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Iron

Fe

Iron, Fe - Essential Metal

Fe

Daily Requirement:

Modified DV:

RDA ?:

Adequate Intake ?:

18

true

mg/day

mg/day

Min Deficiency:

Max Toxicity:

Tolerable UL

Animal:Plant Conv:

8.1

45

mg/day

mg/day

mg/day

Date Discovered:

1932

Short Description:

Iron is pervasive, but particularly rich sources of dietary iron include red meat, oysters, beans, poultry, fish, leaf vegetables, watercress, tofu, and blackstrap molasses. Bread and breakfast cereals are sometimes specifically fortified with iron.

Iron provided by dietary supplements is often found as iron(II) fumarate, although iron(II) sulfate is cheaper and is absorbed equally well. Elemental iron, or reduced iron, despite being absorbed at only one-third to two-thirds the efficiency (relative to iron sulfate), is often added to foods such as breakfast cereals or enriched wheat flour

Interpretation:

• What type of biological processes is Fe involved with

redox, oxygen

• Why is too much Fe dangerous

iron + H2O2 = hydroxyl radical -> damage proteins, lipids, catalyze Fenton chemistry,

• Is Fe deficiency a problem

over a billion people estimated.

• What are some of the Fe overload diseases: what causes them

Unique diseases. Hemochromotosis. Can't sense stored iron, keep absorbing from diet. Thalassemia, Sickle cell anemia , red blood cell - transfusions, iron builds up.

• How is Fe absorbed into enterocytes

Two different pathways, nonheme (less bioavailable) vs heme (bioavailable)

• How is total body Fe distributed, is there a dedicated Fe excretion pathway

Most iron is used to make hemoglobin for red blood cells, which gets recycled. No excretion pathway for iron. Intestine cells, bleeding. Nothing like copper. Stored in the liver.

• What are the two types of dietary Fe, are they absorbed differently

How does hepcidin regulate Fe homeostasis, how is this relevant to: Fe deficiency/overload and infection/inflammation: Essay Question.

Hepcidin is produced in the liver. Increased production when we have infec/inflam, or when we have too much iron in the diet (iron overload). Hepcidin binds with ferroportin (cellular iron exporter) - iron gets trapped in intestinal enterocytes - can't transport it into the blood. Macrophages eat up old red blood cells, but holding onto iron because can't export it out due to hepcidin. Infection - fight for iron between host and pathogen.

• How does the IRE/IRP system work, what is the difference between IRP1 and 2, what proteins are regulated by this system and why are they important to Fe homeostasis

5' or 3' end of the RNA, 3' IRP high amounts of iron -> decreased expression, 5' IRE -> increased expression. IRP2 gets degraded when high iron, IRP1(sulfur iron cluster) changes shape. High iron, no IRE/IRP binding. Low iron, binding. Ferritin, IRE bound to IRP, that prevents translocation of. Transferrin has _ on 3' end, protects from being degraded, expression goes up. IRE on 5', transferrin receptor on 3' -> brings iron into the cell. If low amounts of iron in cell, we want to increase transferrin to move iron in. Cell Iron low -> IRE/IRP binding. Cell iron high -> No binding. 50:51

History & Discovery:

Digestion:

  • Nutritional iron is usually divided into two types:



  1. Heme iron, where iron is absorbed as the stable porphyrin complex unaffected by other food components.

  2. Nonheme iron, which is envisioned as “free” or in weak complexes. Food components such as phytate or tannins can trap iron from weak complexes in other foods during digestion, altering the bioavailability of food iron.


  • Thus it is not the total amount of food iron ingested, but the distribution among different chemical forms of iron and the reactivity among the different chemical forms of iron ingested that will determine the bioavailability of iron.

Absorption and Storage:



Lean beef and beef fat interact to enhance nonheme iron absorption in rats


Abstract

Nonheme iron absorption is enhanced when meat replaces non-meat protein sources in a meal. Our objective was to examine the hypothesis that both lean and fat fractions of meat contribute to this enhancement. Weanling rats were assigned, according to a 3 x 3 factorial design, to one of nine nutritionally complete diets formulated to contain various combinations of protein (lean beef, skim milk or egg white) and fat sources (beef fat, milk fat or partially hydrogenated vegetable fat). Diets contained 20% protein and 20% fat. After 4 d of consuming the assigned diets, the rats were deprived of food overnight and offered a meal of their respective diet labeled extrinsically with 59FeCl3. Feeding of the unlabeled diets was continued for 14 d. Iron absorption was estimated from 59Fe retention, monitored by whole-body counting over the 14-d period. Absorption was highest from diets containing beef regardless of the fat source, but the combination of beef and beef fat was highest of all. In the comparison of absorption from the lean beef and other diets, there was significant interaction between lean beef and fat source on iron absorption. These results suggest that the iron absorption-enhancing properties of meat may involve an interaction between the lean and fat fractions of meat.


Important Pathways:


Iron: Essential but toxic

  • 200 billion new erythrocytes produced daily requires 20 mg of iron for hemoglobin synthesis, accounting for nearly 80% of the iron demand in humans.

  • Anemia affects up to a billion people worldwide.

  • Eukaryotic cells require iron for survival and proliferation: hemoproteins, iron-sulfur (Fe-S) proteins, housekeeping proteins that use iron as a functional cofactor ie. ribonucleotide reductase

  • The importance of iron relates to its chemical properties as a transition metal. It readily engages in one-electron oxidation-reduction reactions between its ferric (3+) and ferrous (2+) states.

  • These same chemical properties explain why an excess of “free,” reactive iron is toxic. Cellular iron is typically ferrous (2+) which can catalyze Fenton chemistry

  • Iron catalyzed radicals damage lipid membranes, proteins, and nucleic acids.

  • Since both cellular iron overload and iron deficiency cause cell death, the levels of reactive iron must be carefully controlled and limited.

  • Most pathologic consequences of systemic iron overload result from chronic iron accumulation in tissues.

  • Diseases that lead to iron overload include: hemochromatosis, thalassemia and sickle cell anemia

  • The dual challenge of avoiding iron deficiency and iron overload requires distinct mechanisms to achieve iron homeostasis in individual cells, in tissues, and systemically


Enterocyte Iron Metabolism


Ferritin solves the oxygen-iron problem.

Ferritin central for Fe and O2 management.

  • Two Types: Animal Specific Ferritin L (FTL) and ubiquitous Ferritin H family (FTH)

  • Ferritin promoters are activated by oxidants such as peroxide and redox active chemicals

  • Regulation mediated through an antioxidant responsive element (ARE) found in the gene promoter?

  • The ARE is found in the promoter of several antioxidant and detoxification genes and allows for a concerted defense against oxidative insults

ARE Pathways

Conclusions

  • FTL DNA (ARE) inducers: redox active compounds and heme

  • FTL mRNA (IRE/IRP) inducers: Physiologic non heme-iron, heme

  • DNA (ARE) + mRNA (IRE) ----HEME----> SYNERGY


A Mechanism for DNA-ARE/mRNA-IRE Synergy


Deficiency Diseases, Detection, Cures:

  • New approaches to solving iron deficiency are critical because the problem remains one of great significance in early childhood as well as in menstruating and pregnant women, where average frequencies of iron deficiency are estimated at 43% and reach 85% in some populations

  • Iron depletion affects not only overall health but also cognitive development. The problem is not restricted to those in poverty or to underdeveloped countries. In Japan, for example, 15% of blood donors are rejected because of iron deficiency and estimates of iron deficits in young women are as high as 25%

  • In the United States, approximately 75% of college-aged women report low iron intake, and suboptimal dietary intake of iron occurs in 90% of pregnant Americans

Iron deficiency can have serious consequences:

  1. Anemia

  2. Impaired cognition


Hunt, J. R Am J Clin Nutr 2003;78:1168-1177

  • Bioavailability of iron, zinc, and other trace minerals from vegetarian diets https://academic.oup.com/ajcn/article/78/3/633S/4690005

  • The high-iron-bioavailability diet = red meat or poultry, refined-cereal and - grain products, no coffee or tea, and foods with 75 mg ascorbic acid in each of the 3 main daily meals

  • The low-iron-bioavailability diet contained no red meat, limited amounts of poultry and fish, legumes and wholegrain cereal and bread products, tea at each meal, and foods with ascorbic acid just sufficient to meet the Recommended Dietary Allowance

  • Figure 2:

Effect of a vegetarian diet on the control of iron absorption in relation to body iron stores (serum ferritin)



How does the body sense iron overload/deficiency?

  • Dietary iron absorption is curtailed when iron stores are high

  • Dietary iron absorption increases in iron deficiency

  • Plasma iron decreases during inflammation and/or infection


What is the molecular mechanism?


Anemia of Infection/Inflammation

  • During infections, microbial invaders must obtain iron for their own metabolic needs

  • Vertebrate hosts have evolved multiple mechanisms to starve microbes of iron during infections

  • Vertebrates respond to infection systemically by rapidly lowering plasma iron concentrations (hypoferremia of inflammation)

  • It is generally believed that this response has a role in host defense, a concept supported by observations that patients with hemochromatosis are more susceptible to certain types of infections

Hepcidin

  • Deemed as the “master regulator” of iron homeostasis

  • Discovered serendipitously when mice with a disrupted upstream unrelated gene developed massive iron overload.

  • Hepcidin gene encodes an 84 amino acid propeptide that is cleaved to form a bioactive 25 amino acid peptide found in plasma and urine.

  • Hepcidin is synthesized in the liver and gene expression is increased by iron overload and inflammation and decreased by hypoxia and anemia.

  • Hepcidin expression is induced in inflammation by interleukin 6 and interleukin 1.

  • Hepcidin expression results in dramatic decreases of plasma iron concentrations. Serum iron levels drop more than 400% within 1hr after injection and remained depressed for 48 hrs

  • Hepcidin gene deletion results in severe iron overload and mutations of the human hepcidin gene have been implicated in the etiology of some forms of the iron overload disease hemochromatosis


Hepcidin expression increases in response to infection and is mediated by IL-6

Injection of Synthetic Hepcidin Causes a Rapid Drop in Serum Iron

Urinary hepcidin in subjects given 65 mg of iron in the morning of days 3, 4, and 5

Hepcidin/ferroportin

  • Hepcidin modulates iron metabolism through interactions with its receptor, ferroportin the only known cellular iron efflux protein.

  • Ferroportin is a basolateral, transmembrane protein that is strongly expressed in placenta, intestine, reticuloendothelial macrophages and hepatocytes.

  • Ferroportin mobilizes iron from cells to the plasma iron carrier transferrin in conjuction with the ferroxidase protein hephaestin.

  • Over expression of ferroportin has been demonstrated to increase iron efflux out of macrophages by 70%.

  • Disruption of the murine ferroportin gene is embryonic lethal due to lack of iron transfer from the extraembryonic visceral endoderm to the placenta.

  • Intestine specific knockout animals are viable but develop severe anemia.

  • Hepcidin induces irreversible internalization of ferroportin through lysomal degradation.

  • The net effect of hepcidin expression and subsequent internalization of ferroportin results in a depletion of plasma iron and accumulation of iron in macrophages and duodenal eneterocytes.

  • Accumulation of iron in these cells creates a feedback circuit; macrophages release less recycled erythrocyte iron and duodenal cells take up less dietary iron which depletes plasma iron as this store is used to synthesize new hemoglobin.

  • It appears that the hepcidin/ferroportin system is the key mechanism to limit iron availability to pathogens as a host defense strategy or increase plasma iron in response to anemia/hypoxia as well as limiting iron efflux from duodenal enterocytes in response to dietary iron overload.

Hepcidin Induces Degradation of the Cellular Iron Efflux Protein Ferroportin

Hepcidin, Obesity and Iron Status

  • Hepcidin mediates the rapid hypoferremic response to inflammation

  • IL-6 increases hepcidin expression and corresponding hypoferremia

  • IL-6 induces hepcidin expression via STAT3 and a STAT3 binding motif (–64–72) in the hepcidin promoter

  • Leptin increases hepcidin expression through the STAT3 pathway

  • Several studies have noted that obesity is related to low iron status

  • Obesity is increasingly being recognized as an inflammatory condition and adipose tissue as an endocrine organ

  • Obesity is characterized by adipocyte hypoxia resulting in increased expression of IL6 in adipose tissue

Obesity and Iron Status

Hepcidin Control of Iron Distribution

The Iron Responsive Element (IRE)/IRE Binding Protein System

Iron and Oxygen Regulation of mRNA (IRE)

The Ferritin IRE Family

How do the IRP proteins act as iron sensors?