Transcript 40_Biochemical functions of liver

LIVER
BIOCHEMISTRY
Liver
• Largest internal organ
• Weighs about 1400-1800 gram
• Located on right side under
ribcage
• Ability to regenerate
• Has over 500 vital functions
• Involved in many digestive,
vascular and metabolic
activities
LIVER STRUCTURE
sinusoids
central vein
portal vein
bile canaliculi
bile duct
hepatic artery
The following processes take
place in the liver:
• 1. The creation of bile pigments synthesis of cholesterol, synthesis
and secretion of bile.
• 2. The detoxication of toxic products, coming from gastrointestinal
tract.
• 3. The synthesis of proteins (proteins of plasma of blood among
them), their deposition, transamination and desamination of
aminoacids, the formation of urea, the synthesis of creatinine.
• 4. The synthesis of glycogene from monosaccharides.
• 5. The oxidation of fatty acids, the formation of acetone (ketone
bodies).
• 6. The deposition and exchange of vitamins (А, В, D), the deposition
of iron, copper, zinc ions.
• 7. The regulation of the balance between coagulant and
anticoagulant blood system, the formation of heparine.
• 8. The destruction of some microorganisms, bacterial and other
toxins.
• 9. The deposition of plasma of blood, the regulation of a total amount
of blood.
• 10. Hemopoiesis in the fetus.
Functions of the Liver
Type
Function
Metabolic
Absorptive Period
Converts glucose to glycogen and triglycerides; stores glycogen.
Converts amino acids to fatty acids or stores amino acids. Makes
lipoprotein from triglycerides and cholesterol.
Postabsorptive
Period
Produces glucose from glycogen (glycogenolysis) and fatty acids and
amino acids (glyconogenesis). Converts fats to ketones (accelerated
if fasting). Produces urea from protein catabolism.
Immunologic
Macrophages filter blood.
Metabolic
Detoxifies or conjugates waste products, hormones, drugs.
Transformation
Clotting Functions
Produces several essential clotting factors.
Plasma Proteins
Synthesizes albumin and other plasma proteins.
Exocrine
Functions
Synthesizes bile salts.
Endocrine
Functions
Involved in activation of vitamin D. Produces angiotensinogen. Secretes
insulin-like growth factors (somatomedin).
Liver’s functions
1. Liver is a main organ which is responsible for
dividing of nutritional substances in our
organism
(for
example,
glucose,
triacylglicerides and ketone bodies).
2. Hepatocytes synthesizes as lot of blood
plasma proteins and lipoproteins, low-weight
bioactive
substances
(creatin,
25oxicalciferol, hem), cholesterol.
3. Synthesis of urea (final product of nitrogen
metabolism) also takes place in the liver.
Liver’s functions
4. Liver synthesizes bile acids and excrete a
bile into intestinal tract. This process plays a
very important role in lipids digestion and
excretion of cholesterin and some products
of metabolism into intestine.
5. Liver play a big desintoxification role,
inactivates
endogenic
and
exogenic
substances (drugs, some hormones, different
toxins).
6. Liver is a depo for iron, some another metals,
vitamines A, D, E, B12, folic acid.
Role of the liver in carbohydrate
metabolism

From intestine glucose pass into the
liver, where most part of it undergone the
phosphorillation.
Glucose-6-phosphate
formed in result of this reaction, which
catalyzed by two enzymes – hexokinase
and glucokinase.

Glucose-6-phosphate is a key product of
carbohydrates metabolism. In the liver this
substance can metabolized into different
ways depend of liver’s and whole
organism’s necessity.
The fate of glucose molecule in the cell
Glucose
Glycogenesis
(synthesis of
glycogen) is
activated in well
fed, resting state
Glucose-6phosphate
Gluconeoge
nesis
is activated if
glucose is
required
Glycogen
Glycogenolysis
(degradation of
glycogen)
Pentose phosphate
pathway supplies
the NADPH for lipid
synthesis and
pentoses for nucleic
acid synthesis
Pyruvate
TCA cycle
Glycolysis
is activated if
energy is required
Ribose,
NADPH
Role of the liver in carbohydrate
metabolism

Synthesis of glycogen. Content in the liver – 70100g

Glucose-6-phosphatase catalize
dephosphorillation of glucose-6-phosphate and
formation of free glucose

Excess of glucose-6-phosphate, which not used
for synthesis of glycogen will follow to form free
glucose

Glucose-6-phosphate decomposed to H2O and
CO2, and free energy for hepatocytes formed.
Role of the liver in carbohydrate
metabolism

Part of glucose-6-phosphate
pentosophosphate cycle.

Hepatocytes
content
full
set
of
gluconeogenesis necessary enzymes. So, in
liver glucose can be formed from lactate,
pyruvate, amino acids, glycerol.

Gluconegenesis from lactate takes place
during intensive muscular work. Lactate
formed from glucose in muscles, transported to
the liver, new glucose formed and transported
to the muscles
oxidized
in
Summary: METABOLISM OF CARBS IN
LIVER
glycolisis
 metabolism of fructose and galactose
 gluconeogenesis
 release of glucose into blood
(maintain the stable glucose
concentration in blood)
 conversion of pyruvate into acetyl
CoA
 tricarboxylic acid cycle
 pentose phosphate pathway
 glycogenolysis, glycogenogenesis
Role of the liver in lipid metabolism
In the liver all processes of lipid metabolism take
place. Most important of them are following:
Lipogenesis (synthesis of fatty acids and lipids).
Substrate for this process – acetyl-CoA, formed
from glucose and amino acids, which are not used
for another purposes
Liver more active than another tissues synthesizes
saturated and monounsaturated fatty acids. Fatty
acids then used for synthesis of lipids,
phospholipids, cholesterol ethers.
Role of the liver in lipid metabolism
Liver play a central role in synthesis of cholesterin,
because near 80 % of its amount is synthesized
there. Biosynthesis of cholesterin regulated by
negative feedback. When the level of cholesterin
in the meal increases, synthesis in liver decreases,
and back to front. Besides synthesis regulated by
insulin and glucagon.
Liver is a place of ketone bodies synthesis. These
substances formed from fatty acids after their
oxidation, and from liver transported to another
tissues, first of all to the heart, muscles, kidneys
and brain
Role of the liver in protein
metabolism
Liver has full set of enzymes, which are
necessary for amino acids metabolism. Amino
acids from food used in the liver for following
pathways:
•
•
•
•
•
protein synthesis, including blood plasma proteins
protein decomposition; urea synthesis
Transformation to the carbohydrates and lipids.
interaction between amino acids.
conversion of proteins into low molecular weight
nitrogen containing substances
• transformation to the different substances with
amino group.
• release to the blood and transport to another
organs and tissues.
 Liver synthesizes 100 % of albumins, 90 %
of α1-globulines, 75 % of α2-globulines,50 %
of β-globulins, blood clotting factors,
fibrinogen, protein part of blood lipoproteins,
such enzyme as cholinesterase.
 Liver can
acids.
synthesize
non-essential
amino
 Liver synthesizes purine and pyrimidine
nucleotides, hem, creatine, nicotinic acid,
choline, carnitine, polyamines.
Role of the liver in detoxification
processes
•
A xenobiotics is a compound that is
foreign to the body.
• The principal classes of xenobiotics of
medical relevance are drugs, chemical
cancerogens, and various compounds that
have found their way into our environment
by one route or another (insecticides,
herbicides, pesticides, food additions,
cosmetics, domestic chemical substances).
Role of the liver in detoxification
processes
• Some internal substances also have toxic
properties (for example, bilirubin, free
ammonia, bioactive amines, products of amino
acids decay in the intestine).
• Moreover, all hormones and mediatores
must be inactivated.
• Reactions of detoxification take place in
the liver.
• Big molecules like bilirubin excreted with
the bile to intestine and leaded out with
feces. Small molecules go to the blood and
excreted via kidney with urine.
General ways of xenobiotics biotransformation and their localization in cell
REACTION
ENZYME
LOCALIZATION
PHASE I
Hydrolysis
Reduction
Oxidation
Esterase
Peptidase
Epoxide hydrolase
Microsomes, cytosol, lysosomes, blood
lysosomes
Microsomes, cytosol
Azo- and nitro-reduction
Carbonyl reduction
Disulfide reduction
Sulfoxide reduction
Microflora, microsomes, cytosol
Cytosol, blood, microsomes
Cytosol
Cytosol
Alcohol dehydrogenase
Aldehyde dehydrogenase
Aldehyde oxidase
Xanthine oxidase
Monoamine oxidase
Diamine oxidase
Flavin-monooxygenases
Cytochrome P450
Cytosol
Mitochondria, cytosol
Cytosol
Cytosol
Mitochondria
Cytosol
Microsomes
Microsomes
PHASE II
Glucuronide conjugation
Sulfate conjugation
Glutathione conjugation
Amino acid conjugation
Acetylation
Methylation
Microsomes
Cytosol, microsomes
Cytosol
Mitochondria, cytosol
Mitochondria, microsomes
Cytosol, microsomes, blood
The metabolism of xenobiotics has 2 phases:
In phase 1, the major reaction involved is
hydroxylation, catalyzed by members of a
class of enzymes referred to as
monooxygenases or cytochrome P-450 species.
These enzymes can also catalyze deamination,
dehalogenation, desulfuration, epoxidation,
peroxidation and reduction reaction.
Hydrolysis reactions and non-P-450-catalyzed
reactions also occur in phase 2.
[1] In the resting state, the heme iron is
trivalent. Initially, the substrate binds
near the heme group.
[2] Transfer of an electron from FADH2
reduces the iron to the divalent form that
is able to bind an O2 molecule.
[3] Transfer of a second electron and a
change in the valence of the iron reduce
the bound O2 to the peroxide.
[4] A hydroxyl ion is now cleaved from
this intermediate. Uptake of a proton
gives rise to H2O and the reactive form
of oxygen mentioned above. In this ferryl
radical, the iron is formally tetravalent.
[5] The activated oxygen atom inserts
itself into a C–H bond in the substrate,
thereby forming an OH group.
[6] Dissociation of the product returns the
enzyme to its initial state.
In phase 2, the hydroxylated or other
compounds produced in phase 1 are
converted by specific enzymes to various
polar metabolites by conjugation with
glucuronic acid, sulfate, acetate,
glutathione, or certain amino acids, or by
methylation.
Transformation of hormones
• inactivation of steroid hormones –
hydrogenation, conjugation
• inactivation of insulin and glucagon (see
next page)
• inactivation of catecholamines and
iodothyronines – conjugation
• dehydrogenation of cholesterol to 7dehydrocholesterol and
• 25-hydroxylation of calciols play an
essential role in calcium homeostasis