontush
- National Institute for Health and Medical Research (INSERM), UMR ICAN 1166, University of Pierre et Marie Curie - Paris 6, AP-HP, Groupe Hospitalier Pitié-Salpétrière, Paris, F-75013, France
| | - Fernando Brites
- Laboratory of Lipids and Atherosclerosis, School of Pharmacy and Biochemistry, INFIBIOC, University of Buenos Aires, CONICET, Buenos Aires, Argentina
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Lu S, Bennett RG, Kharbanda KK, Harrison-Findik DD. Lack of hepcidin expression attenuates steatosis and causes fibrosis in the liver. World J Hepatol 2016; 8:211-225. [PMID: 26855692 PMCID: PMC4733464 DOI: 10.4254/wjh.v8.i4.211] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Revised: 10/14/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of key iron-regulatory protein, hepcidin in non-alcoholic fatty liver disease (NAFLD).
METHODS: Hepcidin (Hamp1) knockout and floxed control mice were administered a high fat and high sucrose (HFS) or a regular control diet for 3 or 7 mo. Steatosis, triglycerides, fibrosis, protein and gene expression in mice livers were determined by histological and biochemical techniques, western blotting and real-time polymerase chain reaction.
RESULTS: Knockout mice exhibited hepatic iron accumulation. Despite similar weight gains, HFS feeding induced hepatomegaly in floxed, but not knockout, mice. The livers of floxed mice exhibited higher levels of steatosis, triglycerides and c-Jun N-terminal kinase (JNK) phosphorylation than knockout mice. In contrast, a significant increase in fibrosis was observed in knockout mice livers within 3 mo of HFS administration. The hepatic gene expression levels of sterol regulatory element-binding protein-1c and fat-specific protein-27, but not peroxisome proliferator-activated receptor-alpha or microsomal triglyceride transfer protein, were attenuated in HFS-fed knockout mice. Knockout mice fed with regular diet displayed increased carnitine palmitoyltransferase-1a and phosphoenolpyruvate carboxykinase-1 but decreased glucose-6-phosphatase expression in the liver. In summary, attenuated steatosis correlated with decreased expression of lipogenic and lipid storage genes, and JNK phosphorylation. Deletion of Hamp1 alleles per se modulated hepatic expression of beta-oxidation and gluconeogenic genes.
CONCLUSION: Lack of hepcidin expression inhibits hepatic lipid accumulation and induces early development of fibrosis following high fat intake. Hepcidin and iron may play a role in the regulation of metabolic pathways in the liver, which has implications for NAFLD pathogenesis.
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Guillemot J, Asselin MC, Susan-Resiga D, Essalmani R, Seidah NG. Deferoxamine stimulates LDLR expression and LDL uptake in HepG2 cells. Mol Nutr Food Res 2015; 60:600-8. [PMID: 26577249 DOI: 10.1002/mnfr.201500467] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 10/02/2015] [Accepted: 10/26/2015] [Indexed: 12/13/2022]
Abstract
SCOPE Iron overload contributes to the pathogenesis of atherosclerosis and iron chelators are beneficial through their antioxidant properties. Hepatic iron loading increases cholesterol synthesis. Whether iron depletion could affect hepatic cholesterol metabolism is unknown. METHODS AND RESULTS We examined the effect of the iron chelator deferoxamine (DFO) on mRNA expression of genes involved in cholesterol metabolism and/or cholesterol uptake. Our results revealed that DFO increases LDL receptor (LDLR) mRNA levels in human hepatocyte-derived cell lines HepG2 and Huh7 cells, and in K562 cells. In HepG2 cells, we observed that DFO increases (i) LDLR-mRNA levels in a time- and dose-dependent manner, (ii) LDLR-protein levels; (iii) cell surface LDLR; and (iv) LDL uptake. In contrast, the mRNA levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, sterol regulatory element-binding proteins, and the mRNA/protein levels of proprotein convertase subtilisin-kexin 9 were not modulated by DFO, suggesting that the LDLR regulation by DFO is not at the transcriptional or posttranslational levels. Since LDLR-mRNA was stabilized by DFO, a posttranscriptional mechanism is suggested for the DFO-mediated upregulation of LDLR. CONCLUSION DFO induced an increase in LDLR expression by a posttranscriptional mechanism resulting in an enhancement of LDL uptake in HepG2 cells, suggesting increased LDLR activity as one of the underlying causes of the hypocholesterolemic effect of iron reduction.
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Affiliation(s)
- Johann Guillemot
- Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal (IRCM), University of Montreal, Montreal, Quebec, Canada
| | - Marie-Claude Asselin
- Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal (IRCM), University of Montreal, Montreal, Quebec, Canada
| | - Delia Susan-Resiga
- Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal (IRCM), University of Montreal, Montreal, Quebec, Canada
| | - Rachid Essalmani
- Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal (IRCM), University of Montreal, Montreal, Quebec, Canada
| | - Nabil G Seidah
- Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal (IRCM), University of Montreal, Montreal, Quebec, Canada
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Fernández-Real JM, McClain D, Manco M. Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes. Diabetes Care 2015; 38:2169-76. [PMID: 26494808 DOI: 10.2337/dc14-3082] [Citation(s) in RCA: 153] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The bidirectional relationship between iron metabolism and glucose homeostasis is increasingly recognized. Several pathways of iron metabolism are modified according to systemic glucose levels, whereas insulin action and secretion are influenced by changes in relative iron excess. We aimed to update the possible influence of iron on insulin action and secretion and vice versa. RESEARCH DESIGN AND METHODS The mechanisms that link iron metabolism and glucose homeostasis in the main insulin-sensitive tissues and insulin-producing β-cells were revised according to their possible influence on the development of type 2 diabetes (T2D). RESULTS The mechanisms leading to dysmetabolic hyperferritinemia and hepatic overload syndrome were diverse, including diet-induced alterations in iron absorption, modulation of gluconeogenesis, heme-mediated disruption of circadian glucose rhythm, impaired hepcidin secretion and action, and reduced copper availability. Glucose metabolism in adipose tissue seems to be affected by both iron deficiency and excess through interaction with adipocyte differentiation, tissue hyperplasia and hypertrophy, release of adipokines, lipid synthesis, and lipolysis. Reduced heme synthesis and dysregulated iron uptake or export could also be contributing factors affecting glucose metabolism in the senescent muscle, whereas exercise is known to affect iron and glucose status. Finally, iron also seems to modulate β-cells and insulin secretion, although this has been scarcely studied. CONCLUSIONS Iron is increasingly recognized to influence glucose metabolism at multiple levels. Body iron stores should be considered as a potential target for therapy in subjects with T2D or those at risk for developing T2D. Further research is warranted.
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Affiliation(s)
- José Manuel Fernández-Real
- University Hospital of Girona "DrJosepTrueta," Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), Girona, Spain CIBER Fisiopatología de la Obesidad y Nutrición, Girona, Spain
| | - Donald McClain
- Departments of Biochemistry and Internal Medicine, University of Utah, Salt Lake City, UT Veterans Administration Research Service, Salt Lake City VAHCS, Salt Lake City, UT
| | - Melania Manco
- Bambino Gesù Children's Hospital and Research Institute, Research Unit for Multifactorial Disease, Rome, Italy
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Remacha AF, Wright I, Fernández-Jiménez MC, Toxqui L, Blanco-Rojo R, Moreno G, Vaquero MP. Vitamin B12 and folate levels increase during treatment of iron deficiency anaemia in young adult woman. Int J Lab Hematol 2015; 37:641-8. [DOI: 10.1111/ijlh.12378] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Accepted: 03/30/2015] [Indexed: 12/24/2022]
Affiliation(s)
- A. F. Remacha
- Hematology Laboratory Department; Hospital Sant Pau; Barcelona Spain
| | - I. Wright
- Institute of Food Science Technology and Nutricion (ICTAN); CSIC; Madrid Spain
| | | | - L. Toxqui
- Institute of Food Science Technology and Nutricion (ICTAN); CSIC; Madrid Spain
| | - R. Blanco-Rojo
- Institute of Food Science Technology and Nutricion (ICTAN); CSIC; Madrid Spain
| | - G. Moreno
- Hematology Department; Hospital Ramón y Cajal; Madrid Spain
| | - M. P. Vaquero
- Institute of Food Science Technology and Nutricion (ICTAN); CSIC; Madrid Spain
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Aigner E, Weiss G, Datz C. Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver. World J Hepatol 2015; 7:177-188. [PMID: 25729473 PMCID: PMC4342600 DOI: 10.4254/wjh.v7.i2.177] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 12/12/2014] [Accepted: 12/31/2014] [Indexed: 02/06/2023] Open
Abstract
Elevated iron stores as indicated by hyperferritinemia with normal or mildly elevated transferrin saturation and mostly mild hepatic iron deposition are a characteristic finding in subjects with non-alcoholic fatty liver disease (NAFLD). Excess iron is observed in approximately one third of NAFLD patients and is commonly referred to as the “dysmetabolic iron overload syndrome”. Clinical evidence suggests that elevated body iron stores aggravate the clinical course of NAFLD with regard to liver-related and extrahepatic disease complications which relates to the fact that excess iron catalyses the formation of toxic hydroxyl-radicals subsequently resulting in cellular damage. Iron removal improves insulin sensitivity, delays the onset of type 2 diabetes mellitus, improves pathologic liver function tests and likewise ameliorates NAFLD histology. Several mechanisms contribute to pathologic iron accumulation in NAFLD. These include impaired iron export from hepatocytes and mesenchymal Kupffer cells as a consequence of imbalances in the concentrations of iron regulatory factors, such as hepcidin, cytokines, copper or other dietary factors. This review summarizes the knowledge about iron homeostasis in NAFLD and the rationale for its therapeutic implications.
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Chakrabarti M, Cockrell AL, Park J, McCormick SP, Lindahl LS, Lindahl PA. Speciation of iron in mouse liver during development, iron deficiency, IRP2 deletion and inflammatory hepatitis. Metallomics 2014; 7:93-101. [PMID: 25325718 DOI: 10.1039/c4mt00215f] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The iron content of livers from (57)Fe-enriched C57BL/6 mice of different ages were investigated using Mössbauer spectroscopy, electron paramagnetic resonance (EPR), electronic absorption spectroscopy and inductively coupled plasma mass spectrometry (ICP-MS). About 80% of the Fe in an adult liver was due to blood; thus removal of blood by flushing with buffer was essential to observe endogenous liver Fe. Even after exhaustive flushing, ca. 20% of the Fe in anaerobically dissected livers was typical of deoxy-hemoglobin. The concentration of Fe in newborn livers was the highest of any developmental stage (∼1.2 mM). Most was stored as ferritin, with little mitochondrial Fe (consisting primarily of Fe-S clusters and haems) evident. Within the first few weeks of life, about half of ferritin Fe was mobilized and exported, illustrating the importance of Fe release as well as Fe storage in liver function. Additional ferritin Fe was used to generate mitochondrial Fe centres. From ca. 4 weeks of age to the end of the mouse's natural lifespan, the concentration of mitochondrial Fe in liver was essentially invariant. A minor contribution from nonhaem high-spin Fe(II) was observed in most liver samples and was also invariant with age. Some portion of these species may constitute the labile iron pool. Livers from mice raised on an Fe-deficient diet were highly Fe depleted; they were devoid of ferritin and contained 1/3 as much mitochondrial Fe as found in Fe-sufficient livers. In contrast, brains of the same Fe-deficient mice retained normal levels of mitochondrial Fe. Livers from mice with inflammatory hepatitis and from IRP2(-/-) mice hyper-accumulated Fe. These livers had high ferritin levels but low levels of mitochondrial Fe.
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Affiliation(s)
- Mrinmoy Chakrabarti
- Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
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Kim J, Jia X, Buckett PD, Liu S, Lee CH, Wessling-Resnick M. Iron loading impairs lipoprotein lipase activity and promotes hypertriglyceridemia. FASEB J 2012; 27:1657-63. [PMID: 23241313 DOI: 10.1096/fj.12-224386] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Iron loading is associated with altered lipid metabolism, but underlying mechanisms remain unknown. We compared serum iron and triglycerides (TGs) in Belgrade rats, a genetic model of iron-loading anemia. Homozygous b/b rats had greater serum iron (68 vs. 28 μM; P=0.0004) and TG levels (180 vs. 84 mg/dl; P=0.014) compared to +/b controls. To confirm the association between iron loading and high TGs, Fischer rats were fed chow containing 1% carbonyl iron. Compared to controls pair-fed normal chow, carbonyl iron-fed rats had elevated serum iron (42 vs. 21 μM; P=0.007) and TGs (190 vs. 115 mg/dl; P=0.009). Despite normal hepatic production and secretion, TG clearance was lower in b/b than +/b rats due to reduced serum lipoprotein lipase (LPL) activity (3.1 vs. 5.0 mM/min; P=0.026). Likewise, LPL was lower in carbonyl iron-fed rats compared to controls (2.4 vs. 3.7 mM/min; P=0.017). Direct addition of iron to serum ex vivo or recombinant LPL in vitro decreased enzymatic activity in a dose-dependent manner. Lowering serum iron in Belgrade rats reduced TG levels (274 to 67 mg/dl, P=0.001). This study explains the relationship between iron status and lipid metabolism and provides mechanistic support for interventions that reduce serum iron levels in individuals at risk for hypertriglyceridemia.
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Affiliation(s)
- Jonghan Kim
- Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA
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Davis MR, Hester KK, Shawron KM, Lucas EA, Smith BJ, Clarke SL. Comparisons of the iron deficient metabolic response in rats fed either an AIN-76 or AIN-93 based diet. Nutr Metab (Lond) 2012; 9:95. [PMID: 23110872 PMCID: PMC3538620 DOI: 10.1186/1743-7075-9-95] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2012] [Accepted: 10/25/2012] [Indexed: 12/31/2022] Open
Abstract
Background Previous studies examining the metabolic consequences of dietary iron deficiency have reported elevated serum glucose concentrations in iron-deficient animals. Importantly, the majority of these findings were observed using an earlier version of a laboratory animal diet (AIN-76A) in which the primary carbohydrate source was sucrose – a disaccharide known to negatively impact both glucose and lipid homeostasis. The AIN-76A diet formula was improved in 1993 (AIN-93) to optimize animal nutrition with a major change being the substitution of cornstarch for sucrose. Therefore, we sought to examine the effects of iron deficiency on steady-state glucose homeostasis and the hepatic expression of glucose- and lipid-related genes in rats fed an iron-deficient diet based on either an AIN-76A or AIN-93 diet. Methods The study design consisted of 6 treatment groups: control (C; 40 mg Fe/kg diet), iron deficient (ID; ≤ 3 mg Fe/kg diet), or pair-fed (PF; 40 mg Fe/kg) fed either an AIN-76A or AIN-93 diet for 21 d. Hemoglobin and hematocrit were measured in whole blood. Serum insulin and cortisol were measure by ELISA. Serum glucose and triacylglycerols were measured by standard colorimetric enzyme assays. Alterations in hepatic gene expression were determined by real-time qPCR. Results Hemoglobin and hematocrit were significantly reduced in both ID groups compared to the C and PF groups. Similarly, animals in the both ID groups exhibited elevated steady-state levels of blood glucose and insulin, and significantly decreased levels of circulating cortisol compared to their respective PF controls. Serum triacyglycerols were only increased in ID animals consuming the AIN-76A diet. Hepatic gene expression analyses revealed a ~4- and 3-fold increase in the expression of glucokinase and pyruvate dehydrogenase kinase-4 mRNA, respectively, in the ID group on either diet compared to their respective PF counterparts. In contrast, the expression of lipogenic genes was significantly elevated in the AIN-76 ID group, while expression of these genes was unaffected by iron status in the AIN-93 ID group. Conclusions These results indicate that an impaired iron status is sufficient to alter glucose homeostasis, though alterations in lipid metabolism associated with ID are only observed in animals receiving the AIN-76A diet.
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Affiliation(s)
- McKale R Davis
- Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
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Ahmed U, Latham PS, Oates PS. Interactions between hepatic iron and lipid metabolism with possible relevance to steatohepatitis. World J Gastroenterol 2012; 18:4651-8. [PMID: 23002334 PMCID: PMC3442203 DOI: 10.3748/wjg.v18.i34.4651] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Revised: 03/27/2012] [Accepted: 03/29/2012] [Indexed: 02/06/2023] Open
Abstract
The liver is an important site for iron and lipid metabolism and the main site for the interactions between these two metabolic pathways. Although conflicting results have been obtained, most studies support the hypothesis that iron plays a role in hepatic lipogenesis. Iron is an integral part of some enzymes and transporters involved in lipid metabolism and, as such, may exert a direct effect on hepatic lipid load, intrahepatic metabolic pathways and hepatic lipid secretion. On the other hand, iron in its ferrous form may indirectly affect lipid metabolism through its ability to induce oxidative stress and inflammation, a hypothesis which is currently the focus of much research in the field of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). The present review will first discuss how iron might directly interact with the metabolism of hepatic lipids and then consider a new perspective on the way in which iron may have a role in the two hit hypothesis for the progression of NAFLD via ferroportin and the iron regulatory molecule hepcidin. The review concludes that iron has important interactions with lipid metabolism in the liver that can impact on the development of NAFLD/NASH. More defined studies are required to improve our understanding of these effects.
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