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COMMONWEALTH OF AUSTRALIA Copyright Regulations 1968
WARNING This material has been reproduced and communicated to you by or on behalf of University of Queensland pursuant to Part VB of the Copyright Act 1968 (the Act ; a copy of the Act is available at SCALEplus the legal information retrieval system owned by the Australian Attorney General's Department, at http://scaleplus.law.gov.au). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Information or material from this material may be used for the purposes of private study, research, criticism or review, as permitted under the Act and may only be reproduced as permitted under the Act Do not remove this notice.
Iron Metabolism: Too little, too much!
Justin Ridge & Simon Worrall School of Chemistry and Molecular Biosciences
MEDI1012 - Biochemistry
Iron A metallic element
Toxic but also an essential nutrient
An important component of many macromolecules
Able to undergo redox reactions (Fe2+, Fe3+, Fe4+)
35mg/kg in women and 45 mg/kg in men
MEDI1012 - Biochemistry
Fe 26
55.85
Iron Content of Foods Iron is found in virtually all foods. Two types:
Non-haem – fruits, vegetables, grain products
Haem – meat and poultry
MEDI1012 - Biochemistry
RDA
Males 8 mg
Females 18 mg
Pregnant 27 mg
RDA for vegetarians
Males 40 mg
Females 60 mg
Iron Trafficking
MEDI1012 - Biochemistry
Total Body Pools Males 3.5g Females 2.5g
DIET 10 mg/
day
GUT
Labile Iron
ECF
FAECES
Plasma
1 mg/day
Ferritin
~11.5%
RES
RBC
~70%
Immature RBC
Enzyme cofactor ~10%
Haemosiderin
~10%
Iron stores
Absorption of Dietary Iron Two forms of Fe in diet:
Non-haem & haem
Main mechanism for non-haem is well understood.
Occurs in first part of the duodenum.
Requires an acidic environment.
Mechanism for haem is as yet unknown but is very efficient.
MEDI1012 - Biochemistry
Duodenal Absorption of Ferrous Iron
MEDI1012 - Biochemistry
Gut Lumen Blood Enterocyte
Fe3+ Fe2+
Tf
vitamin C ferrireductase
Fe2+ Fe2+
H+
DMT1 H+
DMT1 (Nramp1): Fe, Zn, Mn, Co, Cd, Cu, Ni and Pb.
Fe3+
Cp Ferritin (Fe3+)
Fe2+
Hp
Ireg-1
Ceruloplasmin (Cp) Plasma protein
Carries Cu from liver to periphery
Controls oxidation reduction reactions of Fe, Fe transport & utilization
Hephaestin analogous but has a trans-membrane domain at C-terminus
MEDI1012 - Biochemistry Ft
O2 or –S-S-
H2O or –SH
Cp Cu2+ Cp Cu+
Fe2+ Fe3+
Tf
Proposed Duodenal Absorption of Haem Iron
MEDI1012 - Biochemistry
Gut Lumen Enterocyte
haemoglobin
haem
globins are proteolysed
inorganic Fe
Metallo-porphyrin (H)
degraded by haem oxidase
Endocytosis ????
Transferrin – Fe transporter Soluble protein synthesised by the liver
Active as a monomer (80kDa)
Each monomer binds two Fe in ferric form
Is at a large excess in plasma
Delivers Fe from the blood to all cells e.g. erythroid precursors
MEDI1012 - Biochemistry
Transmembrane Iron Transport
MEDI1012 - Biochemistry
1. Tf binds to receptor
2. Receptor endocytosed
3. Endosome acidified
4. Reduced Fe pumped out of endosome
5. Tf and TfR returned to membrane
i
TfR DMT1
5
1
endocytosis 2
i
endosomes H+
3
i
4
DMT1
ferric reductase
Fe3+ → Fe2+
H+
Regulation of iron uptake
Uptake of iron affected by two proteins:
HFE
Hepcidin
MEDI1012 - Biochemistry
HFE Originally known as HLA-H and expressed by most
cell types Binds β2-microglobulin
Also binds to the Tf receptor (TfR) with high affinity. Binding of HFE to TfR leads to HFE stabilisation.
Binding halves the capacity of TfR for Tf and decreases the affinity for apoTf or Tf-Fe.
Decreases iron retention in the cell (some types)
MEDI1012 - Biochemistry
HFE
MEDI1012 - Biochemistry Based on Roy et al. J. Biol. Chem. 274:9022, 1999.
HFE
Fe Fe
Fe
DMT 1
H+
HFE: 1. Decreases TfR capacity 2. Stabilises Tf binding to TfR; less Fe is released into endosome; Tf returns to cell surface carrying Fe HFE
Fe Fe
Hepcidin 25 aa peptide (hec-25) synthesized by
hepatocytes Induced by dietary iron overload
Expression affected by: Plasma conc. of TfFe2 (via TfR)
Hepatocyte Fe stores (indirect; changes in TfR)
Released into blood Acts at enterocytes
Acts at RE macrophages and crypt cells
MEDI1012 - Biochemistry
Hepcidin Action on Enterocytes
Hepcidin interacts with ferroportin (ireg1) Causes internalisation
Decreased Fe export
Fe accumulation leads to Decrease of expression
of DMT; Vit C ferrireductase
Shedding of enterocytes
Net loss of Fe
MEDI1012 - Biochemistry
Action of Hepcidin on Crypt Cells and Macrophages
Interacts with β2-HFE-TfR1
Increase Fe uptake
Crypt cells differentiate with reduced expression of Fe transport proteins
Reduced Fe uptake
MEDI1012 - Biochemistry From Fleming, R. E. & Sly, W. S. (2001) PNAS 98:8160–8162.
Intra-Cellular Storage of Iron Ferritin
Apoferritin consists of a mixture 24 subunits (H or L) H chains oxidise Fe2+ → Fe3+
Synthesis regulated by intracellular [Fe] Each ferritin complex can bind up to 4,500 Fe
Haemosiderin Amorphous Fe deposited near ferritin when capacity
exceeded
Frataxin A potential Fe storage protein in mitochondria (Fe-
dependent function????)
MEDI1012 - Biochemistry
Regulation of Gene Expression by Iron
The expression of these human genes is known to be controlled by intracellular [Fe] in all cells Transferrin receptor
Ferritin DMT1 Ireg-1
γ-aminolevulinate synthase (Hb synthesis) Transferrin (in liver)
MEDI1012 - Biochemistry
Post-transcriptional Control
MEDI1012 - Biochemistry
Iron Deficiency
IRE-BP Inactive Active
5’ AAAAAA
Inhibited degradation
5’ AAAAAA
TfR mRNA
IRE-BP
= increased translation
IRE-BP
ferritin mRNA
No translation
5’ AAAAAA
IRE-BP
5’ AAAAAA
IRE-BP
Congenital Diseases Associated with Iron Metabolism
MEDI1012 - Biochemistry
Disease Affected Gene Function
Haemochromatosis HFE Modulation of Fe transport
Friedrich’s ataxia FRDA Frataxin – a putative Fe storage protein
Hallervorden-Spatz PANK2 Hb synthesis
Hyperferritinaemia-cataract
IRE of L-ferritin mRNA
Fe storage protein
Hypotransferrin-aemia Transferrin (?) Fe transport
Hereditary Haemochromatosis (HH)
Hereditary disorder of small intestine Autosomal, recessive Over-adsorption of Fe from food Organs such as pancreas, liver, and skin store the
excess Fe damage Untreated, it can result in liver disease, heart disease,
and diabetes.
The most common form of Fe overload disease.
Incidence: ~1 in 200 have mutations in HFE gene; affects ~73,000 people in Australia.
MEDI1012 - Biochemistry
Hereditary Haemochromatosis (HH)
Symptoms include: Weakness, fatigue
Abdominal pain, muscle aches, finger joint pain
Shortness of breath with physical exertion
Increased skin pigmentation (bronze colour), loss of body hair
Hepatomegaly
MEDI1012 - Biochemistry
Iron Toxicity
MEDI1012 - Biochemistry
Fe2+ Fe3+
O2 O2- Fe2+ OH
H2O2 H2O Cellular Damage catalase &
peroxidases
Superoxide dismutase
Tissue damage induces fibrosis
Brown, granular pigment indicates the presence of iron in hepatocytes.
Histopathology
MEDI1012 - Biochemistry
Hereditary Haemochromatosis (HH)
Two major hypotheses have been proposed to explain the pathogenesis of HFE-related HH: The hepcidin hypothesis
The duodenal crypt cell programming hypothesis
MEDI1012 - Biochemistry
The Hepcidin Hypothesis - 1
MEDI1012 - Biochemistry
ANRV368-PM04-20 ARI 9 December 2008 15:27
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Ferroportin-mediated
iron export
Reducedplasma iron
Increasediron uptake
Reduced plasmahepcidin levels
Ferroportin
HepcidinFe
Degradedferroportin
Reducediron stores
Hepatocy
Ferrome
iron
asmavels
Reduced hepcidin
expression
Iron deficiency
Macrophage
Plasma
Intestinalenterocyte
Ferroportin-mediated
iron export
Normalplasma iron
Normal plasmahepcidin levels
Hepcidin-mediated
ferroportindegradation
Macrophage
Normaliron stores
Hepatocyte
pmediat
iron exp
smavels
Basal hepcidinexpression
Normal iron absorption
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Lowplasma iron
High plasmahepcidin levels
Hepatocyte
mavels
High hepcidinexpression
Anemia of inflammatory disease
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Increasedplasma iron
High plasmahepcidin levels
Hepcidin-mediatedferroportin
degradation
Macrophage
Increasediron stores
Hepatocyte
mavels
Hepcidinferro
degr
High hepcidinexpression
Iron overload
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Increasedferroportin-
mediatedIron export
Increasedferroportin-
mediatedIron export
Highplasma iron
Low plasmahepcidin levels
Macrophage
Lowiron stores
pladin levels
Low hepcidinexpression
Hemochromatosis
a
b c
d e
Decreasediron uptake
Highiron uptake
Plasma
enterocyte
Lowplasma iron
Elevatedon uptaIr ke
iron accumulation
Macrophage
seasemmatory dis
ironaccumulation
Hepcidin-mediatedferroportin
degradation
Highplasma iron
asmal l
High iron
Normaliron uptake
492 Lee · Beutler
Ann
u. R
ev. P
atho
l. M
ech.
Dis
. 200
9.4:
489-
515.
Dow
nloa
ded
from
ww
w.a
nnua
lrevi
ews.o
rgby
Uni
vers
ity o
f Que
ensl
and
on 0
9/01
/10.
For
per
sona
l use
onl
y.
ANRV368-PM04-20 ARI 9 December 2008 15:27
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Ferroportin-mediated
iron export
Reducedplasma iron
Increasediron uptake
Reduced plasmahepcidin levels
Ferroportin
HepcidinFe
Degradedferroportin
Reducediron stores
Hepatocy
Ferrome
iron
asmavels
Reduced hepcidin
expression
Iron deficiency
Macrophage
Plasma
Intestinalenterocyte
Ferroportin-mediated
iron export
Normalplasma iron
Normal plasmahepcidin levels
Hepcidin-mediated
ferroportindegradation
Macrophage
Normaliron stores
Hepatocyte
pmediat
iron exp
smavels
Basal hepcidinexpression
Normal iron absorption
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Lowplasma iron
High plasmahepcidin levels
Hepatocyte
mavels
High hepcidinexpression
Anemia of inflammatory disease
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Increasedplasma iron
High plasmahepcidin levels
Hepcidin-mediatedferroportin
degradation
Macrophage
Increasediron stores
Hepatocyte
mavels
Hepcidinferro
degr
High hepcidinexpression
Iron overload
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Increasedferroportin-
mediatedIron export
Increasedferroportin-
mediatedIron export
Highplasma iron
Low plasmahepcidin levels
Macrophage
Lowiron stores
pladin levels
Low hepcidinexpression
Hemochromatosis
a
b c
d e
Decreasediron uptake
Highiron uptake
Plasma
enterocyte
Lowplasma iron
Elevatedon uptaIr ke
iron accumulation
Macrophage
seasemmatory dis
ironaccumulation
Hepcidin-mediatedferroportin
degradation
Highplasma iron
asmal l
High iron
Normaliron uptake
492 Lee · Beutler
Ann
u. R
ev. P
atho
l. M
ech.
Dis
. 200
9.4:
489-
515.
Dow
nloa
ded
from
ww
w.a
nnua
lrevi
ews.o
rgby
Uni
vers
ity o
f Que
ensl
and
on 0
9/01
/10.
For
per
sona
l use
onl
y.
ANRV368-PM04-20 ARI 9 December 2008 15:27
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Ferroportin-mediated
iron export
Reducedplasma iron
Increasediron uptake
Reduced plasmahepcidin levels
Ferroportin
HepcidinFe
Degradedferroportin
Reducediron stores
Hepatocy
Ferrome
iron
asmavels
Reduced hepcidin
expression
Iron deficiency
Macrophage
Plasma
Intestinalenterocyte
Ferroportin-mediated
iron export
Normalplasma iron
Normal plasmahepcidin levels
Hepcidin-mediated
ferroportindegradation
Macrophage
Normaliron stores
Hepatocyte
pmediat
iron exp
smavels
Basal hepcidinexpression
Normal iron absorption
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Lowplasma iron
High plasmahepcidin levels
Hepatocyte
mavels
High hepcidinexpression
Anemia of inflammatory disease
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Increasedplasma iron
High plasmahepcidin levels
Hepcidin-mediatedferroportin
degradation
Macrophage
Increasediron stores
Hepatocyte
mavels
Hepcidinferro
degr
High hepcidinexpression
Iron overload
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Increasedferroportin-
mediatedIron export
Increasedferroportin-
mediatedIron export
Highplasma iron
Low plasmahepcidin levels
Macrophage
Lowiron stores
pladin levels
Low hepcidinexpression
Hemochromatosis
a
b c
d e
Decreasediron uptake
Highiron uptake
Plasma
enterocyte
Lowplasma iron
Elevatedon uptaIr ke
iron accumulation
Macrophage
seasemmatory dis
ironaccumulation
Hepcidin-mediatedferroportin
degradation
Highplasma iron
asmal l
High iron
Normaliron uptake
492 Lee · Beutler
Ann
u. R
ev. P
atho
l. M
ech.
Dis
. 200
9.4:
489-
515.
Dow
nloa
ded
from
ww
w.a
nnua
lrevi
ews.o
rgby
Uni
vers
ity o
f Que
ensl
and
on 0
9/01
/10.
For
per
sona
l use
onl
y.
Lee and Beutler Annu. Rev. Pathol. Mech. Dis. 2009. 4:489–515
The Hepcidin Hypothesis - 2
MEDI1012 - Biochemistry
Lee and Beutler Annu. Rev. Pathol. Mech. Dis. 2009. 4:489–515
ANRV368-PM04-20 ARI 9 December 2008 15:27
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Ferroportin-mediated
iron export
Reducedplasma iron
Increasediron uptake
Reduced plasmahepcidin levels
Ferroportin
HepcidinFe
Degradedferroportin
Reducediron stores
Hepatocy
Ferrome
iron
asmavels
Reduced hepcidin
expression
Iron deficiency
Macrophage
Plasma
Intestinalenterocyte
Ferroportin-mediated
iron export
Normalplasma iron
Normal plasmahepcidin levels
Hepcidin-mediated
ferroportindegradation
Macrophage
Normaliron stores
Hepatocyte
pmediat
iron exp
smavels
Basal hepcidinexpression
Normal iron absorption
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Lowplasma iron
High plasmahepcidin levels
Hepatocyte
mavels
High hepcidinexpression
Anemia of inflammatory disease
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Increasedplasma iron
High plasmahepcidin levels
Hepcidin-mediatedferroportin
degradation
Macrophage
Increasediron stores
Hepatocyte
mavels
Hepcidinferro
degr
High hepcidinexpression
Iron overload
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Increasedferroportin-
mediatedIron export
Increasedferroportin-
mediatedIron export
Highplasma iron
Low plasmahepcidin levels
Macrophage
Lowiron stores
pladin levels
Low hepcidinexpression
Hemochromatosis
a
b c
d e
Decreasediron uptake
Highiron uptake
Plasma
enterocyte
Lowplasma iron
Elevatedon uptaIr ke
iron accumulation
Macrophage
seasemmatory dis
ironaccumulation
Hepcidin-mediatedferroportin
degradation
Highplasma iron
asmal l
High iron
Normaliron uptake
492 Lee · Beutler
Ann
u. R
ev. P
atho
l. M
ech.
Dis
. 200
9.4:
489-
515.
Dow
nloa
ded
from
ww
w.a
nnua
lrevi
ews.o
rgby
Uni
vers
ity o
f Que
ensl
and
on 0
9/01
/10.
For
per
sona
l use
onl
y.
ANRV368-PM04-20 ARI 9 December 2008 15:27
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Ferroportin-mediated
iron export
Reducedplasma iron
Increasediron uptake
Reduced plasmahepcidin levels
Ferroportin
HepcidinFe
Degradedferroportin
Reducediron stores
Hepatocy
Ferrome
iron
asmavels
Reduced hepcidin
expression
Iron deficiency
Macrophage
Plasma
Intestinalenterocyte
Ferroportin-mediated
iron export
Normalplasma iron
Normal plasmahepcidin levels
Hepcidin-mediated
ferroportindegradation
Macrophage
Normaliron stores
Hepatocyte
pmediat
iron exp
smavels
Basal hepcidinexpression
Normal iron absorption
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Lowplasma iron
High plasmahepcidin levels
Hepatocyte
mavels
High hepcidinexpression
Anemia of inflammatory disease
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Increasedplasma iron
High plasmahepcidin levels
Hepcidin-mediatedferroportin
degradation
Macrophage
Increasediron stores
Hepatocyte
mavels
Hepcidinferro
degr
High hepcidinexpression
Iron overload
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Increasedferroportin-
mediatedIron export
Increasedferroportin-
mediatedIron export
Highplasma iron
Low plasmahepcidin levels
Macrophage
Lowiron stores
pladin levels
Low hepcidinexpression
Hemochromatosis
a
b c
d e
Decreasediron uptake
Highiron uptake
Plasma
enterocyte
Lowplasma iron
Elevatedon uptaIr ke
iron accumulation
Macrophage
seasemmatory dis
ironaccumulation
Hepcidin-mediatedferroportin
degradation
Highplasma iron
asmal l
High iron
Normaliron uptake
492 Lee · Beutler
Ann
u. R
ev. P
atho
l. M
ech.
Dis
. 200
9.4:
489-
515.
Dow
nloa
ded
from
ww
w.a
nnua
lrevi
ews.o
rgby
Uni
vers
ity o
f Que
ensl
and
on 0
9/01
/10.
For
per
sona
l use
onl
y.
ANRV368-PM04-20 ARI 9 December 2008 15:27
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Ferroportin-mediated
iron export
Reducedplasma iron
Increasediron uptake
Reduced plasmahepcidin levels
Ferroportin
HepcidinFe
Degradedferroportin
Reducediron stores
Hepatocy
Ferrome
iron
asmavels
Reduced hepcidin
expression
Iron deficiency
Macrophage
Plasma
Intestinalenterocyte
Ferroportin-mediated
iron export
Normalplasma iron
Normal plasmahepcidin levels
Hepcidin-mediated
ferroportindegradation
Macrophage
Normaliron stores
Hepatocyte
pmediat
iron exp
smavels
Basal hepcidinexpression
Normal iron absorption
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Lowplasma iron
High plasmahepcidin levels
Hepatocyte
mavels
High hepcidinexpression
Anemia of inflammatory disease
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Increasedplasma iron
High plasmahepcidin levels
Hepcidin-mediatedferroportin
degradation
Macrophage
Increasediron stores
Hepatocyte
mavels
Hepcidinferro
degr
High hepcidinexpression
Iron overload
Macrophage
Plasma
Hepatocyte
Intestinalenterocyte
Increasedferroportin-
mediatedIron export
Increasedferroportin-
mediatedIron export
Highplasma iron
Low plasmahepcidin levels
Macrophage
Lowiron stores
pladin levels
Low hepcidinexpression
Hemochromatosis
a
b c
d e
Decreasediron uptake
Highiron uptake
Plasma
enterocyte
Lowplasma iron
Elevatedon uptaIr ke
iron accumulation
Macrophage
seasemmatory dis
ironaccumulation
Hepcidin-mediatedferroportin
degradation
Highplasma iron
asmal l
High iron
Normaliron uptake
492 Lee · Beutler
Ann
u. R
ev. P
atho
l. M
ech.
Dis
. 200
9.4:
489-
515.
Dow
nloa
ded
from
ww
w.a
nnua
lrevi
ews.o
rgby
Uni
vers
ity o
f Que
ensl
and
on 0
9/01
/10.
For
per
sona
l use
onl
y.
The Duodenal Crypt Cell Programming Hypothesis - 1
Villus enterocytes differentiate from crypt cells during migration from the crypts to the apex of the villus. The crypt cells sense plasma Fe via the HFE-TfR1 complex
on the basolateral surface
Program the level of Fe transport expressed on differentiation to villus absorptive enterocytes.
In HFE-related HH Loss of functional HFE protein
Decreased TfR1-mediated Fe uptake by crypt cells
Relatively Fe-deficient enterocyte phenotype; increased Fe absorption by the villus enterocytes.
MEDI1012 - Biochemistry
The Duodenal Crypt Cell Programming Hypothesis - 2
MEDI1012 - Biochemistry Fleming, R. E. et al. (2004) Clin. Liver Dis. 8:755– 73
Iron Deficiency and Anaemia The most common cause of anaemia
Characterised by small, pale RBCs and Fe depletion
Major causes are: 1. Blood loss (occult GI & menstrual bleeding) 2. Pregnancy (loss of Fe to foetus)
3. Rapid growth (esp. 0-2 yr) 4. Maladsorption
5. Dietary insufficiency
MEDI1012 - Biochemistry
What do RBCs look like?
MEDI1012 - Biochemistry
Normal peripheral blood smear
Anaemic peripheral blood smear
Pathophysiology of Anaemia Fe loss exceeds Fe intake leading to depletion of
storage Fe.
Fe stores can no longer support needs of erythroid marrow.
Anaemia with normal appearing RBCs.
Microcytosis and then hypochromia.
Fe deficiency affects all tissues.
MEDI1012 - Biochemistry
Iron Deficiency and the Immune System
Low Fe can protect against some infectious agents e.g. plasmodia (malaria) and mycobacteria (TB)
Generally it results in immune deficits
↓ macrophage bacteriocidal activity
↓ neutrophil myeloperoxidase activity
↓ T-cell number
Humoral function is spared.
MEDI1012 - Biochemistry
Other Effects of Iron Deficiency
Pregnancy
↓ birth weight
↓ length of gestation (prematurity)
Skeletal muscle
lethargy, apathy, listlessness
decreased exercise tolerance
altered metabolism e.g. ↑ lactate production
MEDI1012 - Biochemistry
References Lee and Beutler (2009) Regulation of Hepcidin and Iron-
Overload Disease Annu. Rev. Pathol. Mech. Dis. 4:489–515
Fleming, R. E. et al. (2004) Pathogenesis of hereditary hemochromatosis. Clin. Liver Dis. 8:755– 773
Roy et al. (1999) The hereditary hemochromatosis protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells. J. Biol. Chem. 274:9022.
Garrick & Garrick (2009) Cellular Iron Transport. Biochimica et Biophysica Acta 1790:309–325
MEDI1012 - Biochemistry