Download LECTURE NOTES: Iron in nutrition, Part 2

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