scholarly journals Oral Administration of Ginger-Derived Lipid Nanoparticles and Dmt1 siRNA Potentiates the Effect of Dietary Iron Restriction and Mitigates Pre-Existing Iron Overload in Hamp KO Mice

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1686
Author(s):  
Xiaoyu Wang ◽  
Mingzhen Zhang ◽  
Regina R. Woloshun ◽  
Yang Yu ◽  
Jennifer K. Lee ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Absorption ◽  
Hereditary Hemochromatosis ◽  
Heme Iron ◽  
Dietary Iron ◽  
Iron Loading ◽  
Body Iron ◽  
Iron Restriction ◽  
Sirna Treatment ◽  
Non Heme Iron

Intestinal iron transport requires an iron importer (Dmt1) and an iron exporter (Fpn1). The hormone hepcidin regulates iron absorption by modulating Fpn1 protein levels on the basolateral surface of duodenal enterocytes. In the genetic, iron-loading disorder hereditary hemochromatosis (HH), hepcidin production is low and Fpn1 protein expression is elevated. High Fpn1-mediated iron export depletes intracellular iron, causing a paradoxical increase in Dmt1-mediated iron import. Increased activity of both transporters causes excessive iron absorption, thus initiating body iron loading. Logically then, silencing of intestinal Dmt1 or Fpn1 could be an effective therapeutic intervention in HH. It was previously established that Dmt1 knock down prevented iron-loading in weanling Hamp (encoding hepcidin) KO mice (modeling type 2B HH). Here, we tested the hypothesis that Dmt1 silencing combined with dietary iron restriction (which may be recommended for HH patients) will mitigate iron loading once already established. Accordingly, adult Hamp KO mice were switched to a low-iron (LFe) diet and (non-toxic) folic acid-coupled, ginger nanoparticle-derived lipid vectors (FA-GDLVs) were used to deliver negative-control (NC) or Dmt1 siRNA by oral, intragastric gavage daily for 21 days. The LFe diet reduced body iron burden, and experimental interventions potentiated iron losses. For example, Dmt1 siRNA treatment suppressed duodenal Dmt1 mRNA expression (by ~50%) and reduced serum and liver non-heme iron levels (by ~60% and >85%, respectively). Interestingly, some iron-related parameters were repressed similarly by FA-GDLVs carrying either siRNA, including 59Fe (as FeCl3) absorption (~20% lower), pancreatic non-heme iron (reduced by ~65%), and serum ferritin (decreased 40–50%). Ginger may thus contain bioactive lipids that also influence iron homeostasis. In conclusion, the combinatorial approach of FA-GDLV and Dmt1 siRNA treatment, with dietary iron restriction, mitigated pre-existing iron overload in a murine model of HH.

Ilex paraguariensis (A. St.-Hil.) leaf infusion decreases iron absorption in patients with hereditary hemochromatosis: a randomized controlled crossover study

2021 ◽  
Author(s):  
Cristiane Manfé Pagliosa ◽  
Francilene Gracieli Kunradi Vieira ◽  
Bruno Vieira Dias ◽  
Vivian Karla Brognoli Franco ◽  
Hanna Pillmann Ramos ◽  
...  
Keyword(s):  
Iron Overload ◽  
Crossover Study ◽  
Iron Absorption ◽  
Hereditary Hemochromatosis ◽  
Heme Iron ◽  
Ilex Paraguariensis ◽  
Overload Control ◽  
Randomized Controlled ◽  
Non Heme Iron ◽  
Acute Intake

The acute intake of Ilex paraguariensis leaf infusion significantly inhibited the absorption of non-heme iron in hereditary hemochromatosis patients with the HFE genotype and should be considered as a potential adjuvant for iron overload control.

scholarly journals Non-Transferrin-Mediated Iron Delivery

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. SCI-22-SCI-22 ◽  
Author(s):  
Mitchell Knutson
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Metal Ion ◽  
Heme Iron ◽  
Iron Loading ◽  
Divalent Metal Transporter 1 ◽  
Cardiac Iron ◽  
Non Heme Iron ◽  
Juvenile Hemochromatosis ◽  
Iron Concentrations

Abstract In iron overload conditions such as thalassemia major and hereditary hemochromatosis, the iron-carrying capacity of plasma transferrin is exceeded, giving rise to non-transferrin-bound iron (NTBI). NTBI is taken up preferentially by the liver, and to a lesser extent, the kidney, pancreas, and heart. How NTBI is taken up by various tissues has been elusive. We recently demonstrated that the plasma membrane metal-ion transporter SLC39A14 (ZIP14) mediates NTBI uptake and iron loading of the liver and pancreas, but not the kidney, heart or most other tissues¹ Given that the heart is particularly susceptible to iron-related toxicity, we are currently investigating the contribution of other iron transporters to iron loading of this organ. Possible alternative cardiac iron importers include L-type and T-type calcium channels, divalent metal transporter 1 (DMT1), and SLC39A8 (ZIP8). To examine the role of DMT1 and ZIP8 in cardiac iron metabolism, we generated mice with cardiomyocyte-specific disruption of DMT1 (Dmt1heart/heart) or ZIP8 (Zip8heart/heart). The mice were then crossed with hemojuvelin knockout (Hjv-/-) mice, a model of juvenile hemochromatosis characterized by high circulating levels of NTBI. Dmt1heart/heart mice were found to have cardiac non-heme iron concentrations that were 30% lower (P<0.01) than those of wild-type littermate controls at 6 weeks of age. Interestingly, however, double mutant Hjv-/-; Dmt1heart/heart mice accumulated more cardiac non-heme iron (3.9X control) than did single-mutant Hjv-/- mice (2.3X control) at 6 weeks of age. Cardiac-specific disruption of Zip8 did not affect cardiac non-heme iron concentrations under basal conditions or when mice were crossed with Hjv-/- mice. Collectively, these data indicate that DMT1 and ZIP8 are dispensable for iron loading of the heart in a mouse model of hemochromatosis. Our data additionally suggest that DMT1 may play a role in normal cardiac iron metabolism. Reference:Jenkitkasemwong S, Wang C, Coffey R, et al. SLC39A14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis.Cell Metabolism.2015; 22(1):138-150. Disclosures No relevant conflicts of interest to declare.

Expression of the DMT1 (NRAMP2/DCT1) iron transporter in mice with genetic iron overload disorders

Blood ◽  
2001 ◽  
Vol 97 (4) ◽  
pp. 1138-1140 ◽  
Author(s):  
François Canonne-Hergaux ◽  
Joanne E. Levy ◽  
Mark D. Fleming ◽  
Lynne K. Montross ◽  
Nancy C. Andrews ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Mouse Models ◽  
Brush Border ◽  
Knockout Mice ◽  
Heme Iron ◽  
Iron Loading ◽  
Non Heme Iron ◽  
Iron Transporter

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.

Pancreatic Iron and Fat Infiltration Are Diabetogenic Risk Factors In Patients With Iron Overload

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2204-2204
Author(s):  
Regine Grosse ◽  
Charlotte Pfeiffer ◽  
Bjoern P Schoennagel ◽  
Gritta E. Janka ◽  
Peter Nielsen ◽  
...  
Keyword(s):  
Iron Overload ◽  
Hereditary Hemochromatosis ◽  
Iron Accumulation ◽  
Blood Parameter ◽  
Iron Loading ◽  
Fat Infiltration ◽  
Body Iron ◽  
Tissue Iron ◽  
Fatty Replacement ◽  
Signal Intensities

Abstract Introduction Chronically transfused patients and patients with hereditary hemochromatosis (HHC) are affected by complications due to excessive body iron accumulation. Therefore, early detection of tissue iron accumulation is mandatory for effective treatment. Besides serum ferritin (SF) as the traditional blood parameter indicating iron overload, the assessment of body iron stores by non-invasive magnetic resonance imaging (MRI) using R2- (T2) or R2*- (T2*) relaxometry is established in clinical routine. Especially the comparison of tissue iron burden and iron loading patterns is a current field of research in iron overload. Although the pancreas seems to play a major role in the endocrinological pathology of patients with siderosis, there are only few studies analyzing pancreatic iron content referring to the head, body and tail region of the pancreas. Method A total of 69 patients (age 9 - 78 years, 31 females) with ß-Thalassemia major (TM: n = 42; 16 splenectomized), Diamond-Blackfan anemia (DBA: n = 7; 1 splenectomized), hereditary hemochromatosis (HHC: n = 11) and iron overload from chronic blood transfusions (n = 9; sideroblastic anemia, aplastic anemia, myelodysplastic syndrome, leukemia post bone marrow transplantation) were scanned between 2007 and 2012 as part of their regular heart and liver iron monitoring by MRI, respectively. 10 healthy subjects (3 females, age 23 - 68 years), voluntarily served as controls. The study was approved by the local ethics committee and all subjects gave their written informed consent. For measuring pancreatic R2*, a stack of 4-8 of slices (thickness = 5.5 mm, no gap, inplane resolution 1.25x1.25 mm2) was selected, covering the whole pancreas. Pancreatic signal intensities were averaged from three different ROIs positioned in the tail, body and head of the pancreas with sufficient distance to the gland boundaries and excluding vascular structures. Only clearly identified and demarcated pancreas tissue was considered. Since fat infiltration is a common problem in the pancreas, especially with phase dependent GRE times, we applied a water/fat separation technique to the in-phase and out-of-phase signal intensities as described by Wehrli et al. Results For patients, the median hepatic R2* rate, pancreatic R2* rate and ferritin level were 261 s-1 (range 42 - 2326 s-1), 130 s-1 (range 23 – 1192 s-1) and 1445 µg/ml (range 62 – 21557 µg/ml), respectively. In 70% of all patients, fatty infiltration of the pancreas was above the range of controls (> 10%), with highest apparent fat content (aFC) in the pancreas of TM patients, especially, in TM patients with diabetes mellitus (median aFC = 29.1%). The highest aFC was found in the pancreatic tail (P = 0.2). Fat infiltration correlated with pancreatic R2* (rS = 0.67, P < 10-4). Conclusion We compared R2* rates in the different pancreatic regions involving patient groups of different iron loading diseases. Patients showed significantly higher pancreatic R2* rates and apparent fat contents than controls. The pancreas tail revealed the highest R2* rates and fat contents so we hypothesize that iron uploading initially occurs in the pancreas tail, especially in TM patients. Fatty replacement and degeneration of the pancreas seems to be an important risk factor on top of pancreatic iron burden for the development of diabetes and should be further investigated in longitudinal studies. Disclosures: No relevant conflicts of interest to declare.

The Precision of in vitro Methods and Algorithms for Predicting the Bioavailability of Dietary Iron

2005 ◽  
Vol 75 (6) ◽  
pp. 436-445 ◽  
Author(s):  
Sean Lynch
Keyword(s):  
Iron Absorption ◽  
Heme Iron ◽  
Iron Bioavailability ◽  
Cell Uptake ◽  
In Vitro Tests ◽  
Cellular Iron ◽  
Non Heme Iron ◽  
Human Volunteers ◽  
Dialyzable Iron

Three factors determine how much iron will be absorbed from a meal. They are the physiological mechanisms that regulate uptake by and transfer through the enterocytes in the upper small intestine, the quantity of iron in the meal, and its availability to the cellular iron transporters. Established methods exist for predicting the effect of physiological regulation and for measuring or estimating meal iron content. Three approaches to estimating bioavailability have been advocated. Two are in vitro screening procedures: measurement of dialyzable iron and Caco-2 cell uptake, both carried out after in vitro simulated gastric and pancreatic digestion. The third is the use of algorithms based on the predicted effects of specific meal components on absorption derived from isotopic studies in human volunteers. The in vitro procedures have been very useful for identifying and characterizing factors that affect non-heme iron absorption, but direct comparisons between absorption predicted from the in vitro tests and measurements in human volunteers have only been made in a limited number of published studies. The available data indicate that dialysis and Caco-2 cell uptake are useful for ranking meals and single food items in terms of predicted iron bioavailability, but may not reflect the magnitudes of the effects of factors that influence absorption accurately. Algorithms based on estimates of the amounts of heme iron and of enhancers and inhibitors of non-heme iron absorption in foods make it possible to classify meals or diets as being of high, medium, or low bioavailability. The precision with which meal iron bioavailability can be predicted in a population, for which a specific algorithm has been developed, is improved by measuring the content of the most important enhancers and inhibitors. However, the accuracy of such predictions appears to be much lower when the algorithm is applied to meals eaten by different populations.

scholarly journals Liver iron sensing and body iron homeostasis

Blood ◽  
2019 ◽  
Vol 133 (1) ◽  
pp. 18-29 ◽  
Author(s):  
Chia-Yu Wang ◽  
Jodie L. Babitt
Keyword(s):  
Iron Deficiency ◽  
Iron Homeostasis ◽  
Inflammatory Diseases ◽  
Genetic Disorders ◽  
Hereditary Hemochromatosis ◽  
Deficiency Anemia ◽  
Iron Loading ◽  
Liver Iron ◽  
Body Iron ◽  
Iron Supply

Abstract The liver orchestrates systemic iron balance by producing and secreting hepcidin. Known as the iron hormone, hepcidin induces degradation of the iron exporter ferroportin to control iron entry into the bloodstream from dietary sources, iron recycling macrophages, and body stores. Under physiologic conditions, hepcidin production is reduced by iron deficiency and erythropoietic drive to increase the iron supply when needed to support red blood cell production and other essential functions. Conversely, hepcidin production is induced by iron loading and inflammation to prevent the toxicity of iron excess and limit its availability to pathogens. The inability to appropriately regulate hepcidin production in response to these physiologic cues underlies genetic disorders of iron overload and deficiency, including hereditary hemochromatosis and iron-refractory iron deficiency anemia. Moreover, excess hepcidin suppression in the setting of ineffective erythropoiesis contributes to iron-loading anemias such as β-thalassemia, whereas excess hepcidin induction contributes to iron-restricted erythropoiesis and anemia in chronic inflammatory diseases. These diseases have provided key insights into understanding the mechanisms by which the liver senses plasma and tissue iron levels, the iron demand of erythrocyte precursors, and the presence of potential pathogens and, importantly, how these various signals are integrated to appropriately regulate hepcidin production. This review will focus on recent insights into how the liver senses body iron levels and coordinates this with other signals to regulate hepcidin production and systemic iron homeostasis.

scholarly journals Iron age: novel targets for iron overload

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 216-221 ◽  
Author(s):  
Carla Casu ◽  
Stefano Rivella
Keyword(s):  
Iron Overload ◽  
Iron Age ◽  
Iron Metabolism ◽  
Iron Absorption ◽  
Hereditary Hemochromatosis ◽  
Therapeutic Approaches ◽  
Hepcidin Expression ◽  
Beneficial Effects ◽  
Excess Iron ◽  
Major Factors

Abstract Excess iron deposition in vital organs is the main cause of morbidity and mortality in patients affected by β-thalassemia and hereditary hemochromatosis. In both disorders, inappropriately low levels of the liver hormone hepcidin are responsible for the increased iron absorption, leading to toxic iron accumulation in many organs. Several studies have shown that targeting iron absorption could be beneficial in reducing or preventing iron overload in these 2 disorders, with promising preclinical data. New approaches target Tmprss6, the main suppressor of hepcidin expression, or use minihepcidins, small peptide hepcidin agonists. Additional strategies in β-thalassemia are showing beneficial effects in ameliorating ineffective erythropoiesis and anemia. Due to the suppressive nature of the erythropoiesis on hepcidin expression, these approaches are also showing beneficial effects on iron metabolism. The goal of this review is to discuss the major factors controlling iron metabolism and erythropoiesis and to discuss potential novel therapeutic approaches to reduce or prevent iron overload in these 2 disorders and ameliorate anemia in β-thalassemia.

scholarly journals Mechanistic and regulatory aspects of intestinal iron absorption

2014 ◽  
Vol 307 (4) ◽  
pp. G397-G409 ◽  
Author(s):  
Sukru Gulec ◽  
Gregory J. Anderson ◽  
James F. Collins
Keyword(s):  
Iron Homeostasis ◽  
Iron Absorption ◽  
Hereditary Hemochromatosis ◽  
Regulatory Protein ◽  
Whole Body ◽  
Deficiency Anemia ◽  
Inherited Disorders ◽  
Intestinal Iron Absorption ◽  
Body Iron ◽  
Proximal Small Bowel

Iron is an essential trace mineral that plays a number of important physiological roles in humans, including oxygen transport, energy metabolism, and neurotransmitter synthesis. Iron absorption by the proximal small bowel is a critical checkpoint in the maintenance of whole-body iron levels since, unlike most other essential nutrients, no regulated excretory systems exist for iron in humans. Maintaining proper iron levels is critical to avoid the adverse physiological consequences of either low or high tissue iron concentrations, as commonly occurs in iron-deficiency anemia and hereditary hemochromatosis, respectively. Exquisite regulatory mechanisms have thus evolved to modulate how much iron is acquired from the diet. Systemic sensing of iron levels is accomplished by a network of molecules that regulate transcription of the HAMP gene in hepatocytes, thus modulating levels of the serum-borne, iron-regulatory hormone hepcidin. Hepcidin decreases intestinal iron absorption by binding to the iron exporter ferroportin 1 on the basolateral surface of duodenal enterocytes, causing its internalization and degradation. Mucosal regulation of iron transport also occurs during low-iron states, via transcriptional (by hypoxia-inducible factor 2α) and posttranscriptional (by the iron-sensing iron-regulatory protein/iron-responsive element system) mechanisms. Recent studies demonstrated that these regulatory loops function in tandem to control expression or activity of key modulators of iron homeostasis. In health, body iron levels are maintained at appropriate levels; however, in several inherited disorders and in other pathophysiological states, iron sensing is perturbed and intestinal iron absorption is dysregulated. The iron-related phenotypes of these diseases exemplify the necessity of precisely regulating iron absorption to meet body demands.

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