Iron Biochemistryin 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 WITHBIOLOGICAL NEED

TOTAL BODY POOL, ~ 3 GRAMS

Absorbed fromthe diet

Iron excreted

Since absorption is not very efficient (5%-25%),the RDA is much greater than the biological need

THIS GRAPHIC DOES NOT TELL THEWHOLE STORY: The type of food MATTERS!

Dietary reference intake (RDA): 18 mg 8 mg ♂♀

Daily iron requirement: ~2 mg ~1 mg ♂♀

1.5 mg / 30 g

1.5 mg / cup

2.2 mg / cup

2.0 mg / 30 g

2.0 mg / 30 g

HOMEWORK ASSIGNMENT: For several foods, determineTOTAL IRON CONTENT vs IRON THAT CAN BE ABSORBED

Factors affecting iron absorption

Ascorbic acid

Dietary protein

Iron chelation (e.g., heme)

Phytic acid (in dietary fiber)

Oxalic acid

Polyphenols (in coffee & tea)

Enhance iron uptake

Inhibit iron uptake

Nutrients Endogenous factors

Enhanced erythropoiesis

Low iron stores

Hemochromatosis

High iron stores

Infection/inflammation

Lack of stomach acid

Human Milk Compared with Infant Human Milk Compared with Infant Formula for Selected IngredientsFormula 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

Storage Iron

Transport Iron

Erythron Iron

EXCESS

Iron Overload Normal

Iron Depletion

Iron- deficient

Erythropoiesis

Iron- deficiency

Anemia

Plasma ferritin (g/L) > 250 100 60 < 20 10 <10

Plasma iron (mol/L) 40 20 10 < 20 < 11 < 7

Transferrin sat (%) > 60 35 15 < 30 < 15 < 10

Hemoglobin (g/dL) 12-15 12-15 12-15 12 < 12

Zn-EPP (μMol/Mole Hb) 10-40 40-90 90-150 150-200 >200

I II III

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 DOESTHE BODY LIMIT IRON ABSORPTION,

AND RELEASE OF STORED IRON?

WHAT HAPPENS IF EXCESSIRON 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)

Clinical symptoms usually become manifest during the 5th decade of life

HH results from a gradual accretion of iron over time.

Toxicity of iron

Fe2+ + H2O2 Fe3+ + OH- + OH●

Lipids Protein DNA

oxidative damage

altered dysfunctional mutations membrane proteins permeability

Free iron (Fe2+) reacts with hydrogenperoxide to create damaging oxidants.

Iron overload is MUCH MORE TOXICin animals that are deficient invitamin E and selenium

Ascorbate + Fe3+ Dehydroascorbate + Fe2

Fe2+ + O2 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-OXIDANTeffect might be beneficial, as seen on the next slide.

Fe(2+) + O2 Fe(3+) + O2-

Reduced iron, formed by vitamin C, acts upon oxygen to formthe superoxide ion.

O2- + 2 H+ H2O2

SOD

The enzyme superoxide dismutase (SOD), which is veryabundant in the extracellular fluid, converts the superoxide to hydrogen peroxide, which can kill some tumor cells.

THE ABILITY OF HIGH-DOSE VITAMIN C TO CREATEHYDROGEN PEROXIDE HAS POTENTIAL VALUE INCANCER 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 absorbedinto the mucosal cell, but then was NOTreleased to the bloostream?

FERROPORTIN IS AN IRON-CHANNEL THATRELEASES 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 TODISAPPEAR 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 thatthe iron export channel (ferroportin, Fp)can be blocked.

IRON-TRANSFERRIN COMPLEX:Increased bound iron in plasma seemsto favor hepcidin production

INFLAMMATION:The IL-6 componentincrease hepcidin

The integrated scheme for iron regulation

IF IRON ABSORPTION FROM THE GI-TRACTCONTINUES AT HIGH LEVELS EVENWITH HIGH PLASMA IRON INPATIENTS WITH HEMACHROMATOSIS..

AFTER MANY YEARS, IRON OVERLOADMAY DEVELOP!

HERE IS NOW A MAJOR LITERATURE ONHEPCIDIN, AND THE PATHWAYS THATREGULATE IRON UPTAKE AND STORAGE.

QUESTION FOR DISCUSSION:

Hepcidin is usually only released when iron stores are HIGH. But in some disorders, whenthere is a lot of inflammation, hepcidin is alsoreleased.

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

IRON STATUS AFFECTSREADING OF mRNA

TO MAKE NEW PROTEINS

At theribosomeribosomes

The messenger molecule

Post-transcriptional regulation of ferritin and transferrin receptor

ferritin mRNA transferrin receptor mRNA

Translation blocked

NO FERRITIN MADE

mRNA is stable and translated

TRANSFERRIN RECEPTOR MADE

LOW IRON

IRE-binding protein

HIGH IRON

mRNA translated

FERRITIN MADE

Fe

mRNA is unstable and degraded

NO TRANSFERRIN RECEPTOR MADE

Fe

Coulson and Cleveland, PNAS, 1993

Study of regulation of the ferritin gene

The iron-response element (IRE)is a protein thatis activated by extra iron in the cytoplasm.It binds to ferritin mRNA upstream of thetranslated region, and stops the mRNAfrom being translated.

In the presence of excess iron in the cell,the IRE changes conformation, and no longerbinds, 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 makeNew iron proteins, such as cytochromes

Fe(3+)

Fe(3+)

Fe(3+)

Fe(3+)Fe(3+)

Packaging intoferritin

If there is abundant iron, ferritin canbe synthesized. The surplus iron

will be package into ferritin

MORE IRON THAN CELL

NEEDS

FERRITIN MADE,IRON PACKAGED

CELL IS LOWON IRON

BLOCK SYNTHESISOF FERRITIN

SYNTHESISOF MUCINREQUIRES

RETINOIC ACID

PRODUCTION OF EPO IS ONE OF MANY GENESREGULATED BY RETINOIC ACID