The metabolic functions of the liverThe metabolic functions of the liver
Catabolism of haemoglobin, bilirubinCatabolism of haemoglobin, bilirubin
Metabolism of iron
Biochemistry II
Lecture 4 2008 (J.S.)
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The major metabolic functions of the liver:
– uptake of most nutrients from the gastrointestinal tract,– uptake of most nutrients from the gastrointestinal tract,
– intensive intermediary metabolism, conversion of nutrients,
– controlled supply of essential compounds (glucose, VLD lipoproteins,
ketone bodies, plasma proteins, etc.),ketone bodies, plasma proteins, etc.),
– ureosynthesis, biotransformation of xenobiotics (detoxification),
– excretion (cholesterol, bilirubin, hydrophobic compounds, some metals).
V. cava inf.
Hepatic veins
Portal vein
2A. hepatica
The hepatocytes (the hepatic parenchymal cells) have an immensely broad range
of synthetic and catabolic functions with a substantial reserve metabolic capacity.of synthetic and catabolic functions with a substantial reserve metabolic capacity.
Many of them are the specialized metabolic functions of the liver:
Metabolism of saccharides
– Primary regulation of the blood glucose concentration. E.g. in the postprandial
state, there is an uptake of about 60 % of glucose supplied in portal bloodstate, there is an uptake of about 60 % of glucose supplied in portal blood
and stored as glycogen, or in hypoglycaemia, glycogenolysis
and gluconeogenesis is initiated.
– The liver cells meet their energy requirements preferentially from fatty acids, not– The liver cells meet their energy requirements preferentially from fatty acids, not
from glycolysis. Glucose (also as glycogen store) is altruistically spared for
extrahepatic tissues.extrahepatic tissues.
Metabolism of lipids
– Completion and secretion of VLDL and HDL.– Completion and secretion of VLDL and HDL.
– Ketogenesis produces ketone bodies, precious nutrients. They cannot be utilized
in the liver, but they are supplied to other tissues.
– Secretion of cholesterol and bile acids into the bile represents the major way of– Secretion of cholesterol and bile acids into the bile represents the major way of
cholesterol elimination from the body.
– Dehydrogenation of cholesterol to 7-dehydrocholesterol and 25-hydroxylation of
calciols play an essential role in calcium homeostasis.
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calciols play an essential role in calcium homeostasis.
Metabolism of nitrogenous compoundsMetabolism of nitrogenous compounds
– Deamination of amino acids that are in excess of requirements.
– Intensive proteosynthesis of major plasma proteins and blood-clotting factors.
– Uptake of ammonium, ureosynthesis.– Uptake of ammonium, ureosynthesis.
– Bilirubin capturing, conjugation, and excretion.
Biotransformation of xenobioticsBiotransformation of xenobiotics
– Detoxification of drugs, toxins, excretion of some metals.
Transformation of hormones
– Inactivation of steroid hormones – hydrogenation, conjugation.– Inactivation of steroid hormones – hydrogenation, conjugation.
– Inactivation of insulin, about 50 % insulin inactivated in its only passage through
the liver (GSH:insulin transhydrogenase splits the disulfide bonds, then
proteolysis of the two chains).proteolysis of the two chains).
– Inactivation of catecholamines and iodothyronines, conjugation of the products.
VitaminsVitamins
– Hydroxylation of calciols to calcidiols, splitting of β-carotene to retinol.
– The liver represent a store of retinol esters and cobalamin (B12).
Iron and copper metabolism
– Synthesis of transferrin, coeruloplasmin, ferritin stores, excretion of copper.
4
The liver parenchymal cell (hepatocyte)
Columns (cords) of hepatocytes are surrounded by sinusoids lined by endothelialColumns (cords) of hepatocytes are surrounded by sinusoids lined by endothelial
fenestrated layer (without a basement membrane) and Kupffer cells (mononuclear
phagocytes).
Plasmatic membrane directed to the space of Disse – the "blood" pole,
the "bile" pole – lateral parts of the membrane with gap junctions and parts
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the "bile" pole – lateral parts of the membrane with gap junctions and parts
forming bile capillaries.
v. hepatica → v. cava inferiorv. hepatica → v. cava inferior
The liver receives venous blood
from the intestine. Thus all thefrom the intestine. Thus all the
products of digestion, in addition
to ingested drugs and other
a. hepatica
to ingested drugs and other
xenobiotics, perfuse the liver
before entering the systemic
circulation. a. hepatica
v. portae
The mixed portal and arterial
blood flows through sinusoids
circulation.
v. portaeblood flows through sinusoids
between columns of hepatocytes.
Hepatocytes are differentiated
in their functions according to thein their functions according to the
decreasing pO2. In a simple liver acini,
there are three zones equipped with
different enzymes.
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ductus choledochusdifferent enzymes.
Hexagonal hepatic lobules
round terminal hepatic venulesround terminal hepatic venules
are not functional units
simple liver ACINUS – a functional unit
efferent vessels
at least two terminal
hepatic venules
arterial blood
bile ductules
portal (venous) blood
from intestine, pancreas,
and spleen
arterial blood
terminal branches
aa. hepaticae
portal field with afferent vessels
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portal field with afferent vessels
Metabolic areas in the acini
ZONE 3
terminal hepatic venule
ZONE 1
terminal hepatic venulebile ductule
art. hepatica
terminal
portal venule
Zone 1 – periportal area Zone 3 – microcirculatory periphery
terminal hepatic venulebile ductule
high pO2
cytogenesis, mitosis
numerous mitochondria
low pO2
high activity of ER (cyt P450, detoxification)
pentose phosphate pathwaynumerous mitochondria
glycogenesis and glycogenolysis
proteosynthesis
ureosynthesis
pentose phosphate pathway
hydrolytic enzymes
glycogen stores, fat and pigment stores
glutamine synthesis
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ureosynthesis glutamine synthesis
Liver of a patient who died in hepatic coma:.
Seastar-shaped necrotic lesion around the terminal hepatic venule. ThisSeastar-shaped necrotic lesion around the terminal hepatic venule. This
shape is produced by necrosis creeping along zones 3 of the simple acini,
intercalating between them and reaching portal spaces.
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Liver – production of bile
Mass concentration / g/l
Composition of bile Hepatic bile Gall-bladder bile
Mass concentration / g/l
Inorganic salts 8.4 6.5Inorganic salts 8.4 6.5
Bile acids 7 – 14 32 – 115
Cholesterol 0.8 – 2.1 3.1 – 16.2Cholesterol 0.8 – 2.1 3.1 – 16.2
Bilirubin glucosiduronates 0.3 – 0.6 1.4
Phospholipids 2.6 – 9.2 5.9
Proteins 1.4 – 2.7 4.5
pH 7.1 – 7.3 6.9 – 7.7pH 7.1 – 7.3 6.9 – 7.7
Functions
The bile acids emulsify lipids and fat-soluble vitamins in the intestine. HighThe bile acids emulsify lipids and fat-soluble vitamins in the intestine. High
concentrations of bile acids and phospholipids stabilize micellar dispersion
of cholesterol in the bile (crystallization of cholesterol → cholesterol gall-stones).
Excretion of cholesterol and bile acids is the major way of removing cholesterol fromExcretion of cholesterol and bile acids is the major way of removing cholesterol from
the body. Bile also removes hydrophobic metabolites, drugs, toxins and metals
(e.g. copper, zinc, mercury).
Neutralization of the acid chyme in conjunction with HCO – from pancreatic secretion.
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Neutralization of the acid chyme in conjunction with HCO3
– from pancreatic secretion.
Degradation of haemoglobin to bilirubin– bile pigments
Erythrocytes are taken up by the reticuloendothelial cells (cells of theErythrocytes are taken up by the reticuloendothelial cells (cells of the
spleen, bone marrow, and Kupffer cells in the liver) by phagocytosis.
ααααHaemoglobin CO
3 O2
Verdoglobin IX-α
Haem oxygenaseHaem oxygenase
(NADPH:cyt P450 oxidoreductase)
Fe3+
globin
Biliverdin IX-α
Biliverdin reductase
NADPH
Biliverdin reductase
In blood plasma, hydrophobic bilirubin molecules (called unconjugated bilirubin) are
Bilirubin IX-α
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In blood plasma, hydrophobic bilirubin molecules (called unconjugated bilirubin) are
transported in the form of complexes bilirubin-albumin.
Bilirubin IXααααBilirubin IXαααα
configuration 4Z,15Z
4
15
Polarity of the two carboxyl groups of unconjugated bilirubin is masked by
formation of hydrogen bonds between the carboxyl groups and the electronegative
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formation of hydrogen bonds between the carboxyl groups and the electronegative
atoms within the opposite halves of bilirubin molecules.
The hepatic uptake, conjugation, and excretion of bilirubin
)(bilirubin-albumin complex)
in hepatic sinusoids
UNCONJUGATED bilirubin
Albumin
plasma membrane of hepatocytes
Albumin
Ligandin
the amount that can leak from excretion
Bilirubin receptor
(bilitranslocase)
Ligandin
(protein Y)
UDP-glucuronate
terminal bile
ductule
UDP
glucosyluronate
transferase
on ER membranes
CONJUGATED bilirubin
is polar, water-soluble –
on ER membranes
bilirubin monoglucosiduronate
is polar, water-soluble –
active transport into bile
capillaries in the form of micelles
depends on the bile acids
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bilirubin monoglucosiduronate
bilirubin bisglucosiduronate
depends on the bile acids
The formation of urobilinoids by the intestinal microflora
Conjugated bilirubin
is secreted into the bile. As far as
bilirubin remains in the conjugated form,bilirubin remains in the conjugated form,
it cannot be absorbed in the small intestine.
In the large intestine,In the large intestine,
bacterial reductases and β-glucuronidases
catalyze deconjugation and hydrogenation
of free bilirubin to mesobilirubin and urobilinogens:
4 H (vinyl → ethyl)
GlcUA
of free bilirubin to mesobilirubin and urobilinogens:
A part of urobilinogens is split to
dipyrromethenes, which can condense
4 H (reduction of bridges)
mesobilirubin
dipyrromethenes, which can condense
to give intensively coloured bilifuscins.
Urobilinogens are partly
i-urobilinogen
Urobilinogens are partly
– absorbed (mostly removed by
the liver), a small part appears
in the urine, urobilin
2 H
4 H
in the urine,
– partly excreted in the feces;
on the air, they are oxidized
to dark brown faecal urobilins.
urobilin
2 H
stercobilinogen
14(l-urobilinogen)
to dark brown faecal urobilins.
stercobilin
stercobilinogen
Healthy individuals: Plasma: unconj. bilirubin-albumin complex
< 20 µµµµmol / l
Uptake of bilirubin,
< 20 µµµµmol / l
bilirubin ← haemoglobin
V. lienalis
(the blood from the spleen
Uptake of bilirubin,
its conjugation and excretion
(the blood from the spleen
flows into the portal vein)
Most of urobilinogens
are removed in the Small amounts of urobilinogens
Portal Conjugated bilirubin
are removed in the
liver (oxidation ?)
Small amounts of urobilinogens
not removed by the liver
Portal
urobilinogens
A. renalis
Urobilinogens
and dipyrromethenes
Urine:
Feces:
Urine:
urobilinogens < 5 mg / d
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Feces:
urobilinoids and bilifuscins ~ 200 mg / d
In the absence of intestinal microflora (before colonization in newborns
or during treatment with broad-spectrum antibiotics):or during treatment with broad-spectrum antibiotics):
Plasma: normal bilirubin concentration
Uptake of bilirubin
and its conjugation
Excretion into the bile
××××
Conjugated bilirubin
××××
××××
Conjugated bilirubin
××××
××××
Intestinal flora is lacking
or inefficient (speedy
passage in diarrhoea)
Urine:
Feces: BILIRUBIN (golden-yellow colour
that turns green on the air),
Urine:
urobilinogens
are absent
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that turns green on the air),
urobilins and bilifuscins are absent
Major types of hyperbilirubinaemias
Hyperbilirubinaemia – serum bilirubin > 20 – 22 µmol / lHyperbilirubinaemia – serum bilirubin > 20 – 22 µmol / l
Icterus (jaundice) – yellowish colouring of scleras and skin,
serum bilirubin usually more than 30 – 35 µmol / l
The causes of hyperbilirubinaemia are conventionally classified as
– prehepatic (haemolytic) – increased production of bilirubin,
– hepatocellular due to inflammatory disease (infectious
hepatitis), hepatotoxic compounds (e.g. ethanol,hepatitis), hepatotoxic compounds (e.g. ethanol,
acetaminophen), or autoimmune disease; chronic
hepatitis can result in liver cirrhosis – fibrosis ofhepatitis can result in liver cirrhosis – fibrosis of
hepatic lobules,
– posthepatic (obstructive) – insufficient drainage of intrahepatic– posthepatic (obstructive) – insufficient drainage of intrahepatic
or extrahepatic bile ducts (cholestasis).
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Prehepatic (haemolytic) hyperbilirubinaemia
– excessive erythrocyte breakdown– excessive erythrocyte breakdown
Blood serum:
unconjugated bilirubin elevatedunconjugated bilirubin elevated
intensive uptake, conjugation,
and excretion into the bileand excretion into the bile
increased urobilinogens
are not removed sufficiently
conj. bilirubin
high portal
high supply of urobilinogens
(bilirubin-albumin complexes
cannot pass the glomerular filter)
are not removed sufficiently
conj. bilirubin
high portal
urobilinogens
cannot pass the glomerular filter)
Feces: polycholic (high amounts
Urine: increased
urobilinogens
(no bilirubinuria)
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Feces: polycholic (high amounts
of urobilinoids and bilifuscins)
(no bilirubinuria)
Hepatocellular hyperbilirubinaemia
The results of biochemical test depend on whether an impairment of hepaticThe results of biochemical test depend on whether an impairment of hepatic
uptake, conjugation, or excretion of bilirubin predominates.
Blood serum: unconj. bilirubin is elevated,
impairment in
Blood serum: unconj. bilirubin is elevated,
when its uptake or conjugation is impaired
conj. bilirubin is elevated,
when its excretion or drainage is impaired
portal urobilinogens
are not removed efficiently
impairment in
uptake, conjugation,
or excretion
when its excretion or drainage is impaired
ALT (and AST) catalytic concentrations increased
urobilinogens and conjugated
bilirubin pass into the urine
(not unconj. bilirubin-albumin complexes)
conj. bilirubin
are not removed efficiently
conj. bilirubin
(unless its excretion is impaired)
Urine: increasedUrine: increased
urobilinogens
(unless bilirubin excretion is impaired)
bilirubinuria
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bilirubinuria
(when plasma conj. bilirubin increases)Feces: normal contents
(unless excretion is impaired)
Obstructive (posthepatic) hyperbilirubinaemia
Blood serum:
conjugated bilirubin elevated
leakage of conj.
bilirubin from the cells
conjugated bilirubin elevated
bile acids concentration increased
catalytic concentration of ALP increased
uptake of bilirubin
bilirubin from the cells
into blood plasma
conjugated bilirubin passes into the urine
uptake of bilirubin
and its conjugation
low conj. bilirubin
conjugated bilirubin passes into the urine
ubg
××××low conj. bilirubin
(if obstruction is not complete)
××××
××××
Urine: urobilinogens
××××
Feces: urobilinoids and bilifuscins decreased
Urine: urobilinogens
are lowered or absent
bilirubinuria
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Feces: urobilinoids and bilifuscins decreased
or absent (grey, acholic feces)
Summary:
Bilirubin (derivatives) Urobilinogens
Summary:
Bilirubin (derivatives) Urobilinogens
Type Blood serum Urine Feces Blood Urine
PREHEPATIC
(or haemolytic)
increased
(unconjugated)
absent increased increased increased
HEPATOCELLULAR
increased
(unconj./conj.)
present
(unconj.)
normal to
decreased
increased or
decreased
increased or
decreased
OBSTRUCTIVE
(posthepatic)
increased
(conjugated)
present
(unconj.)
decreased or
absent
decreased
or absent
decreased or
absent
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Laboratory testsLaboratory tests
for detecting an impairment of liver functions ("liver tests")
• Plasma markers of hepatocyte membrane integrity
Catalytic concentrations of intracellular enzymes in blood serum increase:Catalytic concentrations of intracellular enzymes in blood serum increase:
An assay for alanine aminotransferase (ALT) activity is the most sensitive one.
In severe impairments, the activities of
aspartate aminotransferase (AST) andaspartate aminotransferase (AST) and
glutamate dehydrogenase (GD) also increase.
Increase of catalytic concentrations:
moderate injury
Increase of catalytic concentrations:
ALT AST GD
severe damage
cytoplasm mitochondria
severe damage
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• Tests for decrease in liver proteosynthesis
Serum concentration of albumin (biological half-time about 20 days),Serum concentration of albumin (biological half-time about 20 days),
transthyretin (prealbumin, biological half-time 2 days) and transferrin,
blood coagulation factors (prothrombin time increases),blood coagulation factors (prothrombin time increases),
activity of serum non-specific choline esterase (ChE).
• Tests for the excretory function and cholestasis
Serum bilirubin concentration
Serum catalytic concentration of alkaline phosphatase (ALP)
and γγγγ-glutamyl transpeptidase (γγγγGT)and γγγγ-glutamyl transpeptidase (γγγγGT)
Test for urobilinogens and bilirubin in urine
Estimation of the excretion rate of bromosulphophthalein (BSP test) is
applied to convalescents after acute liver diseases.
Saccharide metabolism low glucose tolerance (in oGT test)
• Tests of major metabolic functions are not very decisive:
applied to convalescents after acute liver diseases.
Saccharide metabolism low glucose tolerance (in oGT test)
Lipid metabolism increase in VLDL (triacylglycerols) and LDL (cholesterol)
Protein catabolism decreased urea, ammonium increaseProtein catabolism decreased urea, ammonium increase
(in the final stage of liver failure, hepatic coma)
• Special tests to specific disorders: serological tests to viral hepatitis,
serum α-foetoprotein (liver carcinoma), porphyrins in porphyrias, etc.
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serum α-foetoprotein (liver carcinoma), porphyrins in porphyrias, etc.
Metabolism of ironMetabolism of iron
The body contains 4 – 4.5 g Fe:
In the form of haemoglobin 2.5 – 3.0 g Fe,In the form of haemoglobin 2.5 – 3.0 g Fe,
tissue ferritin stores up to 1.0 g Fe in men (0.3 – 0.5 g in women),
myoglobin and other haemoproteins 0.3 g Fe,myoglobin and other haemoproteins 0.3 g Fe,
circulating transferrin 3 – 4 mg Fe.
The daily supply of iron in mixed diet is about 10 – 20 mg.The daily supply of iron in mixed diet is about 10 – 20 mg.
From that amount, not more than only l – 2 mg are absorbed.
Iron metabolism is regulated by control of uptake, which have toIron metabolism is regulated by control of uptake, which have to
replace the daily loss in iron and prevent an uptake of excess iron.
A healthy adult individual loses on average 1 – 2 mg Fe per day inA healthy adult individual loses on average 1 – 2 mg Fe per day in
desquamated cells (intestinal mucosa, epidermis) or blood (small
bleeding, so that women are more at risk because of net iron loss
in menstruation and pregnancy).
There is no natural mechanism for eliminating excess iron from the body.
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10 – 20 mf Fe Absorption of iron in duodenum and jejunum
Phosphates, oxalate, and phytate (myo-inositol
hexakis(dihydrogen phosphate), present in vegetable food)
form insoluble Fe3+ complexes and disable absorption.form insoluble Fe3+ complexes and disable absorption.
Fe2+ is absorbed much easier than Fe3+. Reductants such as
ascorbate or fructose promote absorption, as well as Cu2+.
8 – 19 mg Fe Gastroferrin, a component of gastric secretion, is a glycoprotein
that binds Fe2+ maintaining it soluble and prevents its oxidation
to Fe3+, from which insoluble iron salts are formed.
ascorbate or fructose promote absorption, as well as Cu .
elimination of insoluble
Fe salts in feces
to Fe3+, from which insoluble iron salts are formed.
transferrin–2 Fe3+
Fe salts in feces
STOMACH DUODENUM
free haemin (Fe3+)
bile pigments
efficiency about 20 %free haemin (Fe3+)
ferritin
organic
free Fe3+
soluble
Fe3+
efficiency about 20 %
hephaestin
(gastroferrin)
soluble Fe2+
organic
ligands
soluble
Fe3+ chelates
Fe2+
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ENTEROCYTE
(gastroferrin)
Transferrin (Trf)Transferrin (Trf)
is a plasma glycoprotein (a major component of β1-globulin fraction), Mr 79 600.
Plasma (serum) transferrin concentration 2.5 – 4 g / l (30 – 50 µmol / l)
Transferrin molecules have two binding sites for Fe ions,
total iron binding capacity (TIBC) for Fe ions is higher than 60 µµµµmol / l.total iron binding capacity (TIBC) for Fe ions is higher than 60 µµµµmol / l.
Serum Fe3+ (i.e. transferrin-Fe3+) concentration is about 10 – 20 µµµµmol / l,
µ14 – 26 µmol / l in men,
11 – 22 µmol / l in women.
Circadian rhythm exists, the morning concentrations areCircadian rhythm exists, the morning concentrations are
higher by 10 - 30 % than those at night..
Saturation of transferrin with Fe3+ equals usually about 1/3.Saturation of transferrin with Fe equals usually about 1/3.
Because the biosynthesis of transferrin is stimulated during iron deficiency (and
plasma iron concentration decreases), the decrease in saturation of transferrinplasma iron concentration decreases), the decrease in saturation of transferrin
is observed.
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Iron is taken up by the cellsIron is taken up by the cells
through a specific receptor-mediated endocytosis.
transferrin-2Fe3+
•
••
• ••
transferrin
receptorreceptor
Some receptors are released from the plasmatic membranes. Increase in serumSome receptors are released from the plasmatic membranes. Increase in serum
concentration of those soluble transferrin receptors is the earliest marker
of iron deficiency.
27
of iron deficiency.
LIVER CELLS
ENTEROCYTES
LIVER CELLS
biosynthesis of transferrin
Food iron Fe3+ transferrin–Fe3+ ferritinFe3+
ferritin
SPLEEN
ferritinFe3+
haemoglobin haemoglobin
breakdown
ferritinFe3+
BONE MARROW
haemoglobin breakdown
BONE MARROW
haemoglobin
synthesis
ferritin
loss of blood
ferritin
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Ferritin
Ferritin occurs in most tissuesFerritin occurs in most tissues
(especially in the liver, spleen,
bone-marrow, and enterocytes).
Iron(III)
hydroxide hydrate
core
bone-marrow, and enterocytes).
The protein apoferritin is a ballshaped
homopolymer of 24 subunits
core
shaped homopolymer of 24 subunits
that surrounds the core
of hydrated iron(III) hydroxide.
One molecule can bind few
apoferritin
(colourless)
ferritin
(brown)
One molecule can bind few
thousands of Fe3+ ions, which
make up to 23 % of the weight of
ferritin.
Minute amounts of ferritin are released into the blood plasma from the
extinct cells. Plasma ferritin concentration 25 – 300 µg/l is proportional
ferritin.
extinct cells. Plasma ferritin concentration 25 – 300 µg/l is proportional
to the ferritin stored in the cells, unless the liver is impaired (increased
ferritin release from the hepatocytes).
If the loading of ferritin is excessive, ferritin aggregate into its degradedIf the loading of ferritin is excessive, ferritin aggregate into its degraded
form, haemosiderin, in which the mass fraction of Fe3+ can reach 35 %.
Ferritin was discovered by V. Laufberger, professor at Masaryk university, Brno, in 1934.
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Ferritin was discovered by V. Laufberger, professor at Masaryk university, Brno, in 1934.
Hepcidin
is a polypeptide (Mr ~ 2000, 25 amino acid residues, from which 8 are Cys),
discovered as the liver-expressed antimicrobial peptide, LEAP-1, in 2000.
It is produced by the liver (to some extent in myocard and pancreas, too)It is produced by the liver (to some extent in myocard and pancreas, too)
as a hormone that limits the accessibility of iron and also exhibits
certain antimicrobial and antifungal activity.certain antimicrobial and antifungal activity.
The biosynthesis of hepcidin is stimulated in iron overload and
in inflammations (hepcidin belongs to acute phase proteins type 2),
and is supressed during iron deficiency .and is supressed during iron deficiency .
Notice the fact that the same two factors stimulating hepcidin synthesis
inhibit the biosynthesis of transferrin.
Effects of hepcidin: It – reduces Fe2+ absorption in the duodenum,
– prevents the release of recyclable Fe from macrophages,
inhibit the biosynthesis of transferrin.
– prevents the release of recyclable Fe from macrophages,
– inhibits Fe transport across the placenta,
– diminishes the accessibility of Fe for invading pathogens.
Hepcidin is filtered in renal glomeruli and not reabsorbed in the renal tubules. So
the amount of hepcidin excreted into the urine corresponds with the amount
synthesized in the body. There is a positive correlation between this amount of
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synthesized in the body. There is a positive correlation between this amount of
hepcidin and the concentration of ferritin in blood plasma.