Journal articles: 'Dietary iron overload'

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Kincaid, Anne L., and Michael K. Stoskopf. "Passerine dietary iron overload syndrome." Zoo Biology 6, no. 1 (1987): 79–88. http://dx.doi.org/10.1002/zoo.1430060109.

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Omara, Felix O., Barry R. Blakley, and Lusimbo S. Wanjala. "Hepatotoxicity Associated with Dietary Iron Overload in Mice." Human & Experimental Toxicology 12, no. 6 (November 1993): 463–67. http://dx.doi.org/10.1177/096032719301200603.

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1 Weanling male CD-1 mice were fed 120 (control), 5000 and 8000 mg of iron kg-1 for seven weeks. The haematocrit ( P=0.265), water consumption ( P=0.170) and percentage body weight ratios of kidney, spleen and heart were not affected by iron supplementation. 2 Iron supplementation reduced weight gain ( P=0.023), increased weight of liver ( P=0.0001), the iron deposition index and concentration of iron in the liver ( P<0.01). A strong correlation between liver iron concentration and level of iron in the diet ( r=0.989) was observed. Histologically, the deposition of iron was restricted to the hepatocytes, Kupffer cells and splenic macrophages. 3 Consumption of 5000 and 8000 mg of iron kg-1 resulted in hepatic damage, as judged by elevated serum alkaline phosphatase and alanine aminotransferase activities ( P<0.05). 4 This study indicates that prolonged feeding of excess dietary iron has the potential to cause hepatic accumulation of iron with resultant liver toxicity, and that mice may be a suitable model to study the mechanisms of dietary iron overload.

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Sobotka, T. J., P. Whittaker, J. M. Sobotka, R. E. Brodie, D. Y. Wander, M. Robl, M. Bryant, and C. N. Barton. "Neurobehavioral dysfunctions associated with dietary iron overload." Physiology & Behavior 59, no. 2 (February 1996): 213–19. http://dx.doi.org/10.1016/0031-9384(95)02030-6.

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Mori, Mutsuki, Takeshi Izawa, Yohei Inai, Sho Fujiwara, Ryo Aikawa, Mitsuru Kuwamura, and Jyoji Yamate. "Dietary Iron Overload Differentially Modulates Chemically-Induced Liver Injury in Rats." Nutrients 12, no. 9 (September 11, 2020): 2784. http://dx.doi.org/10.3390/nu12092784.

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Hepatic iron overload is well known as an important risk factor for progression of liver diseases; however, it is unknown whether it can alter the susceptibility to drug-induced hepatotoxicity. Here we investigate the pathological roles of iron overload in two single-dose models of chemically-induced liver injury. Rats were fed a high-iron (Fe) or standard diet (Cont) for four weeks and were then administered with allyl alcohol (AA) or carbon tetrachloride (CCl4). Twenty-four hours after administration mild mononuclear cell infiltration was seen in the periportal/portal area (Zone 1) in Cont-AA group, whereas extensive hepatocellular necrosis was seen in Fe-AA group. Centrilobular (Zone 3) hepatocellular necrosis was prominent in Cont-CCl4 group, which was attenuated in Fe-CCl4 group. Hepatic lipid peroxidation and hepatocellular DNA damage increased in Fe-AA group compared with Cont-AA group. Hepatic caspase-3 cleavage increased in Cont-CCl4 group, which was suppressed in Fe-CCl4 group. Our results showed that dietary iron overload exacerbates AA-induced Zone-1 liver injury via enhanced oxidative stress while it attenuates CCl4-induced Zone-3 liver injury, partly via the suppression of apoptosis pathway. This study suggested that susceptibility to drugs or chemical compounds can be differentially altered in iron-overloaded livers.

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Lesjak, Marija, and Surjit K. S. Srai. "Role of Dietary Flavonoids in Iron Homeostasis." Pharmaceuticals 12, no. 3 (August 8, 2019): 119. http://dx.doi.org/10.3390/ph12030119.

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Balancing systemic iron levels within narrow limits is critical for human health, as both iron deficiency and overload lead to serious disorders. There are no known physiologically controlled pathways to eliminate iron from the body and therefore iron homeostasis is maintained by modifying dietary iron absorption. Several dietary factors, such as flavonoids, are known to greatly affect iron absorption. Recent evidence suggests that flavonoids can affect iron status by regulating expression and activity of proteins involved the systemic regulation of iron metabolism and iron absorption. We provide an overview of the links between different dietary flavonoids and iron homeostasis together with the mechanism of flavonoids effect on iron metabolism. In addition, we also discuss the clinical relevance of state-of-the-art knowledge regarding therapeutic potential that flavonoids may have for conditions that are low in iron such as anaemia or iron overload diseases.

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Asare, George A., Michael C. Kew, Kensese S. Mossanda, Alan C. Paterson, Kwanele Siziba, and Christiana P. Kahler-Venter. "Effects of Exogenous Antioxidants on Dietary Iron Overload." Journal of Clinical Biochemistry and Nutrition 44, no. 1 (2009): 85–94. http://dx.doi.org/10.3164/jcbn.08-184.

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Whittaker, Paul, Virginia C. Dunkel, Thomas J. Bucci, Donna F. Kusewitt, J. Dale Thurman, Alan Warbritton, and George L. Wolff. "Genome-Linked Toxic Responses to Dietary Iron Overload." Toxicologic Pathology 25, no. 6 (November 1997): 556–64. http://dx.doi.org/10.1177/019262339702500604.

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McNamara, Lynette, Vanessa R. Panz, Frederick J. Raal, Janice Paiker, Barry I. Joffe, Victor R. Gordeuk, and A. Patrick MacPhail. "Basal Endocrine Status in African Dietary Iron Overload." Endocrine 21, no. 3 (2003): 241–44. http://dx.doi.org/10.1385/endo:21:3:241.

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Volani, Chiara, Giuseppe Paglia, Sigurdur Smarason, Peter Pramstaller, Egon Demetz, Christa Pfeifhofer-Obermair, and Guenter Weiss. "Metabolic Signature of Dietary Iron Overload in a Mouse Model." Cells 7, no. 12 (December 11, 2018): 264. http://dx.doi.org/10.3390/cells7120264.

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Iron is an essential co-factor for several metabolic processes, including the Krebs cycle and mitochondrial oxidative phosphorylation. Therefore, maintaining an appropriate iron balance is essential to ensure sufficient energy production and to avoid excessive reactive oxygen species formation. Iron overload impairs mitochondrial fitness; however, little is known about the associated metabolic changes. Here we aimed to characterize the metabolic signature triggered by dietary iron overload over time in a mouse model, where mice received either a standard or a high-iron diet. Metabolic profiling was assessed in blood, plasma and liver tissue. Peripheral blood was collected by means of volumetric absorptive microsampling (VAMS). Extracted blood and tissue metabolites were analyzed by liquid chromatography combined to high resolution mass spectrometry. Upon dietary iron loading we found increased glucose, aspartic acid and 2-/3-hydroxybutyric acid levels but low lactate and malate levels in peripheral blood and plasma, pointing to a re-programming of glucose homeostasis and the Krebs cycle. Further, iron loading resulted in the stimulation of the urea cycle in the liver. In addition, oxidative stress was enhanced in circulation and coincided with increased liver glutathione and systemic cysteine synthesis. Overall, iron supplementation affected several central metabolic circuits over time. Hence, in vivo investigation of metabolic signatures represents a novel and useful tool for getting deeper insights into iron-dependent regulatory circuits and for monitoring of patients with primary and secondary iron overload, and those ones receiving iron supplementation therapy.

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Fischer, Christine, Chiara Volani, Timea Komlódi, Markus Seifert, Egon Demetz, Lara Valente de Souza, Kristina Auer, et al. "Dietary Iron Overload and Hfe−/− Related Hemochromatosis Alter Hepatic Mitochondrial Function." Antioxidants 10, no. 11 (November 16, 2021): 1818. http://dx.doi.org/10.3390/antiox10111818.

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Iron is an essential co-factor for many cellular metabolic processes, and mitochondria are main sites of utilization. Iron accumulation promotes production of reactive oxygen species (ROS) via the catalytic activity of iron species. Herein, we investigated the consequences of dietary and genetic iron overload on mitochondrial function. C57BL/6N wildtype and Hfe−/− mice, the latter a genetic hemochromatosis model, received either normal diet (ND) or high iron diet (HI) for two weeks. Liver mitochondrial respiration was measured using high-resolution respirometry along with analysis of expression of specific proteins and ROS production. HI promoted tissue iron accumulation and slightly affected mitochondrial function in wildtype mice. Hepatic mitochondrial function was impaired in Hfe−/− mice on ND and HI. Compared to wildtype mice, Hfe−/− mice on ND showed increased mitochondrial respiratory capacity. Hfe−/− mice on HI showed very high liver iron levels, decreased mitochondrial respiratory capacity and increased ROS production associated with reduced mitochondrial aconitase activity. Although Hfe−/− resulted in increased mitochondrial iron loading, the concentration of metabolically reactive cytoplasmic iron and mitochondrial density remained unchanged. Our data show multiple effects of dietary and genetic iron loading on mitochondrial function and linked metabolic pathways, providing an explanation for fatigue in iron-overloaded hemochromatosis patients, and suggests iron reduction therapy for improvement of mitochondrial function.

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Cheng, Aaron, Luke Schissler, Bonnie Patchen, Vera Gaun, Manoj Bhasin, Chris D. Vulpe, and Paula G. Fraenkel. "Identification of Differentially Expressed Genes in Mice with Nutritional or Genetic Causes of Iron Overload." Blood 124, no. 21 (December 6, 2014): 2681. http://dx.doi.org/10.1182/blood.v124.21.2681.2681.

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Abstract Iron overload causes the generation of reactive oxygen species, which can lead to lasting organ damage, particularly to the liver. In patients with hereditary hemochromatosis, transfusion-dependent anemias, and hemoglobinopathies, iron overload is a major cause of mortality. A deeper understanding of iron regulation and the biological pathways involved in maintaining homeostasis may reveal new therapeutic targets for patients with iron overload disorders. We designed this study to discover genes that are differentially expressed in nutritional and genetic models of iron overload. For the nutritional iron overload study, 5-week old male C57BL/6 mice were placed on a soy-free diet (AIN-93G) containing different amounts of iron per kilogram of food: iron-deficient (2.5 mg/kg, n=3), iron-sufficient (37.5 mg/kg, n=3), and iron-excess (750 mg/kg, n=3). In the second study, 5-week old male C57BL/6 mice that were either wild type or HJV knockout mice that exhibited severe early onset iron overload secondary to homozygous deficiency of the bone morphogenic protein coreceptor, hemojuvelin (HJV), were maintained on the iron-deficient (2.5 mg/kg iron) diet (n=2 per group). For both studies animals were sacrificed after 50 days and liver RNA was extracted and sequenced at 40-50 million reads per sample. The RNA integrity number (RIN) for each sample was >6 and assessments of read duplication, base call frequency, and read quality indicated excellent quality of the data. For the HJV knockout mice, we used a false discovery rate <0.05 and a mean-fold change >2, to reveal genes that were differentially expressed compared to wild type mice. For the dietary iron study, genes were grouped by self-organizing maps to identify transcripts whose level of expression trended with increased or decreased dietary iron intake. The resulting analysis identified 148 genes in nutritionally iron-overloaded mice and 688 genes in HJV knockout mice that exhibited significant changes in expression. Of these, 28 genes were differentially regulated in both nutritionally iron overloaded and HJV knockout mice, including expected genes, such as transferrin receptor, HAMP (hepcidin), and bone morphogenic protein 6, and unexpected genes such as cytochrome P450 17a1 (cyp17a1), an enzyme that catalyzes critical steps in steroid synthesis, and nicotinomide N-methyltransferase (nnmt), an enzyme that regulates drug metabolism and DNA methylation. We clustered the 688 differentially expressed genes from the HJV knockout mice into functional pathways using the Functional Analysis tool from DAVID Bioinformatics Resources 6.7 (NIAID). Clusters were considered significant if there were >2 genes in the pathway and the Benjamini-Hochberg P-value was <0.05. We found that the expression of genes involved with PPAR signaling (P=0.0086) was decreased, while expression of transcripts involved with Huntington’s disease (P=0.038) was increased in HJV knockout mice compared to wild-type mice. Our RNA sequencing analysis identified a variety of novel pathways that were differentially regulated in dietary and genetic models of iron overload. Further studies are underway to characterize the potential roles of these genes in iron homeostasis. Disclosures No relevant conflicts of interest to declare.

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Gangaidzo, I. T., V. M. Moyo, T. Saungweme, H. Khumalo, R. M. Charakupa, Z. A. R. Gomo, M. Loyevsky, et al. "Iron overload in urban Africans in the 1990s." Gut 45, no. 2 (August 1, 1999): 278–83. http://dx.doi.org/10.1136/gut.45.2.278.

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BACKGROUNDIn a previously described model, heterozygotes for an African iron loading locus develop iron overload only when dietary iron is high, but homozygotes may do so with normal dietary iron. If an iron loading gene is common, then homozygotes with iron overload will be found even in an urban population where traditional beer, the source of iron, is uncommon.AIMSTo determine whether iron overload and the C282Y mutation characteristic of hereditary haemochromatosis are readily identifiable in an urban African population.METHODSHistological assessment, hepatocellular iron grading, and dry weight non-haem iron concentration were determined in post mortem tissue from liver, spleen, heart, lungs, and skin. DNA of subjects with elevated hepatic iron indexes was analysed for the C282Y mutation. Iron concentrations in other tissues were compared.RESULTSA moderate increase (>30 μmol/g) in hepatic iron concentrations was found in 31 subjects (23%; 95% confidence interval 15.9 to 30.1%), and they were considerably elevated (>180 μmol/g) in seven subjects (5.2%; 95% confidence interval 1.5 to 8.9%). Appreciably elevated hepatic iron concentrations were associated with heavy iron deposition in both hepatocytes and macrophages, and either portal fibrosis or cirrhosis. All were negative for the C282Y mutation. Very high concentrations were uncommon in subjects dying in hospital. Concentrations of iron in spleen, heart, lung, and skin were significantly higher in subjects with elevated hepatic iron.CONCLUSIONSIron overload is readily identified among urban Africans and is associated with hepatic damage and iron loading of several tissues. The condition is unrelated to the genetic mutation found in hereditary haemochromatosis.

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Atarashi, Machi, Takeshi Izawa, Mutsuki Mori, Yohei Inai, Mitsuru Kuwamura, and Jyoji Yamate. "Dietary Iron Overload Abrogates Chemically-Induced Liver Cirrhosis in Rats." Nutrients 10, no. 10 (October 2, 2018): 1400. http://dx.doi.org/10.3390/nu10101400.

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Chronic liver disease is an intractable disease, which can progress to cirrhosis and hepatocellular carcinoma. Hepatic iron overload is considered to be involved in the progression of chronic liver diseases; however, the mechanism remains to be elucidated. Here we investigate the role of dietary iron overload using chemically-induced liver cirrhosis model. Rats were fed a high-iron or standard diet and were injected intraperitoneally with thioacetamide (TAA) or saline twice a week for 20 weeks. Rats with TAA treatment (TAA group) had progressive liver cirrhosis characterized by persistent hepatocellular injury, mononuclear cell inflammation and bridging fibrosis; these lesions were markedly reduced in rats with iron feeding and TAA treatment (Fe-TAA group). Rats with iron feeding alone (Fe group) had no evidence of liver injury. Hepatic expression of cleaved caspase-3, but not phospho-RIP3, was decreased in Fe-TAA group compared with that in TAA group. The number of TUNEL-positive (terminal deoxynucleotidyl transferase dUTP nick end labeling) apoptotic hepatocytes was lower in the Fe-TAA group than in the TAA group. Hepatic xenobiotic metabolism and lipid peroxidation were shown to be less related to the abrogation of liver cirrhosis. Our results suggested that dietary hepatic iron overload abrogates chemically-induced liver cirrhosis in rats, which could partly involve decreased hepatocellular apoptosis.

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Moyo, Victor M., Innocent T. Gangaidzo, Z. A. R. Gomo, Hlosukwazi Khumalo, Thokozile Saungweme, C. F. Kiire, Tracey Rouault, and Victor R. Gordeuk. "Traditional Beer Consumption and the Iron Status of Spouse Pairs From a Rural Community in Zimbabwe." Blood 89, no. 6 (March 15, 1997): 2159–66. http://dx.doi.org/10.1182/blood.v89.6.2159.

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Abstract To examine the relationship between dietary iron exposure through the consumption of traditional beer and the presence of iron overload in black Africans not related by birth, we studied 28 husband and wife pairs from a rural Zimbabwean community. Lifetime traditional beer consumption was estimated by questioning subjects and iron status was assessed by repeated measurements of serum ferritin and transferrin saturation in subjects who were fasting and had received vitamin C supplementation. Each of the 56 study subjects had an estimated lifetime traditional beer consumption <1,000 L. The mean ± standard deviation (SD) concentration of iron in the supernatants of nine samples of traditional beer from the community was 46 ± 10 mg/L. Four of 28 men (14.3%) and no women had the combination of an elevated serum ferritin and a transferrin saturation <70%, suggestive of substantial iron overload. Significant correlations were not found between the iron status of the husbands and their wives or between dietary iron exposure and iron stores. Our findings suggest that dietary iron exposure may not fully explain the development of iron overload in Africans and are consistent with the hypothesis that an iron-loading gene may also be implicated in pathogenesis.

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Cairo, G., L. Tacchini, L. Schiaffonati, E. Rappocciolo, E. Ventura, and A. Pietrangelo. "Translational regulation of ferritin synthesis in rat liver. Effects of chronic dietary iron overload." Biochemical Journal 264, no. 3 (December 15, 1989): 925–28. http://dx.doi.org/10.1042/bj2640925.

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In rats with chronic dietary iron overload, a higher amount of liver ferritin L-subunit mRNA was found mainly engaged on polysomes, whereas in control rats ferritin L-subunit mRNA molecules were largely stored in ribonucleoprotein particles. On the other hand, ferritin H-subunit mRNA was unchanged by chronic iron load and remained in the inactive cytoplasmic pool. In agreement with previous reports, in rats acutely treated with parenteral iron, only the ferritin L-subunit mRNA increased in amount, whereas both ferritin subunit mRNAs shifted to polysomes. This may indicate that, whereas in acute iron overload the hepatocyte operates a translation shift of both ferritin mRNAs to confront rapidly the abrupt entry of iron into the cell, during chronic iron overload it responds to the slow iron influx by translating a greater amount of L-subunit mRNA to synthesize isoferritins more suitable for long-term iron storage.

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Kew, Michael C., and George A. Asare. "Dietary iron overload in the African and hepatocellular carcinoma." Liver International 27, no. 6 (August 2007): 735–41. http://dx.doi.org/10.1111/j.1478-3231.2007.01515.x.

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Gordeuk, VictorR, R. Devee Boyd, and GaryM Brittenham. "DIETARY IRON OVERLOAD PERSISTS IN RURAL SUB-SAHARAN AFRICA." Lancet 327, no. 8493 (June 1986): 1310–13. http://dx.doi.org/10.1016/s0140-6736(86)91230-4.

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Dongiovanni, Paola, Massimiliano Ruscica, Raffaela Rametta, Stefania Recalcati, Liliana Steffani, Stefano Gatti, Domenico Girelli, et al. "Dietary Iron Overload Induces Visceral Adipose Tissue Insulin Resistance." American Journal of Pathology 182, no. 6 (June 2013): 2254–63. http://dx.doi.org/10.1016/j.ajpath.2013.02.019.

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Volani, Chiara, Carolina Doerrier, Egon Demetz, David Haschka, Giuseppe Paglia, Alexandros A. Lavdas, Erich Gnaiger, and Guenter Weiss. "Dietary iron loading negatively affects liver mitochondrial function." Metallomics 9, no. 11 (2017): 1634–44. http://dx.doi.org/10.1039/c7mt00177k.

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Mcnamara, Lynne, A. Macphail, Eberhard Mandishona, Peter Bloom, Alan Paterson, Tracey Rouault, and Victor Gordeuk. "Non-transferrin-bound iron and hepatic dysfunction in African dietary iron overload." Journal of Gastroenterology and Hepatology 14, no. 2 (February 28, 2002): 126–32. http://dx.doi.org/10.1046/j.1440-1746.1999.01830.x.

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Kimura, Mieko, and Katsuhiko Yokoi. "Iron accumulation in tissues of magnesium-deficient rats with dietary iron overload." Biological Trace Element Research 51, no. 2 (February 1996): 177–97. http://dx.doi.org/10.1007/bf02785437.

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Saad, Hanan Kamel M., Alawiyah Awang Abd Rahman, Azly Sumanty Ab Ghani, Wan Rohani Wan Taib, Imilia Ismail, Muhammad Farid Johan, Abdullah Saleh Al-Wajeeh, and Hamid Ali Nagi Al-Jamal. "Activation of STAT and SMAD Signaling Induces Hepcidin Re-Expression as a Therapeutic Target for β-Thalassemia Patients." Biomedicines 10, no. 1 (January 17, 2022): 189. http://dx.doi.org/10.3390/biomedicines10010189.

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Iron homeostasis is regulated by hepcidin, a hepatic hormone that controls dietary iron absorption and plasma iron concentration. Hepcidin binds to the only known iron export protein, ferroportin (FPN), which regulates its expression. The major factors that implicate hepcidin regulation include iron stores, hypoxia, inflammation, and erythropoiesis. When erythropoietic activity is suppressed, hepcidin expression is hampered, leading to deficiency, thus causing an iron overload in iron-loading anemia, such as β-thalassemia. Iron overload is the principal cause of mortality and morbidity in β-thalassemia patients with or without blood transfusion dependence. In the case of thalassemia major, the primary cause of iron overload is blood transfusion. In contrast, iron overload is attributed to hepcidin deficiency and hyperabsorption of dietary iron in non-transfusion thalassemia. Beta-thalassemia patients showed marked hepcidin suppression, anemia, iron overload, and ineffective erythropoiesis (IE). Recent molecular research has prompted the discovery of new diagnostic markers and therapeutic targets for several diseases, including β-thalassemia. In this review, signal transducers and activators of transcription (STAT) and SMAD (structurally similar to the small mothers against decapentaplegic in Drosophila) pathways and their effects on hepcidin expression have been discussed as a therapeutic target for β-thalassemia patients. Therefore, re-expression of hepcidin could be a therapeutic target in the management of thalassemia patients. Data from 65 relevant published experimental articles on hepcidin and β-thalassemia between January 2016 and May 2021 were retrieved by using PubMed and Google Scholar search engines. Published articles in any language other than English, review articles, books, or book chapters were excluded.

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Wessling-Resnick, Marianne. "Iron Imports. III. Transfer of iron from the mucosa into circulation." American Journal of Physiology-Gastrointestinal and Liver Physiology 290, no. 1 (January 2006): G1—G6. http://dx.doi.org/10.1152/ajpgi.00415.2005.

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Transfer of iron from the mucosa is a critical step in dietary iron assimilation that is tightly regulated to ensure the appropriate amount of iron is absorbed to meet the body's demands. Too much iron is highly toxic, and failure to properly control intestinal iron export causes iron overload associated with hereditary forms of hemochromatosis. One form of genetic iron overload, ferroportin disease, originates due to defects in ferroportin, the membrane iron exporter. Ferroportin acts in conjunction with the intestinal ferroxidase hephaestin to mediate release of iron from the enterocyte. How iron is then acquired by transferrin and released into circulation remains an unknown step in this process.

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Qian, Jian, Bradley P. Sullivan, Samuel J. Peterson, and Cory Berkland. "Nonabsorbable Iron Binding Polymers Prevent Dietary Iron Absorption for the Treatment of Iron Overload." ACS Macro Letters 6, no. 4 (March 20, 2017): 350–53. http://dx.doi.org/10.1021/acsmacrolett.6b00945.

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Gordeuk, Victor R., Laura Lovato, James C. Barton, Mara Vitolins, Gordon McLaren, Ronald T. Acton, Christine McLaren, et al. "Dietary Iron Intake and Serum Ferritin Concentration in 213 Patients Homozygous for theHFEC282YHemochromatosis Mutation." Canadian Journal of Gastroenterology 26, no. 6 (2012): 345–49. http://dx.doi.org/10.1155/2012/676824.

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BACKGROUND:HFEC282Yhomozygotes have an increased risk for developing increased iron stores and related disorders. It is controversial whether dietary iron restrictions should be recommended to such individuals.OBJECTIVE: To determine whether dietary iron content influences iron stores inHFEC282Yhomozygotes as assessed by serum ferritin concentration.DESIGN: Serum ferritin concentration was measured and a dietary iron questionnaire was completed as part of the evaluation of 213HFEC282Yhomozygotes who were identified through screening of >100,000 primary care patients at five HEmochromatosis and IRon Overload Screening (HEIRS) Study Field Centers in the United States and Canada.RESULTS: No significant relationships between serum ferritin concentration and dietary heme iron content, dietary nonheme iron content or reports of supplemental iron use were found.CONCLUSION: These results do not support recommending dietary heme or nonheme iron restrictions forHFEC282Yhomozygotes diagnosed through screening in North America.

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Yamamoto, Masayo, Hiroki Tanaka, Lynda Addo, Satoshi Ito, Motohiro Shindo, Katsuya Ikuta, Katsunori Sasaki, et al. "Increased Expression Of NGF In Hepatocytes Is An Early Event In Iron Overloaded Mouse By Transcriptome Analysis." Blood 122, no. 21 (November 15, 2013): 2194. http://dx.doi.org/10.1182/blood.v122.21.2194.2194.

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Abstract The liver plays a central role in iron metabolism by storing and sensing the amounts of iron in the body. The dietary iron from duodenum and recycled-iron by reticuloendothelial system are the main source of body iron. When excess iron enters the liver, hepatocytes secrete hepcidin, an anti-microbial peptide which negatively regulates iron excretion from enterocytes and macrophages, and stores the excess iron as ferritin-bound iron. A dysfunction of this regulatory system causes iron overload in the liver. Aberrant iron accumulation in the liver is found in hereditary hemochromatosis and chronic liver disease, and this is considered to be an exacerbating factor in liver cirrhosis and hepatocellular carcinoma. It is therefore important to understand the precise molecular events that take place as a result of iron accumulation during the early stages of iron overload. In the present study, we performed transcriptome analysis on the liver of dietary iron overloaded mice. Transcriptome analysis using a high throughput sequencer is capable of comprehensive analysis with high sensitivity. We hypothesized that this method will be suitable in detecting the changes in gene expression induced by iron overload, even in slightly expressed genes. C57B1/6 mice were fed a normal diet, and a 2.5% iron diet for 8 weeks. Serum and liver tissue samples were then collected, and histological analysis showed the features of early stage iron overload without significant hepatic damage in the iron-fed mice. From the results of the transcriptome analysis, we found that nerve growth factor (NGF) was significantly expressed in the slightly iron overloaded liver. This observation was also confirmed by real time RT-PCR, Western blotting and immunohistochemistry. Similarly, NGF upregulation was induced in mice primary hepatocytes cultured in conditioned iron overloaded medium (with high concentration of holo-transferrin or ferric ammonium citrate). Furthermore, immunohistochemical analysis showed that TrkA, a high affinity NGF receptor, was expressed in liver sinusoidal endothelial cells (LSECs). Using scanning electron microscopy, we sought to examine any morphological changes in the sinusoids of the iron overloaded liver and observed that although sieve plate structures (so-called ‘fenestrae’) were found in the LSECs of mice fed a normal diet, they were not visible in the iron-fed mice. The loss of fenestrae was also observed in the LSECs of mice that received intraperitoneal injections of NGF. In cultured isolated primary LSECs, treatment with NGF, or conditioned medium from iron overloaded primary hepatocytes reduced the fenestrae while the anti-NGF neutralization antibody or TrkA inhibitor K252a cancelled this effect. In addition, a fresh iron overloaded medium did not reduce the fenestrae in primary LSECs, indicating that iron itself has no direct effects on the fenestrae in LSECs. LSECs constitute the sinusoidal wall in the liver and can be regarded as unique capillaries which differ from other capillaries in the body due to the presence of fenestrae which lack a diaphragm, and are therefore open connections between the lumen of the sinusoid and the space of Disse. The fenestrae in LSECs therefore play an important role in the exchange of solutes between the lumen of the sinusoid and hepatocytes. The results of this study indicate that iron accumulation induces the expression of NGF in hepatoctyes, which in turn leads to the loss of fenestrae in LSECs via TrkA. This phenomenon may therefore contribute to the defensive machinery against iron accumulation in hepatocytes in the early stages of iron overload. These data further suggest a novel function of NGF in the regulation of iron transport. Disclosures: No relevant conflicts of interest to declare.

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Canonne-Hergaux, François, Joanne E. Levy, Mark D. Fleming, Lynne K. Montross, Nancy C. Andrews, and Philippe Gros. "Expression of the DMT1 (NRAMP2/DCT1) iron transporter in mice with genetic iron overload disorders." Blood 97, no. 4 (February 15, 2001): 1138–40. http://dx.doi.org/10.1182/blood.v97.4.1138.

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Abstract Iron overload is highly prevalent, but its molecular pathogenesis is poorly understood. Recently, DMT1 was shown to be a major apical iron transporter in absorptive cells of the duodenum. In vivo, it is the only transporter known to be important for the uptake of dietary non-heme iron from the gut lumen. The expression and subcellular localization of DMT1 protein in 3 mouse models of iron overload were examined: hypotransferrinemic (Trfhpx) mice, Hfeknockout mice, and B2m knockout mice. Interestingly, in Trfhpx homozygotes, DMT1 expression was strongly induced in the villus brush border when compared to control animals. This suggests that DMT1 expression is increased in response to iron deficiency in the erythron, even in the setting of systemic iron overload. In contrast, no increase was seen in DMT1 expression in animals with iron overload resembling human hemochromatosis. Therefore, it does not appear that changes in DMT1 levels are primarily responsible for iron loading in hemochromatosis.

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Tao, Min, and David L. Pelletier. "The effect of dietary iron intake on the development of iron overload among homozygotes for haemochromatosis." Public Health Nutrition 12, no. 10 (October 2009): 1823–29. http://dx.doi.org/10.1017/s1368980008004631.

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AbstractObjectiveTo quantify the role of dietary Fe in total body Fe (TBI) accumulation among homozygotes for theHFEgene associated with haemochromatosis.DesignA Monte Carlo model was built to simulate Fe accumulation based on findings from human feeding experiments and national dietary surveys. A hypothetical cohort of 1000 homozygotes with starting age 25 years was used in 39-year simulations. The impact of reducing dietary Fe intake on Fe accumulation was tested.ResultsIn the baseline model without any dietary intervention, by age 64, the percentage of males with TBI > 10 g, >15 g and >20 g was 93·2 %, 49·6 % and 14·7 %, respectively. When the Fe intake of individuals in the cohort was reduced to ≤200 % of the recommended dietary allowance (RDA), the corresponding percentages were 92·0 %, 40·5 % and 10·2 %, respectively. The corresponding figures were 91·0 %, 40·0 % and 9·3 % for Fe defortification and 70·3 %, 21·3 % and 4·1 % when Fe intake was capped at 100 % RDA. Similar trends were seen with sexes combined, although the impact of interventions was less. Sensitivity analysis revealed that the rate of Fe accumulation and the impact of dietary interventions are highly dependent on assumptions concerning Fe absorption rates.ConclusionsVariation in Fe intake as currently observed in the USA contributes to variation in Fe accumulation among homozygotes, when continued over an extended period. Lifelong dietary habits and national fortification policy can affect the rate of Fe accumulation, although the magnitude of the effect varies by gender, the TBI level of interest and factors affecting the Fe absorption rate.

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Brown, K. E., J. E. Poulos, L. Li, A. M. Soweid, G. A. Ramm, R. O'Neill, R. S. Britton, and B. R. Bacon. "Effect of vitamin E supplementation on hepatic fibrogenesis in chronic dietary iron overload." American Journal of Physiology-Gastrointestinal and Liver Physiology 272, no. 1 (January 1, 1997): G116—G123. http://dx.doi.org/10.1152/ajpgi.1997.272.1.g116.

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It has been suggested that lipid peroxidation plays an important role in hepatic fibrogenesis resulting from chronic iron overload. Vitamin E is an important lipid-soluble antioxidant that has been shown to be decreased in patients with hereditary hemochromatosis and in experimental iron overload. The aim of this study was to determine the effects of vitamin E supplementation on hepatic lipid peroxidation and fibrogenesis in an animal model of chronic iron overload. Rats were fed the following diets for 4, 8, or 14 mo: standard laboratory diet (control), diet with supplemental vitamin E (200 IU/kg, control + E), diet with carbonyl iron (Fe), and diet with carbonyl iron supplemented with vitamin E (200 IU/kg. Fe + E). Iron loading resulted in significant decreases in hepatic and plasma vitamin E levels at all time points, which were overcome by vitamin E supplementation. Thiobarbituric acid-reactive substances (an index of lipid peroxidation) were increased three- to fivefold in the iron-loaded livers; supplementation with vitamin E reduced these levels by at least 50% at all time points. Hepatic hydroxyproline levels were increased twofold by iron loading. Vitamin E did not affect hydroxyproline content at 4 or 8 mo but caused an 18% reduction at 14 mo in iron-loaded livers. At 8 and 14 mo, vitamin E decreased the number of alpha-smooth muscle actin-positive stellate cells in iron-loaded livers. These results demonstrate a dissociation between lipid peroxidation and collagen production and suggest that the profibrogenic action of iron in this model is mediated through effects which cannot be completely suppressed by vitamin E.

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Vinchi, Francesca, Graca Porto, Andreas Simmelbauer, Sandro Altamura, Sara T. Passos, Maciej Garbowski, André M. N. Silva, et al. "Atherosclerosis is aggravated by iron overload and ameliorated by dietary and pharmacological iron restriction." European Heart Journal 41, no. 28 (March 20, 2019): 2681–95. http://dx.doi.org/10.1093/eurheartj/ehz112.

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Abstract Aims Whether and how iron affects the progression of atherosclerosis remains highly debated. Here, we investigate susceptibility to atherosclerosis in a mouse model (ApoE−/− FPNwt/C326S), which develops the disease in the context of elevated non-transferrin bound serum iron (NTBI). Methods and results Compared with normo-ferremic ApoE−/− mice, atherosclerosis is profoundly aggravated in iron-loaded ApoE−/− FPNwt/C326S mice, suggesting a pro-atherogenic role for iron. Iron heavily deposits in the arterial media layer, which correlates with plaque formation, vascular oxidative stress and dysfunction. Atherosclerosis is exacerbated by iron-triggered lipid profile alterations, vascular permeabilization, sustained endothelial activation, elevated pro-atherogenic inflammatory mediators, and reduced nitric oxide availability. NTBI causes iron overload, induces reactive oxygen species production and apoptosis in cultured vascular cells, and stimulates massive MCP-1-mediated monocyte recruitment, well-established mechanisms contributing to atherosclerosis. NTBI-mediated toxicity is prevented by transferrin- or chelator-mediated iron scavenging. Consistently, a low-iron diet and iron chelation therapy strongly improved the course of the disease in ApoE−/− FPNwt/C326S mice. Our results are corroborated by analyses of serum samples of haemochromatosis patients, which show an inverse correlation between the degree of iron depletion and hallmarks of endothelial dysfunction and inflammation. Conclusion Our data demonstrate that NTBI-triggered iron overload aggravates atherosclerosis and unravel a causal link between NTBI and the progression of atherosclerotic lesions. Our findings support clinical applications of iron restriction in iron-loaded individuals to counteract iron-aggravated vascular dysfunction and atherosclerosis.

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Pique, Karina, William Taber, Anthony Thompson, and Charles Gerry Maitland. "Isolated optic neuropathy due to folate deficiency with associated iron overload." BMJ Case Reports 14, no. 7 (July 2021): e242399. http://dx.doi.org/10.1136/bcr-2021-242399.

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Isolated optic neuropathy due to folate deficiency is rarely reported. Poor dietary practices, malabsorption, and tobacco/alcohol abuse are usually responsible. We examined a patient with blinding optic neuropathies and isolated folic acid deficiency. Visual acuity recovered after folate replacement. At the same time, serological investigation revealed high ferritin and iron saturation levels with negative genetic markers for haemochromatosis consistent with the diagnosis of iron overload syndrome. There are no reports of blindness associated with iron overload syndrome.

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Stål, Per, Gen-Sheng Wang, Jerker M. Olsson, and Lennart C. Eriksson. "Effects of dietary iron overload on progression in chemical hepatocarcinogenesis." Liver International 19, no. 4 (August 1999): 326–34. http://dx.doi.org/10.1111/j.1478-3231.1999.tb00057.x.

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MCNAMARA, LYNNE, VICTOR R. GORDEUK, and A. PATRICK MACPHAIL. "Ferroportin (Q248H) mutations in African families with dietary iron overload." Journal of Gastroenterology and Hepatology 20, no. 12 (December 2005): 1855–58. http://dx.doi.org/10.1111/j.1440-1746.2005.03930.x.

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Wang, Tao, Ping Xiang, Jung-Heun Ha, Xiaoyu Wang, Caglar Doguer, Shireen R. L. Flores, Yujian James Kang, and James F. Collins. "Copper supplementation reverses dietary iron overload-induced pathologies in mice." Journal of Nutritional Biochemistry 59 (September 2018): 56–63. http://dx.doi.org/10.1016/j.jnutbio.2018.05.006.

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Bacon, Bruce R., John F. Healey, Gary M. Brittenham, C. H. Park, Jodi Nunnari, Anthony S. Tavill, and Herbert L. Bonkovsky. "Hepatic microsomal function in rats with chronic dietary iron overload." Gastroenterology 90, no. 6 (June 1986): 1844–53. http://dx.doi.org/10.1016/0016-5085(86)90251-9.

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Smith, Allen D., Paul K. South, and Orville A. Levander. "Effects of Dietary Iron Overload on Glutathione Peroxidase Knockout Mice." Biological Trace Element Research 88, no. 1 (2002): 79–86. http://dx.doi.org/10.1385/bter:88:1:79.

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Pietrangelo, Antonello, Emilio Rocchi, Luisa Schiaffonati, Ezio Ventura, and Gaetano Cairo. "Liver gene expression during chronic dietary iron overload in rats." Hepatology 11, no. 5 (May 1990): 798–804. http://dx.doi.org/10.1002/hep.1840110513.

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Horne, Walter I., Bernard Tandler, Michael A. Dubick, Onni Niemelä, Gary M. Brittenham, and Hidekazu Tsukamoto. "Iron Overload in the Rat Pancreas Following Portacaval Shunting and Dietary Iron Supplementation." Experimental and Molecular Pathology 64, no. 2 (April 1997): 90–102. http://dx.doi.org/10.1006/exmp.1997.2212.

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Moon, Seonghwan, Minju Kim, Yeonhee Kim, and Seungmin Lee. "Supplementation with High or Low Iron Reduces Colitis Severity in an AOM/DSS Mouse Model." Nutrients 14, no. 10 (May 12, 2022): 2033. http://dx.doi.org/10.3390/nu14102033.

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The relationship between colitis-associated colorectal cancer (CAC) and the dysregulation of iron metabolism has been implicated. However, studies on the influence of dietary iron deficiency on the incidence of CAC are limited. This study investigated the effects of dietary iron deficiency and dietary non-heme iron on CAC development in an azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model. The four-week-old mice were divided into the following groups: iron control (IC; 35 ppm iron/kg) + normal (NOR), IC + AOM/DSS, iron deficient (ID; <5 ppm iron/kg diet) + AOM/DSS, and iron overload (IOL; approximately 2000 ppm iron/kg) + AOM/DSS. The mice were fed the respective diets for 13 weeks, and the AOM/DSS model was established at week five. FTH1 expression increased in the mice’s colons in the IC + AOM/DSS group compared with that observed in the ID and IOL + AOM/DSS groups. The reduced number of colonic tumors in the ID + AOM/DSS and IOL + AOM/DSS groups was accompanied by the downregulated expression of cell proliferation regulators (PCNA, cyclin D1, and c-Myc). Iron overload inhibited the increase in the expression of NF-κB and its downstream inflammatory cytokines (IL-6, TNFα, iNOS, COX2, and IL-1β), likely due to the elevated expression of antioxidant genes (SOD1, TXN, GPX1, GPX4, CAT, HMOX1, and NQO1). ID + AOM/DSS may hinder tumor development in the AOM/DSS model by inhibiting the PI3K/AKT pathway by increasing the expression of Ndrg1. Our study suggests that ID and IOL diets suppress AOM/DSS-induced tumors and that long-term iron deficiency or overload may negate CAC progression.

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Shemisa, Kamal, Nasima Jafferjee, David Thomas, Gretta Jacobs, and Howard J. Meyerson. "Mycobacterium aviumComplex Infection in a Patient with Sickle Cell Disease and Severe Iron Overload." Case Reports in Infectious Diseases 2014 (2014): 1–5. http://dx.doi.org/10.1155/2014/405323.

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A 34-year-old female with sickle cell anemia (hemoglobin SS disease) and severe iron overload presented to our institution with the subacute presentation of recurrent pain crisis, fever of unknown origin, pancytopenia, and weight loss. A CT scan demonstrated both lung and liver nodules concerning for granulomatous disease. Subsequent biopsies of the liver and bone marrow confirmed the presence of noncaseating granulomas and blood cultures isolatedMycobacterium aviumcomplex MAC. Disseminated MAC is considered an opportunistic infection typically diagnosed in the immunocompromised and rarely in immunocompetent patients. An appreciable number of mycobacterial infection cases have been reported in sickle cell disease patients without immune dysfunction. It has been reported that iron overload is known to increase the risk for mycobacterial infection in vitro and in vivo studies. While iron overload is primarily known to cause end organ dysfunction, the clinical relationship with sickle cell disease and disseminated MAC infection has not been reported. Clinical iron overload is a common condition diagnosed in the sub-Saharan African population. High dietary iron, genetic defects in iron trafficking, as well as hemoglobinopathy are believed to be the etiologies for iron overload in this region. Patients with iron overload in this region were 17-fold more likely to die fromMycobacterium tuberculosis. Both experimental and clinical evidence suggest a possible link to iron overload and mycobacterial infections; however larger observational studies are necessary to determine true causality.

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O'Connor, J. M. "Trace elements and DNA damage." Biochemical Society Transactions 29, no. 2 (May 1, 2001): 354–58. http://dx.doi.org/10.1042/bst0290354.

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A number of studies (mainly in vitro and in vivo animal models) have examined the interaction of trace elements with DNA. Normal dietary levels of various trace elements are required to prevent the occurrence of oxidative damage, and deficiency may increase susceptibility. Conversely, overload of some trace elements, including copper and iron, has been demonstrated to result in adverse effects. However, under normal physiological conditions, such overloads are unlikely to occur.

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Luo, Gang, Lu Xiang, and Lin Xiao. "Acetyl-CoA Deficiency Is Involved in the Regulation of Iron Overload on Lipid Metabolism in Apolipoprotein E Knockout Mice." Molecules 27, no. 15 (August 4, 2022): 4966. http://dx.doi.org/10.3390/molecules27154966.

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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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Zhen, Aileen W., Josephine Volovetz, and Paula G. Fraenkel. "Dietary Supplementation with Genistein Increases Hepcidin Expression in Wild Type Mice." Blood 120, no. 21 (November 16, 2012): 3208. http://dx.doi.org/10.1182/blood.v120.21.3208.3208.

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Abstract Abstract 3208 Iron overload is an important cause of morbidity and death in patients with hemoglobinopathies, transfusion-dependent anemias, and hereditary hemochromatosis. As humans have no means of excreting iron, regulation of iron homeostasis depends on limiting intestinal iron absorption and optimizing iron release from macrophages to developing erythrocytes. Hepcidin, a peptide hormone produced in the liver, modulates intestinal iron absorption and macrophage iron release via effects on ferroportin. Hepcidin is a potential drug target for patients with iron overload syndromes because its levels are inappropriately low in these individuals. We conducted a small-scale chemical screen and found that the isoflavone genistein, a major dietary component of soybeans, enhanced Hepcidin transcript levels in zebrafish embryos. Furthermore genistein treatment increased Hepcidin transcript levels and Hepcidin promoter activity in human hepatocytes (HepG2 cells) in a Stat3 and Smad4-dependent manner. To evaluate genistein's effect in a mammalian model, we placed groups of 4 four-week old male C57BL/6 mice on an iron-sufficient, low soy diet (AIN93G containing 35 mg of iron/kg) supplemented with 0, 250, or 500 mg of genistein per kg of food for 7 weeks, and then sacrificed the animals for analysis. Plasma genistein levels (mean±SE) at the time of sacrifice were 0.015±0.015, 0.52±0.173, and 2.07±0.65 micromolar, respectively. Compared to mice not treated with genistein, the 250 mg/kg dose produced a significant increase in hepatic Hepcidin (HAMP1) transcript levels (1.49±0.10 vs 0.93±0.10, p=0.01), while the 500 mg/kg dose did not. Although liver iron content, spleen iron content, and weight gain were not significantly different among the groups, the ratio of Hepcidin expression to liver iron content was significantly increased in the animals treated with genistein 250 mg/kg compared to controls (0.013±0.0009 vs 0.0074±0.00068, p=0.0068). In conclusion, genistein is the first orally administered small molecule experimental drug shown to increase Hepcidin transcript levels in vivo. Future experiments will evaluate the effects of genistein on genetic models of iron overload syndromes. Disclosures: No relevant conflicts of interest to declare.

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Hubler, Merla J., Keith M. Erikson, Arion J. Kennedy, and Alyssa H. Hasty. "MFehi adipose tissue macrophages compensate for tissue iron perturbations in mice." American Journal of Physiology-Cell Physiology 315, no. 3 (September 1, 2018): C319—C329. http://dx.doi.org/10.1152/ajpcell.00103.2018.

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Resident adipose tissue macrophages (ATMs) play multiple roles to maintain tissue homeostasis, such as removing excess free fatty acids and regulation of the extracellular matrix. The phagocytic nature and oxidative resiliency of macrophages not only allows them to function as innate immune cells but also to respond to specific tissue needs, such as iron homeostasis. MFehi ATMs are a subtype of resident ATMs that we recently identified to have twice the intracellular iron content as other ATMs and elevated expression of iron-handling genes. Although studies have demonstrated that iron homeostasis is important for adipocyte health, little is known about how MFehi ATMs may respond to and influence adipose tissue iron availability. Two methodologies were used to address this question: dietary iron supplementation and intraperitoneal iron injection. Upon exposure to high dietary iron, MFehi ATMs accumulated excess iron, whereas the iron content of MFelo ATMs and adipocytes remained unchanged. In this model of chronic iron excess, MFehi ATMs exhibited increased expression of genes involved in iron storage. In the injection model, MFehi ATMs incorporated high levels of iron, and adipocytes were spared iron overload. This acute model of iron overload was associated with increased numbers of MFehi ATMs; 17% could be attributed to monocyte recruitment and 83% to MFelo ATM incorporation into the MFehi pool. The MFehi ATM population maintained its low inflammatory profile and iron-cycling expression profile. These studies expand the field’s understanding of ATMs and confirm that they can respond as a tissue iron sink in models of iron overload.

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La Carpia, Francesca, Boguslaw Wojczyk, Abdelhadi Rebbaa, Amy Tang, and Eldad A. Hod. "Chronic Transfusion and Iron Overload Modify the Mouse Gut Microbiome." Blood 128, no. 22 (December 2, 2016): 200. http://dx.doi.org/10.1182/blood.v128.22.200.200.

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Abstract BACKGROUND: Although iron is an essential element in critical metabolic pathways of both pathogenic microorganisms and their hosts it is less essential in certain barrier bacteria, such as Lactobacilli. Dietary iron supplementation increases mortality and affects the microbiome in African children, decreasing the abundance of beneficial Lactobacilli. Furthermore, the method of iron repletion influences the microbiome in patients with inflammatory bowel disease. AIM: To determine whether iron status and different methods of iron supplementation/overload affect the gut microbiome in mice. METHODS: Cohorts of iron-deficient, iron-replete, and iron-overloaded wild-type C57BL/6 female mice (n=5 per group) were generated by dietary manipulation and by injection of iron dextran (0.3mg weekly x 6) or RBC transfusion (0.3mL at 60% hematocrit weekly x 6). The day after the last injection/transfusion, mice were sacrificed and tissues (blood, liver, spleen, and duodenum) and feces, from the cecum and rectum, were collected. Iron levels in tissues and in rectal feces were quantified by a wet ashing procedure. Commercial ELISA kits were used to quantify circulating hepcidin and ferritin levels. DNA from feces was extracted using the Fecal DNA extraction kit (Mo Bio) and sent to the Molecular Research (MRDNA) center for 16S rDNA Illumina platform sequencing and analysis. Statistical analyses were performed using LEfSe database (https://huttenhower.sph.harvard.edu/galaxy/) and GraphPad Prism. RESULTS: Mice fed an iron-deficient diet from weaning developed iron deficiency anemia with decreased intracellular iron stores, as measured by serum ferritin and liver and spleen iron (see Table). Iron dextran injections induced iron overload in mice fed either an iron deficient or iron replete diet. Chronic transfusion induced iron overload in mice fed an iron replete diet, but led to iron repletion without overload in mice fed an iron deficient diet. The iron deficient diet decreased, whereas the iron supplemented diet increased, fecal iron significantly. Although, iron dextran injections and chronic transfusion increased hepcidin levels, they did not significantly affect fecal iron. Analysis of microbiome data showed that fecal iron modulated the relative abundance of different bacteria. The phylum Proteobacteria showed a negative trend with increasing fecal iron associated with decreasing relative abundance (R2 0.5; p<0.006), Firmicutes showed a positive trend with increasing fecal iron associated with increasing relative abundance (R2 0.3; p<0.02), whereas the phylum Bacteroidetes did not show a significant association. Within the phylum Firmicutes, fecal iron concentration was a reasonable predictor of family Lactobacillaceae abundance (R2 0.5; p=0.005), with increasing iron reducing the relative abundance; in contrast, increasing iron was associated with increased relative abundance of family Clostridiaceae (R2 0.7; p<0.0001). We next investigated whether iron dextran infusions, chronic transfusions, or oral iron supplementation modulated microbiome composition. Analysis of the families belonging to class Clostrida showed that family Clostridiaceae increased with an iron supplemented diet, iron dextran infusions, or transfusional iron overload; family Eubacteriaceae increased with iron dextran and blood transfusions, but not with the iron supplemented diet, and family Peptococcaceae only increased with iron dextran treatment. These results suggest that different methods of iron supplementation or overload affect families in the class of Clostrida differently. Finally,comparisons of the cecal and rectal microbiomes did not identify any substantial differences. CONCLUSIONS: In this study, iron status modified the microbiome in mice. The microbiome was further modulated by different types of iron overload, especially in the class Clostrida. Similar to human studies, increasing fecal iron decreases the abundance in the gut of potentially beneficial lactobacilli. Although there are differences between mouse and human gut microbiomes, this mouse model can be used to study the effects of iron supplementation strategies and iron overload and can provide the foundation for further studies focused on the role of iron in host-pathogen interactions and immune function. Disclosures No relevant conflicts of interest to declare.

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Burke, Wylie, Giuseppina Imperatore, and Michelle Reyes. "Iron deficiency and iron overload: effects of diet and genes." Proceedings of the Nutrition Society 60, no. 1 (February 2001): 73–80. http://dx.doi.org/10.1079/pns200069.

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Like most essential nutrients, Fe needs to be maintained in the body at a defined level for optimal health, with appropriate adaptation to varying Fe needs and supply. The primary mechanism for controlling Fe level is the regulation of Fe absorption. Several different proteins have been identified as contributors to the process. Despite a complex regulatory system, Fe disorders (both Fe deficiency and Fe overload) occur. Fe deficiency is a common problem worldwide, resulting from inadequate dietary Fe and blood loss. Complications include pre-term labour, developmental delay, and impaired work efficiency. No specific genetic syndromes causing isolated Fe deficiency have been described, but animal studies and clinical observations suggest that such a relationship may be a possibility. Conversely, the known causes of Fe overload are genetic. Fe overload is less common than Fe deficiency, but can result in serious medical complications, including cirrhosis, primary liver cancer, diabetes, cardiomyopathy and arthritis. The most common and best characterized syndrome of Fe overload is hereditary haemochromatosis (HHC), an autosomal recessive disorder. Mutations in the HFE protein cause HHC, but the clinical presentation is variable. Of particular interest is the factor that some HFE genotypes appear to be associated with protection from Fe deficiency. Other genetic variants in the regulatory pathway may influence the likelihood of Fe deficiency and Fe overload. Studies of genetic variants in HFE and other regulatory proteins provide important tools for studying the biological processes in Fe regulation. This work is likely to lead to new insights into Fe disorders and potentially to new therapeutic approaches. It will not be complete, however, until coordinated study of both genetic and nutritional factors is undertaken.

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PLUMMER, JOHN L., MALCOLM MACKINNON, PATRICIA L. CMIELEWSKI, PHIL WILLIAMS, MICHAEL J. AHERN, ANTHONY H. ILSLEY, and PAULINE DE LA M. HALL. "Dose-related effects of dietary iron supplementation in producing hepatic iron overload in rats." Journal of Gastroenterology and Hepatology 12, no. 12 (December 1997): 839–42. http://dx.doi.org/10.1111/j.1440-1746.1997.tb00381.x.

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LIU, DAN, HUAN HE, DONG YIN, AILING QUE, LEI TANG, ZHANGPING LIAO, QIREN HUANG, and MING HE. "Mechanism of chronic dietary iron overload-induced liver damage in mice." Molecular Medicine Reports 7, no. 4 (February 8, 2013): 1173–79. http://dx.doi.org/10.3892/mmr.2013.1316.

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Asare, George A., Michelle Bronz, Vivash Naidoo, and Michael C. Kew. "Interactions between aflatoxin B1 and dietary iron overload in hepatic mutagenesis." Toxicology 234, no. 3 (May 2007): 157–66. http://dx.doi.org/10.1016/j.tox.2007.02.009.

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Bacon, Bruce R., Chanho H. Park, Gary M. Brittenham, Rosemary O-Neill, and Anthony S. Tavill. "Hepatic mitochondrial oxidative metabolism in rats with chronic dietary iron overload." Hepatology 5, no. 5 (September 1985): 789–97. http://dx.doi.org/10.1002/hep.1840050514.

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Journal articles on the topic 'Dietary iron overload'

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