Liver Metabolism: Liver Is The Chief Metabolic Organ of Our Body

LIVER METABOLISM
LIVER IS THE CHIEF

METABOLIC ORGAN OF OUR
BODY 1
GENERAL ASPECTS
LIVER IS THE CHEIF METABOLIC ORGAN IN OUR BODY.
LIVER PERFORMS DIVERSE METABOLIC FUNCTIONS.
GENERAL METABOLIC FUNCTIONS OF THE LIVER CAN BE DISCUSSED UNDER
THE FOLLOWING HEADDINGS
1.Carbohydrate metabolism
2. Lipid and Lipoprotein metabolism
3. Amino acid metabolism
4. Alcohol metabolism
5. Heme metabolism
6. Bilirubin metabolism
7. Bile acid metabolism
8. Vitamin D- metabolism
9. Creatine metabolism
10. Biotransformation
11.Detoxification
Liver function tests
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LIVER & CARBOHYDRATE METABOLISM
Liver plays a very important role in the metabolism of
carbohydrates. The special type of metabolic pathways/
reactions seen in liver are :
1. Glycogen metabolism( Glycogenesis / Glycogenolysis)
2. Gluconeogenesis
3. HMP shunt
4. Glucuronic acid Pathway
5. Coris cycle
(The Pathways of energy metabolism like glycolysis, citric
acid cycle etc are not included in the above list).
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1.GLYCOGEN METABOLISM
Glycogen is a branched polysaccharide composed
of 100s or 1000s of D- Glucose molecule linked
together by alpha 1-4 and alpha, 1-6 glycosidic
linkages.
It is the only reserve carbohydrate in human body.
It is a stored form of energy as well it is the stored
form of D- Glucose.
Glycogen is synthesized from excess glucose in the
body.
It is stored in liver (liver glycogen) and in skeletal
muscles (muscle glycogen).
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1.GLYCOGEN METABOLISM
Liver glycogen and muscle glycogen are structurally
similar, but functionally different(both are branched
polymers of D- Glucose linked together by alpha 1-4 and
alpha 1-6 glycosidic bonds).
Liver glycogen is involved in the maintenance of blood
glucose level, where as muscle glycogen provides
energy for muscle contraction.
Glycogen metabolism includes two processes.
1.Glycogen synthesis (Glycogenesis) anabolic pathway.
2.Glycogen breakdown (Glycogenolysis) Catabolic
pathway.
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GLYCOGENESIS
Glycogenesis refers to the synthesis of complex glycogen molecule
by the polymerization of hundreds or thousands of D- Glucose
molecules.
This takes place in the cytosol of liver cells (hepatocytes) and muscle
cells.
Glycogenesis takes place with the help of a number of enzymes.
They are:-
Hexokinase / Glucokinase
Phosphoglucomutase
UDP glucose pyrrophosphorylase
Glycosyl transferase
Glycogen synthase ( Glycogen synthetase )- the chief enzyme.
Branching enzyme ( amylo 4-6 trans glycosylase )
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GLYCOGENESIS
The process can be described under 4 headings .
1.Activation of D-Glucose :-This involves the
conversion of D Glucose in to UDP- Glucose .
2. Synthesis of Glycogen primer with the help of a
protein called Glycogenin.
3.Extension of the primer by glycogen synthase
enzyme
4. Branching:- An enzyme called amylo 4-6
transferase
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GLYCOGENELYSIS
Glycogenolysis refers to the process of degradation of the
highly branched glycogen molecule to liberate D- Glucose
molecules.
This takes place in liver and muscle.
The end product of Glycogenolysis in liver is D-Glucose.
In muscle the end product is Glucose-6-P due to the absence
of an enzyme called glucose -6- phosphatase.
Glycogenolysis takes place in the cytosol.
The enzymes involved in glycogenolysis are:-
1.Glycogen phosphorylase- the chief enzyme
2.Debranching enzyme- is having two different enzymatic activities.
a) Amylo, 4-4 trans glycosylase activity and
b) Alpha 1-6 glucosidase activity.
3.Phospho glucomutase ( PGM) and
4.Glucose -6- phosphatase .
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GLYCOGENELYSIS
The process of glycogenolysis can be
described under three headings.
1. Action of Glycogen phosphorylase enzyme-
splitting alpha 1- 4 linkage to liberate
Glucose -1-P.
2. Action of debranching enzyme- To split alpha
1-6 linkage ( debranching).
3.The conversion of Glucose -1-P to D-Glucose ( Free
Blood Glucose ) by the action of
Phosphoglucomutase and Glucose 6- phosphatase.
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MAINTENANCE OF NORMAL BLOOD
GLUCOSE LEVEL
The normal blood glucose level is 70-110mg/100ml in
the fasting condition(12 hrs of not consuming any
kind of food).
It is called fasting blood glucose level(FBG). When
FBG is above 110mg/ 100ml, the condition is called as
hyperglycemia.
When FBG is below 70mg/100ml, the condition is
called hypoglycemia.
During hyperglycemia and hypoglycemia, the blood
glucose level is brought to the normal range by
regulation over two processes Glycogenolysis and
Glycogenesis.
This is achieved through hormonal means -involving
three different hormones.
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HORMONAL REGULATION OF
GLYCOGEN METABOLISM
1.Glucagon: secreted by the alpha cells of the islets of Langerhans of
the pancreas .
hyperglycemic hormone.
secreted during hypoglycemia.
increases the rate of glycogenolysis in the liver and increases blood
glucose level.
2.Epinephrine:
Also called as adrenalin is secreted by the medulla of adrenal gland.
hyperglycemic hormone, SECRETED DURING HYPOGLYCEMIA.
increases the rate of glycogenolysis in the liver and skeletal muscle
Epinephrine is also called as emergency hormone as it is secreted
during emergency situations(LIKE FEAR, ANXIETY,ANGER ETC), when the
body needs extra energy.
GLUCAGON AND EPINEPHRINE ACTS THROUGH THE SAME SECOND
MESENGER NAMELY, CYCLIC AMP( c AMP).
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HORMONAL REGULATION OF
GLYCOGEN METABOLISM
3.Insulin:-
Insulin is secreted by the beta cells of the islets of Langerhans of
the pancreas.
A HYPOGLYCEMIC HORMONE,secreted during hyperglycemia.
Insulin is a hypoglycemic hormone that lowers the blood glucose
level by three different mechanisms:-
Increases the uptake of Glucose in the cells(GLUT4 synthesis).
It increases the rate of Glycolysis by increasing the activity of two
enzymes Phosphofructokinase and pyriuvate kinase.
Increases the rate of Glycogen synthesis.
It also favors lipogenesis.
Lack of sufficient insulin will lead to increased blood
glucose concentration( hyper glycemia) a condition called
Diabetes Mellitus( DM).
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DISORDERS OF GLYCOGEN
METABOLISM
Glycogen Storage Diseases
1.Type I, liver deficiency of Glucose-6-phosphatase
(Von Gierke's disease)-hypoglycemia (low blood
glucose) when fasting, liver enlargement.
2.Type IV, deficiency of branching enzyme in
various organs, including liver (Andersen's
disease)-liver dysfunction and early death.
3.Type V, muscle deficiency of Glycogen
Phosphorylase (McArdle's disease)-muscle
cramps during exercise.
4.Type VII, muscle deficiency of
Phosphofructokinase-inability to do exercise.
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2. GLUCONEOGENES
Gluconeogenesis is a biochemical pathway in which
D-Glucose is synthesized from non-carbohydarte
precursors such as pyruvate, Lactate, Oxaloacetate,
certain amino acid etc.
Gluconeogenesis is an anabolic pathway which takes
place mainly in the liver (and to a lesser extent in the
renal cortex).
This pathway is operated partially in the
mitochondria and partially in the cytosol.
Gluconeogenesis accelerated when there is a lack of
sufficient glucose in the body and during starvation.
Under normal condition, Gluconeogenesis in liver is
helpful in the re-utilization of Lactate formed during
anaerobic glycolysis in RBC and skeletal muscle.
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2. GLUCONEOGENES
Most of the enzymes involved in gluconeogenesis are
the same as those involved in Glycolysis.
Takes place by the reversal of glycolysis.
The three irreversible steps in glycolysis are bypassed
in gluconeogenesis with the help of 4 additional
enzymes which are designated as the key enzymes of
gluconeogenesis. They are :-
1.Pyruvate carboxylase
2.Phospho-enol pyruvate carboxykinase
3.Fructose 1,6-bisphosphatase &
4.Glucose -6-phosphatase.
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2. GLUCONEOGENES
Substrate for Gluconeogenesis.
1. Pyruvate It is the end product of aerobic glycolysis. Pyruvate is
also the de- amination product of amino acids such as glycine ,
serine ,threonine, cysteine etc.
2. Lactate- It is formed in the muscle during anaerobic glycolysis.
Lactate is transported to the liver where it gets oxidized to
pyruvate by Lactate dehydrogenase enzyme (LDH). Puruvate
enters the gluconeogenic pathway.
3.Glucogenic amino acids Certain amino acids can act as precursors
of Glucose under emergency conditions. Such amino acids are
called Glucogenic amino acids. Examples include Alanine, Aspartic
acid , Glutamic acid, etc.
These amino acids are either de-aminated or trans-aminated to
form corresponding keto acids (carbon skeleton). These keto acids
enter the Citric acid cycle and are converted to oxalo-acetate
which is the direct substrate for Gluconeogenesis.
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2. GLUCONEOGENES
4. Glycerol Glycerol is a part of neutral fat
(TAG).
Glycerol portion of the TAG will be liberated
during lipid mobilization (associated with
fasting and hypoglycemia).
Glycerol is first phosphorylated to Glycerol-3-
P by an enzyme called Glyceol kinase.
Glycerol-3-P is then oxidized to Dihydroxy
acetone P, an intermediate in gluconeogenic
pathway (also glycolysis).
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2. GLUCONEOGENES
5. Propionyl COA (activated propionic acid/3- C
fatty acid)
Propionyl COA is mainly formed during the
beta-oxidation of odd-chain fatty acid.
Propionyl COA is converted to succinyl COA
(an intermediate of Citric acid cycle).
Succinyl COA is then converted to Oxalo
acetate which enters the gluconeogenic
pathway.
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2. GLUCONEOGENES
Significance /importance of Gluconeogenesis
Gluconeogenesis is involved in the maintenance of blood
glucose level during starvation / hypoglycemia.
D- Glucose is the only source of energy for NS and RBC.
Gluconeogenesis help to utilize the lactate formed during
anaerobic glycolysis and glycerol produced in adipose
tissue.
Only liver can replenish D- Glucose through
Gluconeogenesis because Glucose-6-Phosphatase enzyme
is present only in liver.
Propionic acid (a 3-carbon fatty acid) is converted to
glucose by gluconeogenesis and is the only glucogenic
fatty acid.
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3. HMP SHUNT/PENTOSE SHUNT
Alternate pathway of glucose oxidation other
than glycolysis.
Not for energy production.
Active in liver, adipose tissue lactating
mammary glands, erythrocytes, gonads
adrenal cortex and thyroid tissue.
Operated in the cytosol.
Glucose 6-P is the starting substrate of this
pathway.
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Consists of two different phases- oxidative
phase and non-oxidative phase.
1.Oxidative phase This phase consists of the
first 5- reactions by which Glucose-6-P is en
zymatically converted to Ribulose -5-P
2.Non-oxidative phase glucose -6-P is
regenerated from Ribulose-5-P by the
involvement of trans -aldolase and trans-
ketolase enzymes
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Significance of HMP shunt
1. HMP shunt is the source of NADPH which is essential
for :
reductive biosynthesis of fatty acids, cholesterol, other
steroids, and certain amino acids( Liver is the major site
for the biosynthesis of fatty acids and steroids).
NADPH provides reducing power for the antioxidant
enzymes present in the liver( cytochrome p 450) .It is also
required for the detoxification processes in the liver.
NADPH is essential for the degradation of heme in to
bilirubin in the liver.
2. HMP shunt produces Ribose -5-P important in the
synthesis of Nucleotides (DNA and RNA).
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4. URONIC ACID PATHWAY
( Glucuronic acid cycle)
An alternate pathway for glucose oxidation operated only in the
liver.
It is useful for the biosynthesis of Glucuronic acid ( acid derivative
of Glucose ).
D- Glucuronic acid is a sugar derivative resent in the structure of
certain complex carbohydrates ( heteroplysaccharides) like
heparin, hyaluronic acid and also in the structure of
proteoglycans etc.
Glucuronic acid is highly important for detoxification processes in
the liver ( eg. Conjugation of bilirubin).
In animals other than man , monkey and gunea pig, glucuronic
acid pathway serves to produce Vitamin C ( ascorbic acid).
In man monkey and gunea pig this pathway is incomplete
because of the genetic deficiency of an enzyme called
gulonolactone oxidase.
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5. CORIS CYCLE
Coris cycle is a cyclic metabolic pathway that
involves a number of reactions and processes
operated partially in the liver and partially in the
skeletal muscle.
Coris cycle is helpful in the reutilization of Lactate
formed as a result of anaerobic glycolysis during severe
muscular exercise.
Accumulation of lactate will lead to a muscle pain
known as muscle cramp.
Cori cycle helps to re-utilize lactate and to relieve
muscle cramp , prevent decrease in muscle pH,
prevent decrease in blood pH ( due to lactic acidosis).
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5. CORIS CYCLE
Reutilization of lactate:
As a result of severe muscular exercise too much amounts of Lactate
will be accumulated in the skeletal muscle.
This in turn lead to a decrease in muscular pH resulting in a painful
condition known as muscle cramp.
This lactate is then gradually liberated in to the blood circulation.
Via blood it reaches the liver. In the liver the lactate is effectively
re-utilized for the synthesis of D- Glucose by a process known as
gluconeogenesis.
The cyclic process of conversion of lactate to D-glucose(by
gluconeogenesis) then to glycogen(by glycogenesis in muscle)and
then to D- Glucose( by glycogenolysis in muscle)and again back to
lactate ( (by anaerobic glycolysis in muscle) is known as Coris
cycle( Cori- name of the scientist).
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LIVER AND LIPID METABOLISM
Liver plays a significant role in the metabolism
of different categories of lipids.
1. Choletserol metabolism
2. TAG metabolism
3. Phospholipid metabolism
4. Fatty acid metabolism
5. Lipoprotein metabolism
6. Ketone body metabolism
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LIVER & CHOLESTEROL METABOLISM
In human body cholesterol is mainly accumulated in
tissues such as nervous tissue, liver, kidney spleen and
skin.
A man weighing 70 kg contains approximately 140 gm
of cholesterol in his body.
There are two different sources of cholesterol in our
body.
1.Exogenous cholesterol-dietary sources like meat
(especially liver and brain) and egg yolk.
2.Endogenous cholesterol-about 1 gm of cholesterol is
synthesised in a normal person per day.
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LIVER & CHOLESTEROL METABOLISM
1. Free cholesterol- the free form of cholesterol.
2.Estrified cholesterol- certain fatty acids are
present estrified to the -OH group of the
cholesterol to form cholesteryl esters of fatty
acids.
Liver plays a major role in the synthesis, as
well as in the excretion of cholesterol.
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LIVER & cholesterol metabolism
Biosynthesis of cholesterol
Biosynthesis of cholesterol takes place mainly in the liver
and to a limited extent in tissues such as adrenal cortex,
intestine, skin, kidney, ovary and testes.
The brain tissue of new born can synthesis cholesterol, but
the adult brain cannot.
The biosynthetic pathway of cholesterol is elucidated by
Cornforth for that work he was awarded Nobel Prize in
Medicine in 1975.
The precursor for cholesterol biosynthesis is acetyl COA
and the process is taking place in the cytosol.
Cholesterol biosynthesis takes place in 5 different stages
involving a large number of enzymes.
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Stage -1: Mevalonate, a six carbon compound is synthesized
by the condensation of 3 molecules of acetyl COA.
Stage-2: Isoprenoid units (5 -C) are formed by the
decarboxylation of mevalonate.
Stage-3: Six isoprenoid units condense to form a 30- C
compound called squalene.
Stage-4: Squalene cyclises to form a compound called
Lanosterol.
Stage -5: Squalene is transformed to the 27 carbon
cholesterol in several steps by loosing 3 carbon
atoms(methyl groups). The molecular formula of
Cholesterol- C 27 H46 O.
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Excretion of cholesterol:-Cholesterol is excreted in the form
of bile acids/bile salt in bile(important for emulsification
process as well as for the absorption of fat and Vit. ADEK in
the intestine).
Major portion of bile acids become reabsorbed in the
intestine by entero-hepatic circulation and reutilised by the
liver.
In the small intestine cholesterol become converted to
coprosterol by intestinal bacteria and excreted in the faeces.
Cholesterol bile acid cholesterol copro-sterol
Sometimes, if cholesterol is excreted in the bile in large
quantities may be deposited in the bile duct ( biliary stone)
and gall bladder ( gall stones), solidified ,blocking the bile
flow, a condition called cholelithiasis.
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LIVER & TAG metabolism
Liver is the site for the synthesis of
endogenous TAG or Triacyl glycerol( neutral
fat).
TAG is formed by the association of one
molecule of Glycerol and 3 molecules of Fatty
acids.
TAG is the transported to the adipose tissue
,where it is stored as a reserve energy source
which is being mobilized(utilized)during
starvation.
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LIVER & Phospholipid metabolism
Phospholipids are compound lipids/complex lipids which
contain a phosphoric acid in its chemical structure.
Phospholipids are amphipathic molecule which are the chief
structural constituents of the cell membrane ( Lipid bilayer).
The amphipathic nature with a polar head( hydrophilic) and a
non polar tail( hydrophobic tails ) are very important for the
formation of the bilayer structure of cell membrane.
Phospholipids are also important for the formation of
Lipoprotein structure and involve in lipid transport.
Phospholipids are also important for the formation of mixed
micelle structure and are important in lipid absorption in the
small intestine
Phosphatydyl choline , phosphatidyl ethanolamine, Phsphatidyl serine etc are
the important types of Phospholipids. 48
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Liver and fatty acid metabolism
Liver is the major site for the synthesis of endogenous fatty
acids.
These fatty acids are then incorporated in to the structure of various
other forms of lipids such as TAG, Phospholipids etc .
These lipids are then incorporated in to the structure of Lipoproteins
and transported to the various other tissues.
These are then integrated in to the structure of the tissue /oxidized
or/ stored for future use.
Fatty acid biosynthesis is a very complex process that takes
place with the help of a multi-enzyme complex called fatty
acid synthase complex( FSC).
It takes place in the cytosol.
The raw material/ precursor of fatty acid biosynthesis is
acetyl COA.
Acetyl COA acts as bridge between Carbohydrate
metabolism and Lipid metabolism.
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Liver and fatty acid metabolism
There are 7 enzymes in the structure of FSC
1)Acetyl transferase
2)Malonyl transferase
3) 3- keto acyl ACP synthase
4)3- keto- acyl ACP reductase
5) 3- hydroxyl acyl ACP dehydratase
6) Enoyil ACP reductase and
7) Thio-esterase
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Liver and Lipoprotein metabolism
Liver is the central point of lipoprotein
metabolism.
Chylomicron, VLDL ( very low density
Lipoprotein) LDL ( Low density Lipoprotein) ,IDL (
Intermediate density Lipoprotein) HDL( High
density Lipoprotein) are the various types of
lipoproteins.
They differ in the composition proportion of
various lipid components and also the type of
apoprotein
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Liver synthesises a lipoprotein called VLDL.
VLDL is involved in the transport of endogenously
synthesizzed lipids( Fatty acids, TAG,phospholipids) in
to various tissues .
Liver is also taking part in the metabolism of
exogenous lipids obtained from the diet which are
transported to the liver with the help of chylomicron (
a lipoprotein synthesized in the intestinal mucosal
cells).
Also liver is the site of synthesis of HDL which play an
important role in the excretion of excess cholesterol.
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Generally Lipoproteins are conjugated
proteins composed of a -lipid part consisting
of Triglycerides, cholesteryl esters , free
cholesterol, phospholipids and a -protein part
usually called as apoprotein.
Often lipoproteins are called as lipoprotein
particle( BECAUSE OF LARGER SIZE).
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Chylomicrons are synthesised in the intestinal
mucosal cells and involved in the transport of
lipids from intestine to peripheheral tissues
particularly skeletal muscles, heart and adipose
tissue.
VLDL is synthesised in the liver and transport
lipids from liver to peripheral tissues.
When it receives cholesteryl esters from the HDL
and looses TAG to the HDL, gets transformed in
to IDL and then to LDL.
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LDL is formed in the blood from VLDL and
provides fatty acids to the peripheral tissues.
when it is present in excess can deposit in the
endothelial surface of the blood vessels
leading to atherosclerosis, hypertension CVD,
Myocardial infarction etc. ( CVDs).
There fore, LDL is usually called Bad
lipoprotein
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HDL (nascent) is synthesised in the liver and
intestine and get matured in the peripheral
tissue.
It functions to carry cholesterol from extra-
hepatic tissues to the liver for excretion (in
the form of bile salt and bile acid) and to the
steroidogenic tissues for the synthesis of
steroid hormones Vit. D etc.
HDL is called Good Lipoproteins.
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Liver and ketogenesis
Ketone bodies are formed excessively in the
liver under certain metabolic conditions like
starvation/severe fasting, diabetes mellitus
and also after the ingestion of high fatty diet.
During these conditions the rate of beta
oxidation will be very high resulting in the
excessive production of acetyl COA in the
mitochondrial matrix.
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In order to cope up with this condition, excess acetyl
COA will be converted in to Ketone bodies.
The process of formation of ketone bodies is referred
to as ketogenesis.
Ketogenesis takes place only in liver.
Brain, heart muscles (myocardium) kidney cortex and
skeletal muscles can use ketone bodies as a source of
energy.
The heart muscle and kidney prefer ketone bodies
over D- Glucose whereas, Brain and skeletal muscles
uses ketone body only when there is no / Little D-
Glucose.
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Significance of ketogenesis:
1. Helps to prevent metabolic imbalance caused by
the excessive accumulation of acetyl COA.
2.Ketone bodies are energy sources for important
organs like brain , heart , muscle as well as
kidney during emergency situations like
starvation.
For brain Ketone bodies are the only energy
source ,other than D- Glucose.
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LIVER AND AMINOACID /PROTEIN
METABOLISM
Liver has an important role to play in amino acid /
protein metabolism .
Liver is the central point of amino acid
catabolism and is the major site of synthesis of
most of the plasma proteins.
1. Protein synthesis( Plasma proteins)
2. Amino acid catabolism
3. Glucose alanine cycle ( during starvation)
4. Urea cycle
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Liver and Amino acid /protein
metabolism
Liver and protein synthesis:
1. Liver is the site of synthesis of majority of
the plasma proteins.
pre-albumin,albumin,fibrinogen etc.
Liver is the site of Hb biosynthesis
particularly in foetus.
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metabolism
Liver play a major role in amino acid
catabolism.
Liver is the major site of trans-amination
reaction( transaminase enzyme) and is the
only site of oxidative de-amination reaction
(Glutamate dehydrogenase enzyme) both
reaction are important in the removal of
amino group.
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metabolism
Liver is the only site where urea cycle is
operated.
Urea cycle is a cyclic pathway by which the
toxic ammonia is converted in to less toxic
and water soluble urea.
Urea cycle is also known as Krebs Hansleit
cycle.
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metabolism
Significance of urea cycle:
The normal level of ammonia in the blood is 4050mg /100 ml blood .
Hyperammonemia will affect the functioning of all tissue, especially of the
brain.
a) NH3 accumulation decreases cellular PH
b) Depletion of TCA cycle intermediate especially OAA decreases the
efficiency of TCA cycle leading to a decrease in energy production.
c) The overproduction of glutamate and its accumulation lead to the
excessive formation of GABA an inhibitory neurotransmitter, and is
responsible for the slurred speech and bizarre behavior during toxicity.
d) NH3 increases the osmotic pressure of the tissue resulting in comma.
DURING STARVATION OWING TO AN INCREASE IN THE RATE OF AMINO
ACID CATABOLISM,THE SYNTHESIS OF UREA CYCLE ENZYME INCREASES
TO FACILITATE AMONIA DETOXIFICATION MECHANISM.
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metabolism
Decarboxylation of amino acid lead to the
production of corresponding amines, generally
called as biological amines.
The enzymes are generally called as
decarboxylases which require PLP as a
coenzyme.
Decarboxylation reactions take place mainly in
the liver, kidney and brain.
Many of these amines perform important
physiological functions.
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metabolism
Glucose -alanine cycle:
Glucose Alanine cycle helps in the conversion of
amino acids in to D- Glucose during starvation.
Glucose alanine cycle is a cyclic pathway involving
two tissues liver and muscle.
This pathway helps in the formation of D- Glucose
from glucogenic amino acids present in the muscle .
This takes place with the mediation of an amino acid
called Alanine .
During starvation the muscle proteins are degraded
and amino acids are liberated.
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metabolism
The liberated amino acids are having different
function.
1. Energy production( amino acids are the major
source of energy during severe stages of
starvation).
2. Glucogenic amino acids are the precursors of
D- Glucose( by gluconeogenesis in the liver ).
3. Ketogenic amino acids are the precursors of
ketone bodies ( by ketogeneis in the liver ).
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LIVER AND ALCOHOL METABOLISM
Liver is the only organ concerned with the
catabolsm/ detoxification of ethyl alcohol .
Alcohol absorption starts from the stomach ,
but major portion is absorbed in the small
intestine.
1 % of the ingested alcohol is excreted
through the lungs.
Major portion of the alcohol is oxidised in the
liver.
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Metabolism of alcohol
The re are two mechanism for the degradation of alcohol in the
liver.
1. Major mechanism involving two enzymes ,
alcohol dehydrogenase and aldehyde
dehydrogenase.
Alcohol dehydrogenase oxidises ethanol to acetaldehyde(
cytosol).
Aldehyde dehydrogenase oxidizes acetaldehyde in to acetic acid(
mitochondria).
Acetic acid is excreted via urine to a limited extent.
If the level exceeds it will be converted to acetyl COA by an
enzyme called acetyl COA synthetase.
Acetyl COA is the substrate for fatty genesis.
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2. Minor mechanism involving microsomal ethanol oxidizing
system( MEOS).
It is cytochrome p- 450 dependent enzyme and is inducible.
This accounts for the alcohol tolerance observed in chronic
alcoholics.
ETHANOL AND METHANOL ARE DETOXIFIED BY THE SAME
ENZYME ALCOHOL DEHYDROGENASE.
ETHANOL TO ACETALDEHYDE ( CONVERTED TO ACETIC ACID BY
ALDEHYDE DEHYDROGENASE)
METHANOL TO FORMALDEHYDE (VERY TOXIC COMPOUND THAT
CANNOT BE FURTHER CONVERTED ).
THE MEDICATION FOR METHANOL INTOXICATION IS ETHANOL
SUPPLIMENTATION BECAUSE IT COMPETITIVELY INHIBIT THE
FORMATION OF FORMALDEHYDE FROM METHANOL.
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Biochemical alterations in alcoholism:
Both the oxidation steps of ethyl alcohol ( major
mechanism) produces NADH resulting in high NADH/ NAD+
ratio. This leads to several metabolic alterations. They are :-
High NADH level favours conversion of pyruvate in to
lactate leading to lactacidosis.
Depletion of pyruvate lead to inadequate levels of
Oxaloacetate( OAA is formed from pyruvate by pyruvate
carboxylase enzyme). This leads to depression of
gluconeogenesis leading to hypoglycema.
High levels of NADH facilitate the reverse conversion of
oxaloacetate to malate resulting in the deficiency of
oxaloacetate- which in turn decreases the rate of
gluconeogenesis.
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Inadequate level of OAA also causes suppression of
TCA cycle and energy production.
Depression of TCA cycle lead to accumulation of acetyl
COA resulting in ketogenesis.
Accumulation of acetyl COA lead to an increase in fatty
acid biosynthesis, that accumulate in the liver causing
fatty liver.
Lactic acidosis leads to decreased excretion of uric acid
leading to its accumulation and gout( gouty arthrits).
Alcohol causes CNS depression by the excitation of
inhibitory ( GABA ) neurotransmitter receptors and
inhibiting excitatory ( N- methyl Aspartate ) receptors
in the brain.
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Effect of chronic alcoholism:
1. Alcoholism and liver:
Fatty liver
Accumulate toxic acetaldehyde causes cell death liver
cell necrosis.
Liver cell necrosis lead to fibrosis of the liver , a
condition called cirrhosis.
Hepatic coma
( aldehyde dehydrogenase enzyme is more active in
western population compared to others and are
more prone to alcohol induced cirrhosis).
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2. Alcohol and CNS:
Enlargement of brain ventricles
Neuro-degeneration
Memory loss.
Chronic alcoholism combined with Vit. B1 deficiency
lead to Wernicks disease.
Neuritis
3. Alcohol and Cardiovascular system:
Mild alcohol consumption decreases the risk of CVD and
MI( but this benefit is minor compared to its drastic
deleterious effect on Liver).
86
LIVER AND HEME METABOLISM
LIVER is the site of synthesis of heme (also bone
marrow) as well as its degradation and detoxification.
Heme is the prosthetic group of several proteins
(hemoproteins) including hemoglobin and myoglobin.
Hemoglobin is involved in the transport of oxygen in
the blood and to some extent the transport of CO2
also.
Myoglobin is involved in the storage of O2 in muscle
tissue.
Heme is also present in cytochromes of the electron
transport chain (respiratory chain) and in the
structure of certain enzymes like catalase.
87
Biosynthesis of heme
The site of synthesis of heme is mainly liver and bone marrow-
the mechanism is the same in both locations.
Liver produces a heme containing protein called cyt. P-450.
Bone marrow is the site of Hemoglobin biosynthesis.
The important intermediates in the pathway of heme synthesis
are called porphyrin.
Porphyrin precursors exist in a chemically reduced forms which
are collectively called as porphyrinogens.
The precursors of heme are Glycine ( an amino acid ) and sucinyl
COA ( an intermedicate in Citric acid cycle)
The pathway of heme synthesis, the names of various enzymes
and the disease conditions resulting from enzyme deficiencies are
shown below.
88
89
Disorders of heme biosynthesis
Porphyrias
Enzyme deficiencies in the heme synthetic pathways
lead to the accumulation of different types of
pohyrins in the body. This condition is known as
porphyrias.
When tetrapyrrol intermediates accumulate the skin
becomes photosensitive leading to itches / burns
(pruritis).
Porphyrias are generally grouped in to two-
1) Erythropoetic porphyrias &
2) Hepatic porphyrias.
Erythropoetic include a )congenital erythropoetic
porphyria and b)erythropoetic protoporphyria.
90
Disorders of heme biosynthesis
Hepatic porphyrias include the following types.
a)Chronic hepatic porphyria ( porphyria cutania
tarda)- resulting from the deficiency of
uroporphyrinogen decarboxylase enzyme
Symptoms cutaneous pruritis urine becomes
red / brown in natural light and pink/red in
fluorescent light.
b) Acute hepatic porphyria( acute intermittent
porphria)
Neuropsychiatric disturbances are very common
in this condition.
91
HEME DEGRADATION
Heme is the prosthetic group of hemoglobin
and many other proteins.
Heme is mainly present in hemoglobin in RBCs.
The life span of human RBCs is 120 days.
After 120 days the hemoglobin molecules
reduces its functional abilities as an oxygen
carrier and there for the protein must be
degraded simultaneous with the disintegration
of the RBCs.
The degradation takes place in the reticulo-
endothelial system of liver and spleen.
92
The microsomes of the reticulo-endothelial
system have a heme oxygenase system which
degrade heme in to bilirubin.
This is achieved by the addition of a hydroxyl
group to methylene bridges and takes place in
the presence of NADPH and O2.
Fe 2+ will be oxidized to Fe3 +,followed by the
cleavage of the porphyrin ring and release of
Fe3 + ,CO and an intermediate named biliverdin
( green in colour).
Biliverdin is then reduced to bilirubin (
red/orange in colour).
93
94
The following are the major events taking place after
the formation of bilirubin.
1. The hydrophobic Bilirubin is transported in the blood
(plasma) by serum albumin.
2. Bilirubin binds with hepato-cellular protein ligandin,
and its uptaken in to the hepatocytes.
3. Within the hepatocytes, bilirubin is made water
soluble by the attachment of two glucuronic
acid residues to form bilirubin di-glucuronide , by
an enzymes called as glucuronyl transferases-
conjugation/detoxification of bilirubin.
4. Bilirubin diglucuronide is excreted in the bile to the
duodenum of the small intestine.
95
5. In the intestinal lumen bilirubin digluronide is
hydrolysed and reduced by intestinal bacterial
enzymes to form urobilinogen.
6. Urobilinogen is oxidized to stercobilin by
bacteria in the large intestine. Stercobilin
imparts a brown colour to the stool.
7. Some amount of Urobilinogen will be absorbed
and undergo entero-hepatic circulation and re-
excreted in the bile.
8. Urobilinogen can also be transported to the
kidneys where it is converted in to urobilin and
excreted via the urine.
96
97
Disorders in heme degradation/
detoxification mechanism
JAUNDICE
Jaundice( also known as icterus;) is a condition characterized by
elevated levels of bilirubin pigment in blood (
hyperbilirubinemia)and other tissues of the body leading to the
yellowing of skin eye , nails etc.
The urine will appear yellow in colour. The term jaundice comes from
the French word jaune, meaning yellow.
Concentration of bilirubin in blood plasma is normally below
1.2 mg/dL (<25mol/L).
A concentration higher than 2.5 mg/dL (>50mol/L) leads to
jaundice.
Jaundice is often seen in liver disease such as hepatitis or liver
cancer.
It may also indicate leptospirosis or obstruction of the biliary
tract, for example by gallstones or pancreatic cancer.
98
Types of Jaundice:
Jaundice is classified in to 4 different groups
based on the pathology of development.
Pre-hepatic or hemolytic
Hepato-cellular
Post-hepatic or obstructive
Neo-natal jaundice
99
1. Pre-hepatic or hemolytic
Pre-hepatic jaundice is caused by anything which
causes an increased rate of hemolysis (breakdown
of red blood cells).
Malaria can cause jaundice in this manner.
Certain genetic diseases, such as sickle cell
anemia, spherocytosis, thalassemia and glucose 6-
phosphate dehydrogenase deficiency can lead to
increased red cell lysis and thereby hemolytic
jaundice.
Defects in bilirubin metabolism also present as
jaundice, as in Gilbert's syndrome and Crigler-Najjar
syndrome.
100
Differential Diagnosis
Urine: no bilirubin present(acholuric jaundice),
urobilinogen > 2 units.
Serum: increased unconjugated bilirubin
Vanden Bergh reaction: indirect +ve(purple colour).
Kernicterus is associated with increased unconjugated
bilirubin, neonates are especially vulnerable to this due to
increase permeability of the blood brain barrier.
Deposition of bilirubin in Brain lead to mental
retardation. (Aspirin accelerate this process as it
competitively binds with serum albumin making the
bilirubin in the free from in plasma)
101
2.Hepato cellular
Hepatocellular (hepatic) jaundice can be caused by acute
or chronic hepatitis hepatotoxicity, cirrhosis, drug induced
hepatitis and alcoholic liver disease.
Cell necrosis reduces the liver's ability to metabolize and
excrete bilirubin leading to the accumulation of
unconjugated bilirubin in the blood.
Differential Diagnosis
Urine: Conjugated bilirubin present, urobilirubin > 2 units
but variable.
Serum: cojugated as well as unconjugated bilirubin present
(Vanden Bergh reaction: biphasic-direct test as well as
indirect test +ve)-a purple colour is obtained by direct test
and will be intensified on addition of alcohol.
102
3.Post hepatic or obstructive( re-gurgitative jaundice)
Post-hepatic jaundice, also called obstructive jaundice, is
caused by an interruption of bile duct in the biliary
system.
The most common causes are gallstones in the common
bile duct, and pancreatic cancer in the head of
the pancreas.
Also, a group of parasites known as "liver flukes can live in
the common bile duct, causing obstructive jaundice.
Differential diagnosis:
Urine: contain elevated bilirubin( choluric jaundice).
Serum: cojugated bilirubin present.
(Vanden Bergh reaction: direct +ve).
103
4. Neonatal jaundice( erythroblastosis foetalis)- hemolytic
disease of the new born.
Seen in neonates
Neonatal jaundice is usually harmless.
This condition is often seen in infants around the second
day after birth, lasting until day 8 in normal births, or to
around day 14 in premature births.
Typical causes for neonatal jaundice include normal
physiologic jaundice, jaundice due to breast feeding, and
hemolytic disorders that include hereditary spherocytosis,
glucose-6-phosphate dehydrogenase deficiency, pyruvate
kinase deficiency, ABO/Rh blood type auto antibodies, or
infantile pyknocytosis.
Phototherapy will be effective.
104
detoxification mechanism( GENETIC)
1.Gilberts Syndrome:
Is the most common hereditary cause of increased
bilirubin
Found in up to 5% of the population
The main symptom is harmless jaundice caused by
elevated levels of un-conjugated bilirubin in the
blood
The cause of hyperbilirubinemia is reduced activity
of the enzyme glucuronyltransferase
Gilberts syndrome is caused by approximately 30-
50% reduction in the activity of Uridine-
diphosphate-glucuronosyltransferase isoform 1A1
(UGT1A1).
105
2.Crigler-Najjar syndrome:
Type-I
Inheritance is autosomal recessive
Intense jaundice appears in the first days of life
No UGT1A1 expression can be detected in the hepatic tissues
Type-II
UGT1A1 is present at reduced levels because of single base
pair mutations
Because of the genetic deficiency of glucuronidyl
transferase enzyme in the liver.
106
3.Dubin-Johnson Syndrome:
Is an autosomal recessive disease
Increased conjugated bilirubin without elevation of liver
enzymes (ALT and AST)
Defect in the multi-specific anion transporter (cMOAT)
gene.
This disease is characterized by the genetic deficiency of
the transporter protein that uptake bilirubin in to the
hepatocytes.
Most patients are asymptomatic and have normal life
spans.
Some neonates will have cholestasis.
107
Urinalysis for heme degradation
products
Test for bilirubin:Fouchets test
Test for urobilinogen: Erlichs test
108
LIVER AND BILE ACID/ BILESALT
METABOLISM
Liver is the organ concerned with the
synthesis and secretion of bile .
Bile contain bile salt and is particularly
important for the digestion and absorption of
various type of lipids as well as the
absorption of fat soluble viamins( ADE K).
Cholesterol is the precursor of bile acids and
bile salt.
109
110
SYNTHESIS OF CREATINE
Liver play a partial role in the syntheis of creatine
, the precursor of creatine P , a high energy
molecule required for muscle contraction.
The synthesis of creatine is taking place partially
in the kidney and partially in the liver.
Creatine is synthesized from two amino acids
,namely Arginine and Glycine in a two step
process.
The first /step reaction takes place in the kidney
in which Arginine and glycine combines to form
guanido- acetic aid.
111
SYNTHESIS OF CREATINE
The second step takes place in the liver during
which guanidoacetate is methylated to form
creatine.
Creatine is then transported to the muscle where
it is phosphorylated to creatine P ( the active
form/phosphagen form).
Very negligible amount of creatine P is
dephosphorylated spontaneously and cyclised
(by non-enzymatic reaction) to form creatinine (
a waste product) which is excreted in the urine
112
113
LIVER AND VITAMIN D METABOLISM
LIVER has a role in the synthesis of the active form of Vit. D ( 1, 25, DH
CC). Vit D is involved in the metabolism of Ca and P in the body.
There for liver has an indirect role in maintaining the normal texture of
bone tissue.
Cholecalciferol (Vitamin D3) is derived from 7-dehydrocholesterol in
the skin by sunlight or supplied in the diet
In liver:
Cholecalciferol is converted to 25-hydroxycholecalciferol (25-HCC)
by the enzyme 25 hydroxylase
25-hydroxycholecalciferol is the predominant form of vitamin D
in blood
25-hydroxycholecalciferol is the main storage form of vitamin
in the body
In kidneys:
The 1 hydroxylase enzyme converts 25 hydroxycholecalciferol to
1,25-dihydroxycholecalciferol (1, 25 DHCC or Calcitriol)
which is the biologically active form of vitamin D
114
115
LIVER AND BIOTRANSFORMATION
Liver takes part in several biotransformation reactions
particularly of drugs. The conversion of toxic (
xenobiotics) compounds in to non toxic /less toxic
compounds takes place by various mechanisms-
known as bio-transformations.
Liver is involved in the detoxification of exogenous (
alcohol ( ethanol and methanol),drugs,toxins,dyes,
colouring agents, food preservatives etc) and
endogenous substances( ammonia , bilirubin etc).
There are a number of detoxification mechanisms-
oxidation, reduction, hydrolysis( Phase 1 reactions
conjugation ( phase- 2reactions) etc.
116
Phase 1:
1. Oxidation:
ethanol to acetaldehyde and then to acetic acid
methanol toformaldehyde and then to formic
acid(both are highly toxic)responsible for methanol
toxicity.
2. Reduction:
Picric acid to picramic acid
3. Hydrolysis:
Aspirin is detoxified by hydrolysis in to salicylic acid
and acetic acid
Atropine in to tropine and tropic acid.
117
Phase -2
Conjugation reactions:
Conjugation using D- glucuronic acid
Bilirubin ( water insoluble) to bilirubin
diglucuronide( water soluble).
Conjugation using Glycine
Benzoic acid ( food preservative) to hippuric
acid
118
119
120
LIVER FUNCTION TESTS
The functional status of the liver can be assessed by
analyzing a number of parameters ,collectively called liver
Function Tests( LFTs).
It include the analysis of serum total protein,
albumin/globulin ratio, serum urea level ,serum blirubin
etc.
Also include analysis of certain enzymes in the plasma
such as AST( Aspartate transaminase), ALT( Alanine
transaminase), GGT( Gamma glutamyl transferase) and
ALP( alkaline phosphatase).
GGT is a very specific marker enzyme for chronic
alcoholism( GGT is involved in Glutathione synthesis).
During liver malfunction low serum total protein,
decreased albumin Globulin ratio( A/G ratio), decreased
urea level, increased ammonia level, increased serum
bilirubin level, increased activity of AST, ALT, GGT, and ALP
are noticed.
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LIVER METABOLISM

LIVER IS THE CHIEF

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