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Iron Biochemistry in Nutrition Part 2 October 29, 2014 Challenging topics in nutrition and the biochemistry of iron: • Can newborn children rapidly become iron-deficient? • Does iron-deficiency often develop in women after adolescence? • How does the body regulate uptake and storage of iron? IRON REQUIREMENT: DIETARY RDA COMPARED WITH BIOLOGICAL NEED Absorbed from the diet TOTAL BODY POOL, ~ 3 GRAMS Iron excreted Since absorption is not very efficient (5%-25%), the RDA is much greater than the biological need THIS GRAPHIC DOES NOT TELL THE WHOLE STORY: The type of food MATTERS! Dietary reference intake (RDA): 18 mg ♀ Daily iron requirement: ~2 mg ♀ 1.5 mg / cup 8 mg ♂ ~1 mg ♂ 2.0 mg / 30 g 1.5 mg / 30 g 2.0 mg / 30 g 2.2 mg / cup HOMEWORK ASSIGNMENT: For several foods, determine TOTAL IRON CONTENT vs IRON THAT CAN BE ABSORBED Factors affecting iron absorption Enhance iron uptake Nutrients Endogenous factors Ascorbic acid Enhanced erythropoiesis Dietary protein Low iron stores Iron chelation (e.g., heme) Hemochromatosis Inhibit iron uptake Phytic acid (in dietary fiber) High iron stores Oxalic acid Infection/inflammation Polyphenols (in coffee & tea) Lack of stomach acid Human Milk Compared with Infant Formula for Selected Ingredients Dude, et al, 2010 study. Children that nursed with given fortified foods starting at 6 months. SLIGHT increase in iron-deficiency, group that nursed, but not very substantial. Assessment of iron status Iron Overload Normal Iron Depletion I EXCESS IronIrondeficient deficiency Erythropoiesis Anemia II III Storage Iron Transport Iron Erythron Iron Plasma ferritin (mg/L) > 250 100 60 < 20 10 <10 Plasma iron (mmol/L) 40 20 10 < 20 < 11 <7 > 60 35 15 < 30 < 15 < 10 Transferrin sat (%) Hemoglobin (g/dL) Zn-EPP (μMol/Mole Hb) 12-15 10-40 12-15 12-15 12 < 12 40-90 90-150 150-200 >200 Halterman et al (Pediatrics, 2001) reported that iron-deficient girls (defined by low ferritin) performed less well on math exams. SEVERAL MORE RECENT STUDIES HAVE REPORTED THAT IF WOMEN WITH MODERATE IRON-DEFICENCY (low ferritin, high-Zn-EPP, not anemic) are given iron supplements to improve iron status: They perform better in some academic areas and in athletic competition. IRON REGULATION – HOW DOES THE BODY LIMIT IRON ABSORPTION, AND RELEASE OF STORED IRON? WHAT HAPPENS IF EXCESS IRON ACCUMULATES? Iron overload Primary Iron Overload •Hereditary Hemochromatosis: there is no mechanism to stop absorption of iron from the diet. •If body stores exceed 10 grams or more, excess iron may appear all over the body, in a form that is not safely bound to proteins. HUMANS CANNOT ELIMINATE EXCESS IRON: They can however regulate absorption from the diet, and release from storage. Clinical manifestations of hereditary hemochromatosis (HH) HH results from a gradual accretion of iron over time. Clinical symptoms usually become manifest during the 5th decade of life Toxicity of iron Fe2+ + H2O2 Fe3+ + OH- + OH● Free iron (Fe2+) reacts with hydrogen peroxide to create damaging oxidants. Iron overload is MUCH MORE TOXIC in animals that are deficient in vitamin E and selenium oxidative damage Lipids altered membrane permeability Protein dysfunctional proteins DNA mutations Ascorbate + Fe3+ Fe2+ + O2 Dehydroascorbate + Fe2 Fe3+ + O2- After iron is reduced to Fe2+ (known as ferrous), this form of iron can add its electron to oxygen, forming SUPEROXIDE. Thus, vitamin C can be a PRO-OXIDANT (usually, vitamin C does not cause radical injury). BUT: under some circumstances, this PRO-OXIDANT effect might be beneficial, as seen on the next slide. Reduced iron, formed by vitamin C, acts upon oxygen to form the superoxide ion. Fe(2+) + Fe(3+) + O2- O2 The enzyme superoxide dismutase (SOD), which is very abundant in the extracellular fluid, converts the superoxide to hydrogen peroxide, which can kill some tumor cells. O 2 - + 2 H+ SOD H2O2 THE ABILITY OF HIGH-DOSE VITAMIN C TO CREATE HYDROGEN PEROXIDE HAS POTENTIAL VALUE IN CANCER THERAPY (ONLY TUMOR CELLS ARE DESTROYED.) TO ACHIEVE THESE RESULTS, VITAMIN C IS GIVEN IV, AT DOSES OF 50 GRAMS! Oral doses are not effective. Question: What would happen to iron, if it was absorbed into the mucosal cell, but then was NOT released to the bloostream? FERROPORTIN IS AN IRON-CHANNEL THAT RELEASES IRON TO THE BLOODSTREAM. After iron is absorbed into the mucosal cell of the intestine, ferroportin is needed to move iron to the bloodstream Ferroportin is also needed to release iron from macrophage storage sites, to be used for RBC synthesis. HEPCIDIN IS A SMALL PROTEIN (28 AMINO ACIDS) THAT CAUSES FERROPORTIN TO DISAPPEAR FROM THE CELL SURFACE. This prevents mucosal cells from releasing iron after it was absorbed, and holds stored iron in the hepatocyte. IRON FROM DEGRADED RBC CAN BE RETURNED TO THE BLOODSTREAM TO MAKE NEW RBC. WHAT ELSE CAN HAPPEN TO THAT IRON? IF HEPCIDIN IS HIGH: Low hepcidin: iron leaves mucosal cell for bloodstream High hepcidin: ferroportin is low. iron remains in mucosal cell, is lost from body when the cell is sloughed off HEPCIDIN: a 25-amino acid peptide that blocks release of iron from intestinal cells and storage cells. This model indicates that the iron export channel (ferroportin, Fp) can be blocked. IRON-TRANSFERRIN COMPLEX: Increased bound iron in plasma seems to favor hepcidin production INFLAMMATION: The IL-6 component increase hepcidin The integrated scheme for iron regulation IF IRON ABSORPTION FROM THE GI-TRACT CONTINUES AT HIGH LEVELS EVEN WITH HIGH PLASMA IRON IN PATIENTS WITH HEMACHROMATOSIS.. AFTER MANY YEARS, IRON OVERLOAD MAY DEVELOP! HERE IS NOW A MAJOR LITERATURE ON HEPCIDIN, AND THE PATHWAYS THAT REGULATE IRON UPTAKE AND STORAGE. QUESTION FOR DISCUSSION: Hepcidin is usually only released when iron stores are HIGH. But in some disorders, when there is a lot of inflammation, hepcidin is also released. What would happen to a person, if inflammation caused hepcidin to rise to a very high level in the bloodstream? Central dogma of molecular biology The messenger molecule At the ribosome ribosomes IRON STATUS AFFECTS READING OF mRNA TO MAKE NEW PROTEINS Post-transcriptional regulation of ferritin and transferrin receptor LOW IRON IRE-binding protein ferritin mRNA transferrin receptor mRNA Translation blocked mRNA is stable and translated TRANSFERRIN RECEPTOR MADE NO FERRITIN MADE HIGH IRON Fe Fe mRNA translated FERRITIN MADE mRNA is unstable and degraded NO TRANSFERRIN RECEPTOR MADE Coulson and Cleveland, PNAS, 1993 Study of regulation of the ferritin gene The iron-response element (IRE)is a protein that is activated by extra iron in the cytoplasm. It binds to ferritin mRNA upstream of the translated region, and stops the mRNA from being translated. In the presence of excess iron in the cell, the IRE changes conformation, and no longer binds, allowing the mRNA to be translated. Fe(3+) Fe(3+) Fe(3+) Fe(3+) Fe(3+) Synthesis of iron-containing proteins Cellular iron can be used to make New iron proteins, such as cytochromes Fe(3+) Fe(3+) Fe(3+) Fe(3+) Fe(3+) Packaging into ferritin If there is abundant iron, ferritin can be synthesized. The surplus iron will be package into ferritin MORE IRON THAN CELL NEEDS FERRITIN MADE, IRON PACKAGED CELL IS LOW ON IRON BLOCK SYNTHESIS OF FERRITIN SYNTHESIS OF MUCIN REQUIRES RETINOIC ACID PRODUCTION OF EPO IS ONE OF MANY GENES REGULATED BY RETINOIC ACID