Inhibiting Dietary Iron Absorption in Subjects With Hereditary Hemochromatosis by a Natural Polyphenol Supplement

2019 ◽  
Author(s):  
Keyword(s):  
Iron Absorption ◽  
Hereditary Hemochromatosis ◽  
Dietary Iron ◽  
Natural Polyphenol

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.

Intestinal expression of genes involved in iron absorption in humans

2002 ◽  
Vol 282 (4) ◽  
pp. G598-G607 ◽  
Author(s):  
Andreas Rolfs ◽  
Herbert L. Bonkovsky ◽  
James G. Kohlroser ◽  
Kristina McNeal ◽  
Ashish Sharma ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Iron Absorption ◽  
Genetic Disorders ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
High Serum ◽  
Deficiency Anemia ◽  
Dependent Manner ◽  
Expression Levels

Hereditary hemochromatosis (HHC) is one of the most frequent genetic disorders in humans. In healthy individuals, absorption of iron in the intestine is tightly regulated by cells with the highest iron demand, in particular erythroid precursors. Cloning of intestinal iron transporter proteins provided new insight into mechanisms and regulation of intestinal iron absorption. The aim of this study was to assess whether, in humans, the two transporters are regulated in an iron-dependent manner and whether this regulation is disturbed in HHC. Using quantitative PCR, we measured mRNA expression of divalent cation transporter 1 (DCT1), iron-regulated gene 1 (IREG1), and hephaestin in duodenal biopsy samples of individuals with normal iron levels, iron-deficiency anemia, or iron overload. In controls, we found inverse relationships between the DCT1 splice form containing an iron-responsive element (IRE) and blood hemoglobin, serum transferrin saturation, or ferritin. Subjects with iron-deficiency anemia showed a significant increase in expression of the spliced form, DCT1(IRE) mRNA. Similarly, in subjects homozygous for the C282Y HFE mutation, DCT1(IRE) expression levels remained high despite high serum iron saturation. Furthermore, a significantly increased IREG1 expression was observed. Hephaestin did not exhibit a similar iron-dependent regulation. Our data show that expression levels of human DCT1 mRNA, and to a lesser extent IREG1 mRNA, are regulated in an iron-dependent manner, whereas mRNA of hephaestin is not affected. The lack of appropriate downregulation of apical and basolateral iron transporters in duodenum likely leads to excessive iron absorption in persons with HHC.

scholarly journals Intestinal Mucosal Mechanisms Controlling Iron Absorption

Blood ◽  
1963 ◽  
Vol 22 (4) ◽  
pp. 406-415 ◽  
Author(s):  
MARCEL E. CONRAD ◽  
WILLIAM H. CROSBY ◽  
Betty Merrill
Keyword(s):  
Iron Deficiency ◽  
Epithelial Cells ◽  
Iron Absorption ◽  
The Body ◽  
Iron Store ◽  
Dietary Iron ◽  
Receptor System ◽  
Excess Iron ◽  
Metabolic Requirement ◽  
Iron Receptor

Abstract Radioautographic studies provide evidence to support a concept of the mechanism whereby the small intestine controls absorption of iron. Three different states of the body’s iron stores have been considered in this regard: iron excess, iron deficiency and normal iron repletion. As the columnar epithelial cells of the duodenal villi are formed they incorporate a portion of intrinsic iron from the body’s iron store, the amount depending upon the body’s requirement for new iron. It is predicated that with iron excess the iron-receptor mechanism in these cells is saturated with intrinsic iron; this then prevents the cell from accepting dietary iron. In the normal state of iron repletion the receptor mechanism remains partly unsaturated, allowing small amounts of dietary iron to enter the cell. Part of this proceeds into the body to satisfy any metabolic requirement for iron. Part is retained in the mucosal epithelial cells to complete the saturation of the iron-receptor mechanism. This bound iron is subsequently lost when the epithelial cells are sloughed at the end of their life cycle. In iron deficiency it is postulated that the receptor system is inactive or diminished so that entry of dietary iron into the body is relatively uninhibited.

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.

Dietary iron absorption during early postnatal life

BioMetals ◽  
2019 ◽  
Vol 32 (3) ◽  
pp. 385-393 ◽  
Author(s):  
Sheridan L. Helman ◽  
Gregory J. Anderson ◽  
David M. Frazer
Keyword(s):  
Iron Absorption ◽  
Postnatal Life ◽  
Dietary Iron ◽  
Early Postnatal Life

Physiologic systemic iron metabolism in mice deficient for duodenal Hfe

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4511-4517 ◽  
Author(s):  
Maja Vujic Spasic ◽  
Judit Kiss ◽  
Thomas Herrmann ◽  
Regina Kessler ◽  
Jens Stolte ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Binding Capacity ◽  
Hereditary Hemochromatosis ◽  
Direct Interaction ◽  
Hfe Gene ◽  
Hepatic Iron ◽  
Primary Role ◽  
Genes Encoding

Abstract Mutations in the Hfe gene result in hereditary hemochromatosis (HH), a disorder characterized by increased duodenal iron absorption and tissue iron overload. Identification of a direct interaction between Hfe and transferrin receptor 1 in duodenal cells led to the hypothesis that the lack of functional Hfe in the duodenum affects TfR1-mediated serosal uptake of iron and misprogramming of the iron absorptive cells. Contrasting this view, Hfe deficiency causes inappropriately low expression of the hepatic iron hormone hepcidin, which causes increased duodenal iron absorption. We specifically ablated Hfe expression in mouse enterocytes using Cre/LoxP technology. Mice with efficient deletion of Hfe in crypt- and villi-enterocytes maintain physiologic iron metabolism with wild-type unsaturated iron binding capacity, hepatic iron levels, and hepcidin mRNA expression. Furthermore, the expression of genes encoding the major intestinal iron transporters is unchanged in duodenal Hfe-deficient mice. Our data demonstrate that intestinal Hfe is dispensable for the physiologic control of systemic iron homeostasis under steady state conditions. These findings exclude a primary role for duodenal Hfe in the pathogenesis of HH and support the model according to which Hfe is required for appropriate expression of the “iron hormone” hepcidin which then controls intestinal iron absorption.

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