Lipid metabolism
hussamdr
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235 slides
Sep 12, 2011
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About This Presentation
lipid
Slide Content
A- PROCESSING OF DIETARY LIPIDS IN STOMACH:-
Lipid digestion begins in the stomach by
-LINGUAL LIPASE --- acid stable.
Primary target ----- fatty acids of short or medium
chain length ( milk fat ).
-GASTRIC LIPASE ----- acid stable.
Both enzymes ---- optimum pH 4 to 6
Particular importance in neonates and in patients with
pancreatic insufficiency.
Lipid digestion begins in the stomach by
-LINGUAL LIPASE --- acid stable.
Primary target ----- fatty acids of short or medium
chain length ( milk fat ).
-GASTRIC LIPASE ----- acid stable.
Both enzymes ---- optimum pH 4 to 6
Particular importance in neonates and in patients with
pancreatic insufficiency.
CYSTIC FIBROSIS:-
An autosomal recessive disorder
Prevalence of 1:3,000 births
Cause ; decreased secretion of chloride and
increased reabsorption of water due to defect
in the transmembrane conductance regulator
protein.
Result is thickened secretions of glands.
In pancreas ---- pancreatic insufficiency
An autosomal recessive disorder
Prevalence of 1:3,000 births
Cause ; decreased secretion of chloride and
increased reabsorption of water due to defect
in the transmembrane conductance regulator
protein.
Result is thickened secretions of glands.
In pancreas ---- pancreatic insufficiency
Emulsification increases the surface area of
the hydrophobic fat droplets so that digestive
enzymes can act effectively.
Site is duodenum
Done by
- peristalsis---- mechanical mixing
- Bile salts ---- detergent properties as they
decrease the surface tension and cause fat
emulsification.
the hydrophobic fat droplets so that digestive
enzymes can act effectively.
Site is duodenum
Done by
- peristalsis---- mechanical mixing
- Bile salts ---- detergent properties as they
decrease the surface tension and cause fat
emulsification.
Pancreatic enzymes degrade ---- TAG,
cholesteryl esters and phospholipids.
1- Degradation of TAG:-
- Pancreatic Lipase ----
removes fatty acids at carbon 1 and 3
and forms 2-monoacylglycerol and
free fatty acids
cholesteryl esters and phospholipids.
1- Degradation of TAG:-
- Pancreatic Lipase ----
removes fatty acids at carbon 1 and 3
and forms 2-monoacylglycerol and
free fatty acids
2- Degradation of cholesteryl esters:-
Cholesteryl estrase produces cholesterol and free fatty
acids.
Activity is increased in presence of Bile salts.
3- Degradation of Phospholipids :-
Phospholipase A2 in proenzyme form, activated by
Trypsin, requires bile salts for activity. Removes one
fatty acid from carbon 2 of a phospholipid
lysophospholipid.
Lysophospholipase removes fatty acid at carbon 1 and
forms glycerylphosphoryl base that is excreted, degraded
or absorbed.
Cholesteryl estrase produces cholesterol and free fatty
acids.
Activity is increased in presence of Bile salts.
3- Degradation of Phospholipids :-
Phospholipase A2 in proenzyme form, activated by
Trypsin, requires bile salts for activity. Removes one
fatty acid from carbon 2 of a phospholipid
lysophospholipid.
Lysophospholipase removes fatty acid at carbon 1 and
forms glycerylphosphoryl base that is excreted, degraded
or absorbed.
Hormonal control
Cholecystokinin
site of release ------released in blood from jejunum and
lower duodenum
in response to lipids and partially digested proteins
entering small intestines.
Actions ;
-Gall bladder------- contraction and release of bile
- Pancreatic exocrine cells ------ release of digestive
enzymes
- Decreases gastric motility
Cholecystokinin
site of release ------released in blood from jejunum and
lower duodenum
in response to lipids and partially digested proteins
entering small intestines.
Actions ;
-Gall bladder------- contraction and release of bile
- Pancreatic exocrine cells ------ release of digestive
enzymes
- Decreases gastric motility
Secretin
site -released in blood from other
intestinal cells
- in response to low pH of chyme
Actions;
- release of a watery solution by pancreas
and liver, high in bicarbonate ------
appropriate pH for action of pancreatic
enzymes.
site -released in blood from other
intestinal cells
- in response to low pH of chyme
Actions;
- release of a watery solution by pancreas
and liver, high in bicarbonate ------
appropriate pH for action of pancreatic
enzymes.
Jejunum gets ---- free fatty acids
free cholesterol
2-monoacylglycerol
Combine with bile and fat soluble vitamins
Formation of micelles ---- soluble in
aqueous intestinal environment, absorbed at
the brush border of enterocytes .
Fatty acids with short and medium chain
length do not need micelles for absorption.
free cholesterol
2-monoacylglycerol
Combine with bile and fat soluble vitamins
Formation of micelles ---- soluble in
aqueous intestinal environment, absorbed at
the brush border of enterocytes .
Fatty acids with short and medium chain
length do not need micelles for absorption.
Absorbed lipids move to endoplasmic reticulum
long chain fatty acids converted to fatty acyl coA by fatty acyl Co
A synthetase .
2-monoacylglycerols use fatty acyl CoA and converted to TAG by
TAG Synthase.--- Acyltransferases
Reacylation of lysophospholipids caused by acyltransferases
forms phospholipids.
Cholesteryl ester formation by Acyl CoA:cholesteryl
acyltransferase.
Free fatty acids with short and medium chains are released into
portal circulation.
long chain fatty acids converted to fatty acyl coA by fatty acyl Co
A synthetase .
2-monoacylglycerols use fatty acyl CoA and converted to TAG by
TAG Synthase.--- Acyltransferases
Reacylation of lysophospholipids caused by acyltransferases
forms phospholipids.
Cholesteryl ester formation by Acyl CoA:cholesteryl
acyltransferase.
Free fatty acids with short and medium chains are released into
portal circulation.
Steatorrhea ----- increased lipid and fat
soluble vitamin excretion in feces.
Caused by defects in
lipid digestion
and/or lipid absorption
soluble vitamin excretion in feces.
Caused by defects in
lipid digestion
and/or lipid absorption
Formation of Chylomicrons :-
Aggregates of TAG and cholesteryl esters are
formed,
surrounded by
a thin layer phospholipids
free cholesterol and
special protein Apolipoprotein B-48
Chylomicrons are released into lacteals by
exocytosis.
After a lipid rich meal , lymph is called chyle.
From lymph, chylomicrons finally enter blood.
Aggregates of TAG and cholesteryl esters are
formed,
surrounded by
a thin layer phospholipids
free cholesterol and
special protein Apolipoprotein B-48
Chylomicrons are released into lacteals by
exocytosis.
After a lipid rich meal , lymph is called chyle.
From lymph, chylomicrons finally enter blood.
In capillaries of tissues
TAG in chylomicrons degraded into free fatty
acids and glycerol.
Enzyme lipoprotein lipase, formed mainly by
adipocytes and muscle cells.
Fate of free fatty acids ---- direct entry into
muscle cells or adipocytes. Used for energy
production or reesterify to form TAG in
adipocytes.
Free fatty acids may be transported in blood
with albumin.
TAG in chylomicrons degraded into free fatty
acids and glycerol.
Enzyme lipoprotein lipase, formed mainly by
adipocytes and muscle cells.
Fate of free fatty acids ---- direct entry into
muscle cells or adipocytes. Used for energy
production or reesterify to form TAG in
adipocytes.
Free fatty acids may be transported in blood
with albumin.
Fate of Glycerol ---- used by liver to form
glycerol 3- phosphate which can enter
glycolysis or gluconeogenesis.
Fate of the remaining Chylomicron
components ---- endocytosed by liver and
the remnants are hydrolysed to their
components.
glycerol 3- phosphate which can enter
glycolysis or gluconeogenesis.
Fate of the remaining Chylomicron
components ---- endocytosed by liver and
the remnants are hydrolysed to their
components.
Fatty acids are taken up by cells, where they
may serve as
-precursors in the synthesis of other compounds,
- as fuels for energy production, and
-as substrates for ketone body synthesis.
Ketones bodies may then be exported to other
tissues, where they can be used for energy
production. In addition, some cells synthesize
fatty acids for storage or export.
may serve as
-precursors in the synthesis of other compounds,
- as fuels for energy production, and
-as substrates for ketone body synthesis.
Ketones bodies may then be exported to other
tissues, where they can be used for energy
production. In addition, some cells synthesize
fatty acids for storage or export.
Intermediates in Synthetic processes
Fatty acids are intermediates in the synthesis of other
important compounds. Examples include:
Phospholipids (in membranes).
Eicosanoids, including prostaglandins and
leucotrienes, which play a role in physiological
regulation.
Energy
- Fats are an important source of dietary calories.
Typically 30-40% of calories in the American diet are
from fat.
- Fat is the major form of energy storage.
Fatty acids are intermediates in the synthesis of other
important compounds. Examples include:
Phospholipids (in membranes).
Eicosanoids, including prostaglandins and
leucotrienes, which play a role in physiological
regulation.
Energy
- Fats are an important source of dietary calories.
Typically 30-40% of calories in the American diet are
from fat.
- Fat is the major form of energy storage.
Precursors of Acetyl CoA
Acetyl CoA is at the center of lipid metabolism. It is produced from:
Fatty acids
Glucose (through pyruvate)
Amino acids
Ketone bodies
Products of Acetyl CoA Metabolism
It can be converted to fatty acids, which in turn give rise to:
triglycerides (triacylglycerols)
phospholipids
eicosanoids (e.g., prostaglandins)
ketone bodies
It is the precursor of cholesterol, which can be converted to:
steroid hormones
bile acids
It produces energy, generated by the complete oxidation of acetyl CoA to carbon
dioxide and water through the tricarboxylic acid cycle and oxidative
phosphorylation.
Acetyl CoA is at the center of lipid metabolism. It is produced from:
Fatty acids
Glucose (through pyruvate)
Amino acids
Ketone bodies
Products of Acetyl CoA Metabolism
It can be converted to fatty acids, which in turn give rise to:
triglycerides (triacylglycerols)
phospholipids
eicosanoids (e.g., prostaglandins)
ketone bodies
It is the precursor of cholesterol, which can be converted to:
steroid hormones
bile acids
It produces energy, generated by the complete oxidation of acetyl CoA to carbon
dioxide and water through the tricarboxylic acid cycle and oxidative
phosphorylation.
Structure of Acetyl CoA
The structure of Acetyl CoA consists of two
parts.
1. Acetyl group
2. Coenzyme A
- Beta-mercaptoethylamine
- Pantothenic acid (not synthesized in man
-- an essential nutrient)
- Phosphate
- 3', 5'-adenosine diphosphate
The structure of Acetyl CoA consists of two
parts.
1. Acetyl group
2. Coenzyme A
- Beta-mercaptoethylamine
- Pantothenic acid (not synthesized in man
-- an essential nutrient)
- Phosphate
- 3', 5'-adenosine diphosphate
Fatty acid synthesis is the process of combining
eight two-carbon fragments (acetyl groups from
acetyl CoA) to form a 16-carbon saturated fatty
acid, palmitate.
Palmitate can then be modified to give rise to
the other fatty acids. These modifications may
include:
-chain elongation to give longer fatty acids, such
as the 18-carbon stearate.
-Desaturation , giving unsaturated fatty acids.
eight two-carbon fragments (acetyl groups from
acetyl CoA) to form a 16-carbon saturated fatty
acid, palmitate.
Palmitate can then be modified to give rise to
the other fatty acids. These modifications may
include:
-chain elongation to give longer fatty acids, such
as the 18-carbon stearate.
-Desaturation , giving unsaturated fatty acids.
Tissue locations
Fatty acid synthesis occurs primarily in :
liver
Adipose tissue (fat)
lactating mammary glands
Fatty acid synthesis occurs primarily in :
liver
Adipose tissue (fat)
lactating mammary glands
Sum of the reactions;
8 acetyl CoA + 7 ATP + 14 (NADPH + H
+
) ->
palmitate + 8 CoA + 7 (ADP + P
i
) + 14
NADP
+
+ 6 H
2
O
This is the overall process for fatty acid
synthesis. Acetyl CoA for fatty acid synthesis
comes mostly from glycolytic breakdown of
glucose.
8 acetyl CoA + 7 ATP + 14 (NADPH + H
+
) ->
palmitate + 8 CoA + 7 (ADP + P
i
) + 14
NADP
+
+ 6 H
2
O
This is the overall process for fatty acid
synthesis. Acetyl CoA for fatty acid synthesis
comes mostly from glycolytic breakdown of
glucose.
Glucose is first degraded to pyruvate by aerobic glycolysis in the
cytoplasm.
Pyruvate is then transported into the mitochondria, where its
oxidation forms mitochondrial acetyl CoA and other products.
Also formed by catabolism of fatty acids, ketone bodies and
certain amino acids.
Acetyl CoA can then serve as a substrate for citrate synthesis.
Citrate, in turn, can be transported out of the mitochondria to the
cytoplasm (where fatty acid synthesis occurs), and there split to
generate cytoplasmic acetyl CoA for fatty acid synthesis. Enzyme
is ATP Citrate Lyase.
cytoplasm.
Pyruvate is then transported into the mitochondria, where its
oxidation forms mitochondrial acetyl CoA and other products.
Also formed by catabolism of fatty acids, ketone bodies and
certain amino acids.
Acetyl CoA can then serve as a substrate for citrate synthesis.
Citrate, in turn, can be transported out of the mitochondria to the
cytoplasm (where fatty acid synthesis occurs), and there split to
generate cytoplasmic acetyl CoA for fatty acid synthesis. Enzyme
is ATP Citrate Lyase.
Enzymes and Isolated Reactions
Acetyl CoA carboxylase catalyzes the
reaction:
acetyl CoA + HCO
3
-
+ ATP -> malonyl CoA +
ADP + P
i
Acetyl CoA carboxylase catalyzes the
reaction:
acetyl CoA + HCO
3
-
+ ATP -> malonyl CoA +
ADP + P
i
Acetyl CoA carboxylase
three important features.
1-It contains the prosthetic group, biotin.
The enzyme, using its biotin prosthetic group as a
carrier, transfers CO
2
from bicarbonate to the
acetyl group.
Biotin is not synthesized in humans, and is an
essential nutrient.
three important features.
1-It contains the prosthetic group, biotin.
The enzyme, using its biotin prosthetic group as a
carrier, transfers CO
2
from bicarbonate to the
acetyl group.
Biotin is not synthesized in humans, and is an
essential nutrient.
2-The carboxylation reaction is driven to completion by
hydrolysis of ATP.
3-The enzyme catalyzes the rate-limiting reaction for fatty
acid synthesis, and is under tight short-term control.
DOWN REGULATION --- long chain fatty acyl coA (end
product) , Phosphorylation of enzyme caused
by glucagon , protein kinase activated by AMP
UP REGULATION ----- Citrate (allosteric),
dephosphorylation of enzyme caused by insulin,
high caloric food
hydrolysis of ATP.
3-The enzyme catalyzes the rate-limiting reaction for fatty
acid synthesis, and is under tight short-term control.
DOWN REGULATION --- long chain fatty acyl coA (end
product) , Phosphorylation of enzyme caused
by glucagon , protein kinase activated by AMP
UP REGULATION ----- Citrate (allosteric),
dephosphorylation of enzyme caused by insulin,
high caloric food
To summarize, it is controlled allosterically
----citrate, fatty acyl CoA
and by covalent modification--------
phosphorylation/dephosphorylation of
Enzymes
----citrate, fatty acyl CoA
and by covalent modification--------
phosphorylation/dephosphorylation of
Enzymes
Multifunctional, dimeric
Each monomer with seven different enzymic
activities plus a domain that binds a molecule
of phosphopantetheine.
Phosphopantetheine has a terminal SH
group. This binding domain is referred to as
ACP.
Each monomer with seven different enzymic
activities plus a domain that binds a molecule
of phosphopantetheine.
Phosphopantetheine has a terminal SH
group. This binding domain is referred to as
ACP.
1-In the first reaction a molecule of acetate is
transferred from acetyl CoA to SH group of
the ACP. ----- transacylase
2- This two carbon fragment is shifted to SH
group of cysteine residue.
3- ACP is vacant and accepts a three carbon
malonate unit from malonyl CoA. ----
transacylase
transferred from acetyl CoA to SH group of
the ACP. ----- transacylase
2- This two carbon fragment is shifted to SH
group of cysteine residue.
3- ACP is vacant and accepts a three carbon
malonate unit from malonyl CoA. ----
transacylase
4- The acetyl group is transferred to malonyl
group with the release of carbon dioxide. This
results in a four carbon unit attached to the
ACP domain.
5- The keto group is reduced to an alcohol.
6- A molecule of water is removed to add a
double bond between C 2 and C 3.
7-The double bond is reduced.
group with the release of carbon dioxide. This
results in a four carbon unit attached to the
ACP domain.
5- The keto group is reduced to an alcohol.
6- A molecule of water is removed to add a
double bond between C 2 and C 3.
7-The double bond is reduced.
In the seventh reaction the double bond is
reduced by NADPH, yielding a saturated fatty
acyl group two carbons longer than the initial
one (an acetyl group was converted to a
butyryl group in this case):
2-butenoyl-ACP + NADPH + H
+
-> butyryl-
ACP + NADP
+
The butyryl group is then transferred from
the ACP sulfhydryl group to the CE
sulfhydryl:
reduced by NADPH, yielding a saturated fatty
acyl group two carbons longer than the initial
one (an acetyl group was converted to a
butyryl group in this case):
2-butenoyl-ACP + NADPH + H
+
-> butyryl-
ACP + NADP
+
The butyryl group is then transferred from
the ACP sulfhydryl group to the CE
sulfhydryl:
The butyryl group is now ready to condense
with a new malonyl group to repeat the
process. Each time a two carbon unit is
added into the growing fatty acid chain at the
carboxyl end .
When the fatty acyl group becomes 16
carbons long, a thioesterase activity cleaves
the thioester bond, forming free palmitate .
with a new malonyl group to repeat the
process. Each time a two carbon unit is
added into the growing fatty acid chain at the
carboxyl end .
When the fatty acyl group becomes 16
carbons long, a thioesterase activity cleaves
the thioester bond, forming free palmitate .
Fatty acid synthetase is essential, but not rate-
limiting, for fatty acid synthesis. It is not
subject to short term control .
limiting, for fatty acid synthesis. It is not
subject to short term control .
HMP pathway
Cytosolic conversion of malate to pyruvate
Cytosolic conversion of malate to pyruvate
The palmitate produced by fatty acid
synthase is typically modified to give rise to
the other fatty acids.
Fatty acids from dietary sources, too, are
often modified.
These modifications may include:
-chain elongation to give longer fatty acids
-desaturation, giving unsaturated fatty acids.
synthase is typically modified to give rise to
the other fatty acids.
Fatty acids from dietary sources, too, are
often modified.
These modifications may include:
-chain elongation to give longer fatty acids
-desaturation, giving unsaturated fatty acids.
Elongation can occur in most tissues; the
process differs in the endoplasmic reticulum
vs. the mitochondria.
Elongation: Fatty Acid Synthesis in the
Endoplasmic Reticulum
In endoplasmic reticulum malonyl CoA
combines with long chain fatty acyl CoA to
form fatty acyl CoA lenghthened by two
carbons.
process differs in the endoplasmic reticulum
vs. the mitochondria.
Elongation: Fatty Acid Synthesis in the
Endoplasmic Reticulum
In endoplasmic reticulum malonyl CoA
combines with long chain fatty acyl CoA to
form fatty acyl CoA lenghthened by two
carbons.
Mitochondrial elongation:
a minor process, uses acetyl CoA for
chain elongation.
a minor process, uses acetyl CoA for
chain elongation.
In endoplasmic reticulum
Addition of cis double bonds
Use of enzyme Desaturases
In humans there are four types of distinct
desaturases ----------- for carbon 9, 6, 5 and
4.
Double bonds cannot be added from C10 to
omega end of the chain.
This is the reason of nutritional essentiality of
linoleic and linolenic acids.
Addition of cis double bonds
Use of enzyme Desaturases
In humans there are four types of distinct
desaturases ----------- for carbon 9, 6, 5 and
4.
Double bonds cannot be added from C10 to
omega end of the chain.
This is the reason of nutritional essentiality of
linoleic and linolenic acids.
1- Pyruvate is produced in glycolysis and is
used for the synthesis of mito. Acetyl CoA.
2- Mitochondrial oxaloacetate is produced in
the first step of gluconeogenesis.
3- Formation of citrate is the first step in TCA
cycle.
4- NADH is produced during glycolysis and
this NADH causes reduction of NADP to
NADPH which is used for palmitoyl CoA
synthesis.
used for the synthesis of mito. Acetyl CoA.
2- Mitochondrial oxaloacetate is produced in
the first step of gluconeogenesis.
3- Formation of citrate is the first step in TCA
cycle.
4- NADH is produced during glycolysis and
this NADH causes reduction of NADP to
NADPH which is used for palmitoyl CoA
synthesis.
Site of fatty acid synthesis ----- liver
Starts after a meal rich in carbohydrates
Carbons for fatty acid synthesis provided by
acetyl CoA
Energy provided by ATP
Reducing equivaqlents provided by NADPH
Starts after a meal rich in carbohydrates
Carbons for fatty acid synthesis provided by
acetyl CoA
Energy provided by ATP
Reducing equivaqlents provided by NADPH
Glycerol + three fatty acids
Fatty acids esterified through carboxyl
groups resulting in loss of negative charge
and thus called Neutral Fats.
Low solubility in water
Stored in cytosole of adipocytes
Fatty acids esterified through carboxyl
groups resulting in loss of negative charge
and thus called Neutral Fats.
Low solubility in water
Stored in cytosole of adipocytes
1- Synthesis of glycerol phosphate
2- Formation of fatty acyl CoA
3- Formation of a molecule of TAG
2- Formation of fatty acyl CoA
3- Formation of a molecule of TAG
Sites ---- liver ( primary site ) and adipose
tissue
In both liver and adipose tissue , during
glycolysis , glucose is converted Dihydroxy
acetone phosphate.
DHAP is reduced to glycerol phosphate with
the help of enzyme Glycerol phosphate
dehydrogenase.
tissue
In both liver and adipose tissue , during
glycolysis , glucose is converted Dihydroxy
acetone phosphate.
DHAP is reduced to glycerol phosphate with
the help of enzyme Glycerol phosphate
dehydrogenase.
In liver ---- free glycerol coming to liver is
converted to glycerol phosphate by enzyme
Glycerol kinase.
In liver this process depends on supply of
glucose.
In adipose tissue glucose uptake is insulin
dependent as it has GLUT-4 receptors . Low
glucose--- low insulin ----- no synthesis of
TAG in adipocytes.
converted to glycerol phosphate by enzyme
Glycerol kinase.
In liver this process depends on supply of
glucose.
In adipose tissue glucose uptake is insulin
dependent as it has GLUT-4 receptors . Low
glucose--- low insulin ----- no synthesis of
TAG in adipocytes.
Long chain fatty acids are converted to fatty
acyl CoA .
Enzyme required is Fatty acyl CoA synthase.
Fatty acyl CoA participates in TAG synthesis.
acyl CoA .
Enzyme required is Fatty acyl CoA synthase.
Fatty acyl CoA participates in TAG synthesis.
Glycerol phosphate combines with a fatty
acyl CoA and forms Lysophosphatidic acid.
Enzyme is Acyltransferase which removes
CoA.
Lysophosphatidic acid combines with the
second fatty acyl CoA to form DAG
phosphate. Enzyme is Acyltransferase.
Phosphatase removes phosphate and forms
DAG. DAG combines with the third fatty acyl
CoA and forms TAG.
acyl CoA and forms Lysophosphatidic acid.
Enzyme is Acyltransferase which removes
CoA.
Lysophosphatidic acid combines with the
second fatty acyl CoA to form DAG
phosphate. Enzyme is Acyltransferase.
Phosphatase removes phosphate and forms
DAG. DAG combines with the third fatty acyl
CoA and forms TAG.
Adipose tissue ---- TAG stored in cytosol
Liver --- very little stored. Exported out of
liver in VLDL , which exports endogenous
lipids to peripheral tissues.
TAG --- stores of energy ---- energy yield
from complete oxidation of fatty acid to
carbon dioxide and water is 9 kcal/g of fat.
Liver --- very little stored. Exported out of
liver in VLDL , which exports endogenous
lipids to peripheral tissues.
TAG --- stores of energy ---- energy yield
from complete oxidation of fatty acid to
carbon dioxide and water is 9 kcal/g of fat.
TAG from diet----- absorbed from intestines
------ transported as chylomicrons
TAG from liver ------ transported as VLDL
FFA in circulation ----- transported with
albumin
------ transported as chylomicrons
TAG from liver ------ transported as VLDL
FFA in circulation ----- transported with
albumin
Breakdown of TAG ------ Lipolysis
Caused by ---- Hormone sensitive Lipase
There are three adipolytic lipases
1- Hormone sensitive lipase
2- Diacyl glycerol lipase
3- Monoacyl glycerol lipase
Caused by ---- Hormone sensitive Lipase
There are three adipolytic lipases
1- Hormone sensitive lipase
2- Diacyl glycerol lipase
3- Monoacyl glycerol lipase
Located in the walls of blood capillaries i.n
inactive form.
It is activated by phosphorylation
Phosphorylation is caused by -------------
cAMP Dependent Protein Kinase
inactive form.
It is activated by phosphorylation
Phosphorylation is caused by -------------
cAMP Dependent Protein Kinase
Catecholamines ---- epinephrine and
norepinephrine
Glucagon
Growth hormone
Glucocorticoids
These hormones bind to receptors on cell
membrane in adipocytes and activate
Adenylyl Cyclase which produces cAMP and
Protein kinase is activated.
norepinephrine
Glucagon
Growth hormone
Glucocorticoids
These hormones bind to receptors on cell
membrane in adipocytes and activate
Adenylyl Cyclase which produces cAMP and
Protein kinase is activated.
Insulin ------ causes dephosphorylation of
Hormone sensitive lipase.
This effect is achieved by ------- decreased
levels of cAMP
and increased levels of Phosphatase
enzyme.
High glucose level---- high insulin -----
decreased lipolysis.
Hormone sensitive lipase.
This effect is achieved by ------- decreased
levels of cAMP
and increased levels of Phosphatase
enzyme.
High glucose level---- high insulin -----
decreased lipolysis.
Phosphorylation caused by hormones
- inhibits Acetyl CoA carboxylase
- activates cAMP mediated cascade
Therefore Fatty acid synthesis is turned off
and
TAG degradation is turned on
- inhibits Acetyl CoA carboxylase
- activates cAMP mediated cascade
Therefore Fatty acid synthesis is turned off
and
TAG degradation is turned on
Not utilized in adipocytes
Transported to liver through blood
In liver it is phosphorylated to synthesize TAG
It can be converted back to DHAP which can
take part in Glycolysis and Gluconeogenesis.
Transported to liver through blood
In liver it is phosphorylated to synthesize TAG
It can be converted back to DHAP which can
take part in Glycolysis and Gluconeogenesis.
Breakdown of TAG releases free or
unesterified fatty acids
Transported in plasma bound with albumin
Enter into cells
In cells activated and oxidised to form energy
Plasma Free Fatty acids cannot be used by
Erythrocytes as they have no mitochondria.
Free Fatty acids cannot cross blood brain
barrier -- not a source of energy for brain.
unesterified fatty acids
Transported in plasma bound with albumin
Enter into cells
In cells activated and oxidised to form energy
Plasma Free Fatty acids cannot be used by
Erythrocytes as they have no mitochondria.
Free Fatty acids cannot cross blood brain
barrier -- not a source of energy for brain.
Pathway for catabolism of saturated fatty
acids
Site--- mitochondria
Two-carbon fragments are successively
removed from carboxyl end of fatty acyl CoA
producing acetyl CoA, NADH and FADH2.
acids
Site--- mitochondria
Two-carbon fragments are successively
removed from carboxyl end of fatty acyl CoA
producing acetyl CoA, NADH and FADH2.
Fatty acids inside the cell must be activated
before proceeding through metabolism.
Activation consists of conversion of the
nonesterified fatty acid to its CoA derivative.
The faty acyl CoA may then be transported
into the mitochondrion for energy
production. Transport across the
mitochondrial membrane requires a carrier.
before proceeding through metabolism.
Activation consists of conversion of the
nonesterified fatty acid to its CoA derivative.
The faty acyl CoA may then be transported
into the mitochondrion for energy
production. Transport across the
mitochondrial membrane requires a carrier.
Beta oxidation occurs in mitochondrial matrix
Mitochondrial membrane is impermeable to
CoA
Specialized carrier is required to transport
long chain acyl groups from cytosol to
mitochondria
This carrier is CARNITINE
It is a rate-limiting transport process and is
called CARNITINE SHUTTLE.
Mitochondrial membrane is impermeable to
CoA
Specialized carrier is required to transport
long chain acyl groups from cytosol to
mitochondria
This carrier is CARNITINE
It is a rate-limiting transport process and is
called CARNITINE SHUTTLE.
1-In the intermembrane space of the
mitochondria, fatty acyl CoA reacts with
carnitine in a reaction catalyzed by carnitine
acyltransferase I (CAT-I), yielding CoA and
fatty acyl carnitine. The resulting acyl
carnitine crosses the inner mitochondrial
membrane.
mitochondria, fatty acyl CoA reacts with
carnitine in a reaction catalyzed by carnitine
acyltransferase I (CAT-I), yielding CoA and
fatty acyl carnitine. The resulting acyl
carnitine crosses the inner mitochondrial
membrane.
CAT-I is associated with the outer
mitochondrial membrane.
CAT-I reaction is rate-limiting;
The enzyme is allosterically inhibited by
malonyl CoA. Malonyl CoA concentration
would be high during fatty acid synthesis.
Inhibition of CAT-I by malonyl CoA prevents
simultaneous synthesis and degradation of
fatty acids.
mitochondrial membrane.
CAT-I reaction is rate-limiting;
The enzyme is allosterically inhibited by
malonyl CoA. Malonyl CoA concentration
would be high during fatty acid synthesis.
Inhibition of CAT-I by malonyl CoA prevents
simultaneous synthesis and degradation of
fatty acids.
2-Fatty acyl carnitine is transported across
the inner mitochondrial membrane in
exchange for carnitine by carnitine-
acylcarnitine translocase.
In the mitochondrial matrix fatty acyl
carnitine reacts with CoA in a reaction
catalyzed by carnitine acyltransferase II
(CAT-II), yielding fatty acyl CoA and carnitine.
The fatty acyl CoA is now ready to undergo
beta-oxidation.
the inner mitochondrial membrane in
exchange for carnitine by carnitine-
acylcarnitine translocase.
In the mitochondrial matrix fatty acyl
carnitine reacts with CoA in a reaction
catalyzed by carnitine acyltransferase II
(CAT-II), yielding fatty acyl CoA and carnitine.
The fatty acyl CoA is now ready to undergo
beta-oxidation.
Diet- meat products
Can be synthesized in liver and kidney from
amino acids lysine and methionine.
Skeletal and heart muscles cannot synthesize
carnitine and depend on diet or endogenous
synthesis.
Can be synthesized in liver and kidney from
amino acids lysine and methionine.
Skeletal and heart muscles cannot synthesize
carnitine and depend on diet or endogenous
synthesis.
PRIMARY CAUSES:-
- Genetic CAT-I deficiency --- mainly affects
liver. Liver cannot synthesize glucose in a fast
, results in hypoglycemia, coma and death.
- CAT-II deficiency ---- mainly affects skeletal
and cardiac muscles.
-Defect in renal tubular reabsorption of
carnitine.
- Defect in carnitine uptake by cells.
- Genetic CAT-I deficiency --- mainly affects
liver. Liver cannot synthesize glucose in a fast
, results in hypoglycemia, coma and death.
- CAT-II deficiency ---- mainly affects skeletal
and cardiac muscles.
-Defect in renal tubular reabsorption of
carnitine.
- Defect in carnitine uptake by cells.
SECONDARY CAUSES :---
-liver diseases----- decreased endogenous
synthesis.
- malnutrition or strict vegetarian diet
- increased metabolic demands
- hemodialysis
-liver diseases----- decreased endogenous
synthesis.
- malnutrition or strict vegetarian diet
- increased metabolic demands
- hemodialysis
Carnitine and CAT system not required for
fatty acids shorter than 12 carbon length.
They are activated to their CoA form inside
mitochondrial matrix.
Not inhibited by malonyl CoA.
fatty acids shorter than 12 carbon length.
They are activated to their CoA form inside
mitochondrial matrix.
Not inhibited by malonyl CoA.
Beta-oxidation is the process by which long
chain fatty acyl CoA is degraded. The
products of beta-oxidation are:
acetyl CoA
FADH
2
, NADH and H
+
chain fatty acyl CoA is degraded. The
products of beta-oxidation are:
acetyl CoA
FADH
2
, NADH and H
+
There are four individual reactions of beta-
oxidation, each catalyzed by a separate
enzyme.
1-Dehydrogenation between carbon 2 and 3 in
a FAD-linked reaction. Enzyme is acyl CoA
dehydrogenase.
2-Hydration of the double bond by enoyl CoA
hydratase.
oxidation, each catalyzed by a separate
enzyme.
1-Dehydrogenation between carbon 2 and 3 in
a FAD-linked reaction. Enzyme is acyl CoA
dehydrogenase.
2-Hydration of the double bond by enoyl CoA
hydratase.
3-A second dehydrogenation in a NAD-linked
reaction. Enzyme is 3-hydroxyacyl CoA
dehydrogenase.
4-Thiolytic cleavage of the thioester by beta-
ketoacyl CoA thiolase.
This sequence of four steps is repeated until
the fatty acyl chain is completely degraded to
acetyl CoA
reaction. Enzyme is 3-hydroxyacyl CoA
dehydrogenase.
4-Thiolytic cleavage of the thioester by beta-
ketoacyl CoA thiolase.
This sequence of four steps is repeated until
the fatty acyl chain is completely degraded to
acetyl CoA
Long chain fatty acyl CoA dehydrogenase
(LCAD) acts on chains greater than C12.
Medium chain fatty acyl CoA dehydrogenase
(MCAD) acts on chains of C6 to C12.
Short chain fatty acyl CoA dehydrogenase
(SCAD) acts on chains of C4 to C6.
MCAD deficiency is thought to be one of the
most common inborn errors of metabolism.
(LCAD) acts on chains greater than C12.
Medium chain fatty acyl CoA dehydrogenase
(MCAD) acts on chains of C6 to C12.
Short chain fatty acyl CoA dehydrogenase
(SCAD) acts on chains of C4 to C6.
MCAD deficiency is thought to be one of the
most common inborn errors of metabolism.
The products are acetyl CoA and a long chain
fatty acyl CoA that is two carbons shorter
than the original fatty acyl CoA.
The shortened fatty acyl group is now ready
for another round of beta-oxidation. After
the fatty acyl CoA has been reduced to acetyl
or propionyl CoA, beta-oxidation is complete.
fatty acyl CoA that is two carbons shorter
than the original fatty acyl CoA.
The shortened fatty acyl group is now ready
for another round of beta-oxidation. After
the fatty acyl CoA has been reduced to acetyl
or propionyl CoA, beta-oxidation is complete.
Fate of acetyl CoA
- Oxidation by the citric acid cycle to CO
2
and
H
2
O.
-In liver only, acetyl CoA may be used for
ketone body synthesis.
Fate of the FADH
2
and NADH + H
+
- FADH
2
and NADH + H
+
are oxidized by the
mitochondrial electron transport system,
yielding ATP.
- Oxidation by the citric acid cycle to CO
2
and
H
2
O.
-In liver only, acetyl CoA may be used for
ketone body synthesis.
Fate of the FADH
2
and NADH + H
+
- FADH
2
and NADH + H
+
are oxidized by the
mitochondrial electron transport system,
yielding ATP.
Beta-oxidation is regulated as a whole
primarily by fatty acid availability; once fatty
acids are in the mitochondria they are
oxidized as long as there is adequate NAD
+
and CoA.
primarily by fatty acid availability; once fatty
acids are in the mitochondria they are
oxidized as long as there is adequate NAD
+
and CoA.
Oxidation of one molecule of palmitoyl CoA
to CO2 and water produces
-8 acetyl CoA
-7 NADH
-7 FADH2
to CO2 and water produces
-8 acetyl CoA
-7 NADH
-7 FADH2
7 FADH2 = 2X 7 = 14 ATP
7 NADH = 3 X 7 = 21 ATP
8 Acetyl CoA = 12 x 8 = 96 ATP
Total ATP = 131 ATP
2 ATP are utilized during the formation of
acyl CoA . Therefore net yield is 129 ATP.
7 NADH = 3 X 7 = 21 ATP
8 Acetyl CoA = 12 x 8 = 96 ATP
Total ATP = 131 ATP
2 ATP are utilized during the formation of
acyl CoA . Therefore net yield is 129 ATP.
Oxidation of fatty acids with odd number of
carbons yield acetyl CoA and one molecule of
propionyl CoA ---- a 3 C compound.
Propionyl CoA is converted to
Methylmalonyl CoA by carboxylase --- a
biotin requiring enzyme.
MMCoA is moved within the molecule by
MMCoA mutase (vit.B12 coenzyme) to form
succinyl CoA… gluconeogenic.
carbons yield acetyl CoA and one molecule of
propionyl CoA ---- a 3 C compound.
Propionyl CoA is converted to
Methylmalonyl CoA by carboxylase --- a
biotin requiring enzyme.
MMCoA is moved within the molecule by
MMCoA mutase (vit.B12 coenzyme) to form
succinyl CoA… gluconeogenic.
Succinyl CoA enters TCA cycle and then
yields energy.
Deficiency of vit. B 12 results in urinary
excretion of propionate and methylmalonate
as mutase enzyme cannot function.
yields energy.
Deficiency of vit. B 12 results in urinary
excretion of propionate and methylmalonate
as mutase enzyme cannot function.
Less energy yield
Less formation of reducing equivalents as
unsaturated F.A are not highly reduced.
The action of enoyl CoA isomerase is required
to handle double bonds at odd-numbered
carbons because beta-oxidation requires pre-
existing double bonds at even-numbered
carbons.
Less formation of reducing equivalents as
unsaturated F.A are not highly reduced.
The action of enoyl CoA isomerase is required
to handle double bonds at odd-numbered
carbons because beta-oxidation requires pre-
existing double bonds at even-numbered
carbons.
If there is a double bond at an odd-numbered
carbon (e.g., 18:1
9
), the action of enoyl CoA
isomerase is required to move the naturally
occurring cis- bond and convert it to the
trans- bond used in beta-oxidation.
The product, with a trans- double bond, is a
substrate for enoyl CoA hydratase, the
second enzyme of beta-oxidation.
carbon (e.g., 18:1
9
), the action of enoyl CoA
isomerase is required to move the naturally
occurring cis- bond and convert it to the
trans- bond used in beta-oxidation.
The product, with a trans- double bond, is a
substrate for enoyl CoA hydratase, the
second enzyme of beta-oxidation.
In case of polyunsaturated fatty acids, e.g
linoleic acid that is 18:2(9,12),
NADPH- dependent Dienoyl CoA
Reductase is required in addition to
isomerase.
linoleic acid that is 18:2(9,12),
NADPH- dependent Dienoyl CoA
Reductase is required in addition to
isomerase.
Fatty acids with 20 or more carbons
( VLCFA ) are first oxidized in the
peroxisomes.
The shortened fatty acid then goes to the
mitochondria.
The enzyme for initial dehydrogenation is
FAD containing Acyl CoA oxidase.
H2O2 is produced during the process which is
toxic to cells and is therefore converted to
H2O by Catalase.
( VLCFA ) are first oxidized in the
peroxisomes.
The shortened fatty acid then goes to the
mitochondria.
The enzyme for initial dehydrogenation is
FAD containing Acyl CoA oxidase.
H2O2 is produced during the process which is
toxic to cells and is therefore converted to
H2O by Catalase.
Zellweger syndrome ----- rare inherited
disorder.
Absence of peroxisomes.
VLCFA cannot be oxidized
Accumulation of VLCFA in brain, blood and
other tissues like liver and kidney.
disorder.
Absence of peroxisomes.
VLCFA cannot be oxidized
Accumulation of VLCFA in brain, blood and
other tissues like liver and kidney.
Fatty acids undergo oxidation at the carbon
atom farthest from the carboxyl carbon (ω
carbon).
Oxidation of carbon results in the formation
of dicarboxylic acid.
This dicarboxylic acid then undergoes beta
oxidation.
atom farthest from the carboxyl carbon (ω
carbon).
Oxidation of carbon results in the formation
of dicarboxylic acid.
This dicarboxylic acid then undergoes beta
oxidation.
This involves hydroxylation at alpha carbon.
Seen in branched chain fatty acid, phytanic
acid.
Phytanic acid has methyl group on beta
carbon and therefore it cannot be a substrate
for acyl CoA dehydrogenase.
Its alpha carbon is first of all hydroxylated by
fatty acid alpha hydroxylase.
Seen in branched chain fatty acid, phytanic
acid.
Phytanic acid has methyl group on beta
carbon and therefore it cannot be a substrate
for acyl CoA dehydrogenase.
Its alpha carbon is first of all hydroxylated by
fatty acid alpha hydroxylase.
Then it is decarboxylated and activated to its
CoA derivative.
This CoA derivative undergoes beta
oxidation.
CoA derivative.
This CoA derivative undergoes beta
oxidation.
Refsum disease ------ genetic disorder.
Caused by a deficiency of alpha hydroxylase.
There is accumulation of phytanic acid in the
plasma and tissues.
The symptoms are mainly neurological.
Treatment involves dietary restriction of
phytanic acid.
Caused by a deficiency of alpha hydroxylase.
There is accumulation of phytanic acid in the
plasma and tissues.
The symptoms are mainly neurological.
Treatment involves dietary restriction of
phytanic acid.
These are the compounds known as ketone bodies. Notice that beta-hydroxybutyrate is not chemically a ketone. It is considered to be physiologically equivalent to one because beta hydroxybutyrate and acetoacetate are readily interconverted in the body.
When there is a condition of high rate of fatty
acid oxidation, large amounts of acetyl CoA
are formed which exceed the oxidative
capacity of liver and then liver produces large
amounts of compounds ( organic acids ) like
acetoacetate and beta hydroxy butyric acid ,
which pass into blood and then to peripheral
tissues where they can be utilized.
acid oxidation, large amounts of acetyl CoA
are formed which exceed the oxidative
capacity of liver and then liver produces large
amounts of compounds ( organic acids ) like
acetoacetate and beta hydroxy butyric acid ,
which pass into blood and then to peripheral
tissues where they can be utilized.
Soluble in aqueous solution.
Skeletal muscles, cardiac muscles, renal
cortex and brain can use ketone bodies to get
energy.
Skeletal muscles, cardiac muscles, renal
cortex and brain can use ketone bodies to get
energy.
Ketone bodies are synthesized from acetyl
CoA.
Ketone body synthesis from acetyl CoA
occurs in hepatic mitochondria.
First, acetoacetate is produced in a three-
step process.
Acetoacetate can be reduced to beta-
hydroxybutyrate.
Acetone also arises in small amounts as a
biologically inert side product.
CoA.
Ketone body synthesis from acetyl CoA
occurs in hepatic mitochondria.
First, acetoacetate is produced in a three-
step process.
Acetoacetate can be reduced to beta-
hydroxybutyrate.
Acetone also arises in small amounts as a
biologically inert side product.
Ketone body production is regulated
primarily by availability of acetyl CoA. If
mobilization of fatty acids from adipose
tissue is high, hepatic beta-oxidation will
occur at a high rate, and so will synthesis of
ketone bodies from the resulting acetyl CoA.
The rate of ketone body production increases
in starvation.
primarily by availability of acetyl CoA. If
mobilization of fatty acids from adipose
tissue is high, hepatic beta-oxidation will
occur at a high rate, and so will synthesis of
ketone bodies from the resulting acetyl CoA.
The rate of ketone body production increases
in starvation.
Synthesis from acetyl CoA: Step 1
The first step is formation of acetoacetyl CoA
in a reversal of the thiolase step of beta-
oxidation.
The first step is formation of acetoacetyl CoA
in a reversal of the thiolase step of beta-
oxidation.
Reversal of thiolase step:-
Step 2
In the second step, a third molecule of acetyl
CoA condenses with the acetoacetyl CoA,
forming 3-hydroxy-3-methylglutaryl CoA
(HMG CoA) in a reaction catalyzed by HMG
CoA synthase… present only in liver.
HMG CoA Synthase is the rate limiting
enzyme for ketogenesis.
In the second step, a third molecule of acetyl
CoA condenses with the acetoacetyl CoA,
forming 3-hydroxy-3-methylglutaryl CoA
(HMG CoA) in a reaction catalyzed by HMG
CoA synthase… present only in liver.
HMG CoA Synthase is the rate limiting
enzyme for ketogenesis.
Step 2
Step 3
In the third step HMG CoA is cleaved to yield
acetoacetate (a ketone body) in a reaction
catalyzed by HMG CoA lyase (HMG CoA
cleavage enzyme)… present only in liver.
One molecule of acetyl CoA is also produced.
In the third step HMG CoA is cleaved to yield
acetoacetate (a ketone body) in a reaction
catalyzed by HMG CoA lyase (HMG CoA
cleavage enzyme)… present only in liver.
One molecule of acetyl CoA is also produced.
Step 3
Synthesis of β hydroxybutyrate
Acetoacetate can be reduced to beta-
hydroxybutyrate by beta-hydroxybutyrate
dehydrogenase in a NADH-requiring
reaction.
The extent of this reaction depends on the
state of the NAD pool of the cell; when it is
highly reduced, most or all of the ketones can
be in the form of beta-hydroxybutyrate.
Acetoacetate can be reduced to beta-
hydroxybutyrate by beta-hydroxybutyrate
dehydrogenase in a NADH-requiring
reaction.
The extent of this reaction depends on the
state of the NAD pool of the cell; when it is
highly reduced, most or all of the ketones can
be in the form of beta-hydroxybutyrate.
Synthesis of β hydroxybutyrate
Synthesis of Acetone
-Some acetoacetate spontaneously
decarboxylates to yield acetone.
-It cannot be metabolised any further and
excreted through lungs.
The odor of acetone can be smelled on the
breath of individuals with severe ketosis.
-Some acetoacetate spontaneously
decarboxylates to yield acetone.
-It cannot be metabolised any further and
excreted through lungs.
The odor of acetone can be smelled on the
breath of individuals with severe ketosis.
Synthesis of acetone
Ketone bodies are utilized exclusively by
extrahepatic tissues; particularly heart and
skeletal muscle. Brain can also use ketone
bodies.
If the ketone is beta-hydroxybutyrate, the
first step must be conversion to acetoacetate
and enzyme is dehydrogenase.
extrahepatic tissues; particularly heart and
skeletal muscle. Brain can also use ketone
bodies.
If the ketone is beta-hydroxybutyrate, the
first step must be conversion to acetoacetate
and enzyme is dehydrogenase.
Acetoacetate is activated by transfer of CoA
from succinyl CoA in a reaction catalyzed by
succinyl CoA: 3-ketoacid CoA transferase also
called Thiophrase.
from succinyl CoA in a reaction catalyzed by
succinyl CoA: 3-ketoacid CoA transferase also
called Thiophrase.
The enzyme catalyzing this reaction is absent
from liver; hence liver, which synthesizes
ketone bodies, cannot use them. This places
liver in the role of being a net producer of
ketones.
from liver; hence liver, which synthesizes
ketone bodies, cannot use them. This places
liver in the role of being a net producer of
ketones.
The resulting acetoacetyl CoA can be cleaved
by thiolase to form two molecules of acetyl
CoA, which can then be oxidized by the
tricarboxylic acid cycle.
by thiolase to form two molecules of acetyl
CoA, which can then be oxidized by the
tricarboxylic acid cycle.
Peripheral tissues use ketone bodies in
proportion to their blood levels.
They are preferred over glucose and FFA for
energy.
Ketone bodies can be utilised upto a blood
level of 70mg/dl. After this level the oxidative
mechanism is saturated --- ketonemia,
ketosis and ketonuria.
proportion to their blood levels.
They are preferred over glucose and FFA for
energy.
Ketone bodies can be utilised upto a blood
level of 70mg/dl. After this level the oxidative
mechanism is saturated --- ketonemia,
ketosis and ketonuria.
In blood of a well fed individual …. Less than
3 mg/dl.
In urine … less than 125 mg in 24 hrs.
3 mg/dl.
In urine … less than 125 mg in 24 hrs.
Ketosis…… accumulation of abnormal
amounts of ketone bodies in tissues and body
fluids . Urinary excretion of ketone bodies
exceeds the normal amounts.
Ketonemia …. level of ketone bodies in blood
above normal level.
Ketonuria … excretion of ketone bodies in
urine.
amounts of ketone bodies in tissues and body
fluids . Urinary excretion of ketone bodies
exceeds the normal amounts.
Ketonemia …. level of ketone bodies in blood
above normal level.
Ketonuria … excretion of ketone bodies in
urine.
Ketoacidosis …. Acetoacetic acid and beta
hydroxy butyric acid are moderately strong
acids. When their synthesis exceeds their
utilization, their amount exceeds in blood
and tissues. They need to be buffered. There
can be progressive loss of buffer cations and
this results in ketoacidosis.
hydroxy butyric acid are moderately strong
acids. When their synthesis exceeds their
utilization, their amount exceeds in blood
and tissues. They need to be buffered. There
can be progressive loss of buffer cations and
this results in ketoacidosis.
1-Starvation ----- no carbohydrate reserves.
Mobilization of FFA and their oxidation to get
energy…. Exceeds liver capacity to oxidise
acetyl CoA….. Ketongenesis.
2 - Uncontrolled insulin dependent diabetes
mellitus.
3- High fat intake
4- Strenuous exercise
Mobilization of FFA and their oxidation to get
energy…. Exceeds liver capacity to oxidise
acetyl CoA….. Ketongenesis.
2 - Uncontrolled insulin dependent diabetes
mellitus.
3- High fat intake
4- Strenuous exercise
In uncontrolled type 1 diabetes mellitus -----
severe deficiency or absence of insulin ----
lipolysis ---- very high levels of FFA ---- high
levels of acetyl CoA ---- raised ketogenesis.
In severe ketosis ---- blood level above 90 mg/
dl and urine level above 5000 mg/24 hrs.
With each ketone body , one hydrogen atom
is released in blood --- lowering of pH….
Acidosis.
severe deficiency or absence of insulin ----
lipolysis ---- very high levels of FFA ---- high
levels of acetyl CoA ---- raised ketogenesis.
In severe ketosis ---- blood level above 90 mg/
dl and urine level above 5000 mg/24 hrs.
With each ketone body , one hydrogen atom
is released in blood --- lowering of pH….
Acidosis.
Polar, ionic compounds
alcohol
Phosphodiester bridge
Diacylglycerol or Sphingosine
Types:
-Glycerophospholipids
-Sphingophospholipids (sphingosine)
alcohol
Phosphodiester bridge
Diacylglycerol or Sphingosine
Types:
-Glycerophospholipids
-Sphingophospholipids (sphingosine)
Synthesized in smooth endoplasmic
reticulum.
Transferred to golgi apparatus.
Move to membranes of organelles or to the
plasma membrane or released out via
exocytosis.
All cells except mature erythrocytes can
synthesize phospholipids.
reticulum.
Transferred to golgi apparatus.
Move to membranes of organelles or to the
plasma membrane or released out via
exocytosis.
All cells except mature erythrocytes can
synthesize phospholipids.
Phosphatidic acid is the basic component for
glycerophospholipid synthesis which then
combines with an alcohol.
This may involve two processes, i.e
- phosphatidic acid may be donated from
CDP-diacylglycerol to an alcohol or
- CDP- alcohol may donate its
phosphomonoester to diacylglycerol.
glycerophospholipid synthesis which then
combines with an alcohol.
This may involve two processes, i.e
- phosphatidic acid may be donated from
CDP-diacylglycerol to an alcohol or
- CDP- alcohol may donate its
phosphomonoester to diacylglycerol.
Diacylglycrol with a phosphate group on the
third carbon.
Synthesized from glycerol phosphate and
two fatty acyl CoAs.
Glycerol phosphate combines a fatty acyl
CoA at C 1 to form Lysophosphatidic acid.
Enzyme is acyltransferase.
Second fatty acyl CoA combines at C2 to
form PA.
third carbon.
Synthesized from glycerol phosphate and
two fatty acyl CoAs.
Glycerol phosphate combines a fatty acyl
CoA at C 1 to form Lysophosphatidic acid.
Enzyme is acyltransferase.
Second fatty acyl CoA combines at C2 to
form PA.
One of the most abundant PL in cells.
Substrates required are :-
- Choline ---- preexisting obtained from
diet or from turnover of PL.
- Diacylglycerol --- formed by removal of
phosphate from phosphatidic acid. Enzyme is
phosphatidate hydrolase.
PC can also be formed from PS in the liver.
Substrates required are :-
- Choline ---- preexisting obtained from
diet or from turnover of PL.
- Diacylglycerol --- formed by removal of
phosphate from phosphatidic acid. Enzyme is
phosphatidate hydrolase.
PC can also be formed from PS in the liver.
- Phosphorylation of choline by kinase –----
phosphocholine.
-Converted to CDP-choline which is the
activated form. Enzyme is phosphocholine
citidyl transferase.
-CDP- choline reacts with diacylglycerol .
Enzyme is phosphocholine diacyl glycerol
transferase.
phosphocholine.
-Converted to CDP-choline which is the
activated form. Enzyme is phosphocholine
citidyl transferase.
-CDP- choline reacts with diacylglycerol .
Enzyme is phosphocholine diacyl glycerol
transferase.
Transfer of Phosphocholine from CDP to
diacylglycerol forms Phosphatidylcholine
(lecithin) . CMP is left behind.
Dipalmitoyl-phosphatidylcholine is formed if
there is palmitate on position 1 and 2 of
glycerol. DPPC is made by pneumocytes and
is the major component of surfactant.
diacylglycerol forms Phosphatidylcholine
(lecithin) . CMP is left behind.
Dipalmitoyl-phosphatidylcholine is formed if
there is palmitate on position 1 and 2 of
glycerol. DPPC is made by pneumocytes and
is the major component of surfactant.
Takes place only in liver.
Liver can make PC by this process even when
free choline levels are low.
PS is converted to PE. Enzyme is PS
decarboxylase.
PE undergoes methylation . Enzyme is
methyltransferase. Result is the formation of
phosphatidylcholine.
Liver can make PC by this process even when
free choline levels are low.
PS is converted to PE. Enzyme is PS
decarboxylase.
PE undergoes methylation . Enzyme is
methyltransferase. Result is the formation of
phosphatidylcholine.
Formed from preexisting Ethanolamine.
Phosphorylation of ethanolamine by Kinase.
Formation of CDP-Ethanolamine.
Transfer of Ethanolamine Phosphate from
CDP to Diacylglycerol forms PE.
PS can be converted to PE by reversal of
decarboxylation.
Phosphorylation of ethanolamine by Kinase.
Formation of CDP-Ethanolamine.
Transfer of Ethanolamine Phosphate from
CDP to Diacylglycerol forms PE.
PS can be converted to PE by reversal of
decarboxylation.
Formed from PE.
PE reacts with serine to form PS. Enzyme is
PE-Serine transferase.
This is a base exchange reaction in which
ethanolamine of PE is exchanged for free
serine.
Reversible reaction.
PE reacts with serine to form PS. Enzyme is
PE-Serine transferase.
This is a base exchange reaction in which
ethanolamine of PE is exchanged for free
serine.
Reversible reaction.
Substrates required are free inositol and
CDP-diacylglycerol.
Diacylglycerol 3 phosphate (PA) reacts with
CTP to form CDP-diacylglycerol. Enzyme is
Diacylglycerol-CDP synthase.
CDP-Diacylglycerol reacts with inositol and
forms Phosphatidyl inositol. Enzyme is PI
Synthase.
CMP is left behind.
CDP-diacylglycerol.
Diacylglycerol 3 phosphate (PA) reacts with
CTP to form CDP-diacylglycerol. Enzyme is
Diacylglycerol-CDP synthase.
CDP-Diacylglycerol reacts with inositol and
forms Phosphatidyl inositol. Enzyme is PI
Synthase.
CMP is left behind.
PI plays a role in signal transmission across
membranes through the activation of Protein
kinase C. Acts as second messenger of
hormone action.
Membrane bound PI can have specific
proteins attached to it , e.g Alkaline
phosphatase and Acetyl choline estrase.
PI is unusual phospholipid as it has
Arachadonic acid on C2 and thus acts as a
source of arachadonic acid for PG synthesis.
membranes through the activation of Protein
kinase C. Acts as second messenger of
hormone action.
Membrane bound PI can have specific
proteins attached to it , e.g Alkaline
phosphatase and Acetyl choline estrase.
PI is unusual phospholipid as it has
Arachadonic acid on C2 and thus acts as a
source of arachadonic acid for PG synthesis.
Phosphatidylglycerol is present in
mitochondria and is a precursor of
Cardiolipin.
The substrates required are CDP-
diacylglycerol and Glycerol-3 phosphate.
They react together to form
phosphatidylglycerol.
mitochondria and is a precursor of
Cardiolipin.
The substrates required are CDP-
diacylglycerol and Glycerol-3 phosphate.
They react together to form
phosphatidylglycerol.
Cardiolipin is di-phosphatidyl glycerol in
nature.
It is composed of two molecules of
phosphatidic acid connected by a molecule of
glycerol.
CDP- diacylglycerol transfers
diacylglycerophosphate to
phosphatidylglycerol to form cardiolipin.
nature.
It is composed of two molecules of
phosphatidic acid connected by a molecule of
glycerol.
CDP- diacylglycerol transfers
diacylglycerophosphate to
phosphatidylglycerol to form cardiolipin.
Plasmalogens are the PL in which F.A at C1 of
glycrol is attached by an ether linkage.
Substrates required are di-hydroxy acetone
phosphate and acyl CoA.
glycrol is attached by an ether linkage.
Substrates required are di-hydroxy acetone
phosphate and acyl CoA.
If alcohol is Choline and Ethanolamine --------
activation of alcohol takes place by CDP.
If alcohol is Glycerol and Inositol ------------
activation of Diacylglycerol takes place by
CDP.
activation of alcohol takes place by CDP.
If alcohol is Glycerol and Inositol ------------
activation of Diacylglycerol takes place by
CDP.
These are the PL which have sphingosine as
their backbone.
A long chain F.A attached to the amino group
of sphingosine through an amide linkage
produces a ceramide.
The alcohol group at C1 of sphingosine is
esterified to choline through a phosphate
group and produces sphingomyelin.
their backbone.
A long chain F.A attached to the amino group
of sphingosine through an amide linkage
produces a ceramide.
The alcohol group at C1 of sphingosine is
esterified to choline through a phosphate
group and produces sphingomyelin.
Palmitoyl CoA condenses with Serine. It is an
NADPH requiring reaction and results in the
formation of Sphinganine.
A long chain fatty acid attaches to its amino
group and forms a ceramide.
Phosphatidylcholine transfers its
phosphorylcholine to the ceramide , thus
producing Sphingomyelin.
NADPH requiring reaction and results in the
formation of Sphinganine.
A long chain fatty acid attaches to its amino
group and forms a ceramide.
Phosphatidylcholine transfers its
phosphorylcholine to the ceramide , thus
producing Sphingomyelin.
Degradation of glycerophospholipids --------
Phospholipases
Degradation of sphingomyelin ------
Sphingomyelinase
Phospholipases
Degradation of sphingomyelin ------
Sphingomyelinase
Degradation of phosphoglycerides is
achieved by the hydrolysis of phosphodiester
bonds by phospholipases.
Phospholipases remove one fatty acid from
C1 or C2 and form lysophosphoglyceride.
Lysophospholipases act upon
lysophosphoglycerides.
achieved by the hydrolysis of phosphodiester
bonds by phospholipases.
Phospholipases remove one fatty acid from
C1 or C2 and form lysophosphoglyceride.
Lysophospholipases act upon
lysophosphoglycerides.
Products of glycerophospholipid degradation
are :-
Glycerol
Fatty acids
Phosphate
Alcohols
are :-
Glycerol
Fatty acids
Phosphate
Alcohols
Phospholipase A1:-
-found in many mammalian tissues.
-removes fatty acid from C1
Phospholipase A2:-
-found in many tissues and pancreatic juice
-removes F.A at C2
-when acts on PI, releases arachidonic acid
-inhibited by glucocorticoids
-found in many mammalian tissues.
-removes fatty acid from C1
Phospholipase A2:-
-found in many tissues and pancreatic juice
-removes F.A at C2
-when acts on PI, releases arachidonic acid
-inhibited by glucocorticoids
Phospholipase C:-
- cleaves phosphate group at C3
- found in liver lysosomes and some bacteria
- role in producing second messengers.
Phospholipase D:-
- found primarily in plant tissues.
- removes the compound with alcohol group
on C3
- cleaves phosphate group at C3
- found in liver lysosomes and some bacteria
- role in producing second messengers.
Phospholipase D:-
- found primarily in plant tissues.
- removes the compound with alcohol group
on C3
Enzyme is Sphingomyelinase, a lysosomal
enzyme.
It removes phosphorylcholine hydrolytically
and ceramide is produced.
Ceramide is cleaved by ceramidase and
leaves behind sphingosine and a free fatty
acid.
Sphingosine and ceramide act as intracellular
messengers.
enzyme.
It removes phosphorylcholine hydrolytically
and ceramide is produced.
Ceramide is cleaved by ceramidase and
leaves behind sphingosine and a free fatty
acid.
Sphingosine and ceramide act as intracellular
messengers.
Carbohydrate and lipid components
Derivatives of ceramide
Essential components of all membranes,
greatest amount in nerve tissue
Interact with the extracellular environment
No phospholipid but oligo or mono-
saccharide attached to ceramide by O-
glycosidic bond.
Derivatives of ceramide
Essential components of all membranes,
greatest amount in nerve tissue
Interact with the extracellular environment
No phospholipid but oligo or mono-
saccharide attached to ceramide by O-
glycosidic bond.
Neutral glycosphingolipids :-
- cerebrosides
- Globosides
Acidic glycosphingolipids:-
- Ganglioside
- Sulfatides
- cerebrosides
- Globosides
Acidic glycosphingolipids:-
- Ganglioside
- Sulfatides
Site – golgi apparatus
Subtrates – Ceramide, sugar activated by
UDP
Galactocerobrosides – Ceramide + UDP-
galactose
Glucocerebrosides – Ceramide + UDP –
glucose
Enzymes – Glycosyl transferases
Subtrates – Ceramide, sugar activated by
UDP
Galactocerobrosides – Ceramide + UDP-
galactose
Glucocerebrosides – Ceramide + UDP –
glucose
Enzymes – Glycosyl transferases
Gangliosides --- ceramide + two or more
UDP- sugars react together to form
Globoside. NANA combines with globoside
to form Ganglioside.
Sulfatides ----- galactocerebroside gets a
sulphate group from a sulphate carrier with
the help of sulfotransferase and forms a
sulfatide.
UDP- sugars react together to form
Globoside. NANA combines with globoside
to form Ganglioside.
Sulfatides ----- galactocerebroside gets a
sulphate group from a sulphate carrier with
the help of sulfotransferase and forms a
sulfatide.
Done by lysosomal enzymes
Different enzymes act on specific bonds
hydrolytically ---- the groups added last are
acted first.
Different enzymes act on specific bonds
hydrolytically ---- the groups added last are
acted first.
Lipid storage diseases
Accumulation of sphingolipids in lysosomes
Partial or total absence of a specific hydrolase
Autosomal recessive disorders
Accumulation of sphingolipids in lysosomes
Partial or total absence of a specific hydrolase
Autosomal recessive disorders
Gaucher disease:-
- most common lysosomal storage disease
- accumulation of glucocerebrosides
- enlargement of liver and spleen
- osteoprosis of long bones
- CNS involvement in infants
- most common lysosomal storage disease
- accumulation of glucocerebrosides
- enlargement of liver and spleen
- osteoprosis of long bones
- CNS involvement in infants
Krebbe disease:-
- accumulation of galactocerebrosides
- mental and motor function defect
- blindness and deafness
- loss of myelin
- accumulation of galactocerebrosides
- mental and motor function defect
- blindness and deafness
- loss of myelin
Farber disease:-
- accumulation of ceramide
- joints and skin involvement
Niemann pick disease:-
- accumulation of sphingomyelin
- liver and spleen enlargement
- neuronal degeneration
- accumulation of ceramide
- joints and skin involvement
Niemann pick disease:-
- accumulation of sphingomyelin
- liver and spleen enlargement
- neuronal degeneration
Fabry disease:-
- accumulation of globosides
- skin rash
- kidney and heart failure
- burning pain in legs
- accumulation of globosides
- skin rash
- kidney and heart failure
- burning pain in legs
Tay Sach’s disease:-
- accumulation of GM2 gangliosides
- neuronal degeneration
- eye involvement
- muscular weakness
- seizures
- accumulation of GM2 gangliosides
- neuronal degeneration
- eye involvement
- muscular weakness
- seizures
Sandhoff’s disease:-
- accumulation of GM2 and globosides
- neurological and visceral involvement
GM1 Gangliosidosis
Metachromatic Leukodystrophy
- sulfatide accumulation
- accumulation of GM2 and globosides
- neurological and visceral involvement
GM1 Gangliosidosis
Metachromatic Leukodystrophy
- sulfatide accumulation
Prostaglandins, leukotrienes and
thromboxanes ---- eicosanoids.
Originate from polyunsatyrated fatty acids
with 20 carbons.
Physiologic and pathologic roles.
Produced in small amounts by almost all
tissues , act locally , very short half life.
thromboxanes ---- eicosanoids.
Originate from polyunsatyrated fatty acids
with 20 carbons.
Physiologic and pathologic roles.
Produced in small amounts by almost all
tissues , act locally , very short half life.
Linoleic acid is the dietary precursor of PGs.
Arachidonic acid is formed by elongation and
desaturation of linoleic acid.
Membrane bound phospholipids contain
arachidonic acid.
Phospholipase A2 causes the release of
arachidonic acid from membrane
phospholipids.
Arachidonic acid is formed by elongation and
desaturation of linoleic acid.
Membrane bound phospholipids contain
arachidonic acid.
Phospholipase A2 causes the release of
arachidonic acid from membrane
phospholipids.
Arachidonic acid undergoes oxidative
cyclization to form PGH2.
Enzyme is PGH Synthase-- two catalytic
activities –--- fatty acid cyclooxygenase and
peroxidase
PGH synthase has two isoenzymes
- COX 1 ----- made in most tissues. Causes
synthesis of PG with physiologic functions . - -
COX2 ---- induced in some tissues in
pathological conditions.
cyclization to form PGH2.
Enzyme is PGH Synthase-- two catalytic
activities –--- fatty acid cyclooxygenase and
peroxidase
PGH synthase has two isoenzymes
- COX 1 ----- made in most tissues. Causes
synthesis of PG with physiologic functions . - -
COX2 ---- induced in some tissues in
pathological conditions.
PGs formed through COX1 pathway :-
- PGG2 is the first PG formed which is
converted into PGH2 by peroxidase. PGH2 is
then converted by different enzymes into ;-
- Thromboxane A2
- PGI2 ( prostacyclins )
- PGF2 alpha
- PGE2
Through COX2 ----- PGG2 is formed.
- PGG2 is the first PG formed which is
converted into PGH2 by peroxidase. PGH2 is
then converted by different enzymes into ;-
- Thromboxane A2
- PGI2 ( prostacyclins )
- PGF2 alpha
- PGE2
Through COX2 ----- PGG2 is formed.
Cortisol ---- a steroid hormone with anti-
inflammatory effects. It inhibits
phospholipase activity due to which
arachidonic acid is not available and no PGs
can be formed.
Non- steroidal anti-inflammatory drugs e.g
Aspirin, Indomethacin , Phenylbutazone,
inhibit COX1 and COX2, thus no PGH2.
inflammatory effects. It inhibits
phospholipase activity due to which
arachidonic acid is not available and no PGs
can be formed.
Non- steroidal anti-inflammatory drugs e.g
Aspirin, Indomethacin , Phenylbutazone,
inhibit COX1 and COX2, thus no PGH2.
Phospholipase A2 is stimulated by trauma
and hypoxia.
Cyclooxygenase 2 is stimulated by
- cytokines
- endotoxins
- growth factors
- tumor promotors
and hypoxia.
Cyclooxygenase 2 is stimulated by
- cytokines
- endotoxins
- growth factors
- tumor promotors
PGs bind to specific receptors on plasma
membrane of target cells
This causes changes in concentration of
Second Messengers which mediate the
biological effects.
These second messengers may be
- cyclic AMP
- calcium
- cyclic GMP
membrane of target cells
This causes changes in concentration of
Second Messengers which mediate the
biological effects.
These second messengers may be
- cyclic AMP
- calcium
- cyclic GMP
Leukotrienes are linear hydroperoxy acids.
Mediators of allergic response and inflamm.
Synthesized by a separate pathway from
Arachidonic acid in leukocytes, macrophages
and mast cells.
Involves a family of enzymes ---
lipoxygenases.
Neutrophils contain 5- lipoxygenase
Mediators of allergic response and inflamm.
Synthesized by a separate pathway from
Arachidonic acid in leukocytes, macrophages
and mast cells.
Involves a family of enzymes ---
lipoxygenases.
Neutrophils contain 5- lipoxygenase
5-lipoxygenase converts Arachidonic acid
into 5-HPETE.
5-HPETE is then converted into different
leukotrienes.
First formed is LTA4 which is then converted
into LTC4 which forms LTD4 which forms
LTE4.
LTA4 also gets converted into LTB4.
into 5-HPETE.
5-HPETE is then converted into different
leukotrienes.
First formed is LTA4 which is then converted
into LTC4 which forms LTD4 which forms
LTE4.
LTA4 also gets converted into LTB4.
LTC4, LTD4, LTE4 cause contraction of
smooth muscles and cause bronchospasm.
Important role in asthma.
LTB4 has role in inflammation and release of
lysosomal enzymes.
smooth muscles and cause bronchospasm.
Important role in asthma.
LTB4 has role in inflammation and release of
lysosomal enzymes.
A steroid alcohol of animal tissues.
Consists of four fused hydrocarbon rings.
Three phenanthrene rings and one
cyclopentane ring.
Called a sterol --- OH group at carbon no.3,
no carboxyl group, contains a hydro- carbon
tail ( 8 carbons ) at C 17.
Ester form– a fatty acid at OH group at C3.
Great physiological and clinical importance.
Consists of four fused hydrocarbon rings.
Three phenanthrene rings and one
cyclopentane ring.
Called a sterol --- OH group at carbon no.3,
no carboxyl group, contains a hydro- carbon
tail ( 8 carbons ) at C 17.
Ester form– a fatty acid at OH group at C3.
Great physiological and clinical importance.
Site--- synthesized in almost all tissues in the
body. Liver is the major organ for synthesis.
Cellular site ---- cytoplasm as the enzymes
involved are in cytosol and membrane of
endoplasmic reticulum.
Source of carbon atoms --- acetate
Source of reducing equivalents ---- NADPH
Source of energy ---- high energy bonds of
acetyl CoA and ATP.
body. Liver is the major organ for synthesis.
Cellular site ---- cytoplasm as the enzymes
involved are in cytosol and membrane of
endoplasmic reticulum.
Source of carbon atoms --- acetate
Source of reducing equivalents ---- NADPH
Source of energy ---- high energy bonds of
acetyl CoA and ATP.
Six major steps:-
I- HMGCoA from acetyl CoA.
II-mevalonate (6C) from acetyl CoA.
III - isoprenoid units (5C) from mevalonate --
building blocks of steroids.
IV - squalene (30 C ) by condensation of 6
isoprenoid units.
V- Lanosterol by cyclization of squalene.
VI- cholesterol from lanosterol.
I- HMGCoA from acetyl CoA.
II-mevalonate (6C) from acetyl CoA.
III - isoprenoid units (5C) from mevalonate --
building blocks of steroids.
IV - squalene (30 C ) by condensation of 6
isoprenoid units.
V- Lanosterol by cyclization of squalene.
VI- cholesterol from lanosterol.
Condensation of two acetyl CoA molecules to
form acetoacetyl CoA. Enzyme is Thiolase.
Addition of another acetyl CoA to form
HMGCoA …. A 6 Carbon compound.
Enzyme is HMGCoA synthase ( the cytosolic
isoenzyme ).
form acetoacetyl CoA. Enzyme is Thiolase.
Addition of another acetyl CoA to form
HMGCoA …. A 6 Carbon compound.
Enzyme is HMGCoA synthase ( the cytosolic
isoenzyme ).
Formed by the reduction of HMGCoA.
Enzyme --- HMGCoA reductase.
In cytosol.
Uses NADPH .
Irreversible as CoA is released.
Most important, Rate-limiting and the key
regulated step in cholesterol synthesis.
Enzyme --- HMGCoA reductase.
In cytosol.
Uses NADPH .
Irreversible as CoA is released.
Most important, Rate-limiting and the key
regulated step in cholesterol synthesis.
Mevalonate is phosphorylated twice by ATP
to form 5-pyrophosphomevalonate. Enzyme
is Kinase.
When PO4 and the nearby carboxyl group
leave 5-PPM, it results in the formation of
Isopentenyl pyrophosphate (IPP). It is a 5
carbon isoprenoid unit with a double bond.
IPP undergoes isomerization to form
Dimethyl allyl pyrophosphate-- DPP (5C)…
second isoprene.
to form 5-pyrophosphomevalonate. Enzyme
is Kinase.
When PO4 and the nearby carboxyl group
leave 5-PPM, it results in the formation of
Isopentenyl pyrophosphate (IPP). It is a 5
carbon isoprenoid unit with a double bond.
IPP undergoes isomerization to form
Dimethyl allyl pyrophosphate-- DPP (5C)…
second isoprene.
IPP and DPP condense to form 10 carbon
compound Geranyl Pyrophosphate – GPP
(10 C ). Enzyme is transferase.
GPP condenses with one more IPP to form a
15 C compound --- Farnesyl Pyrophosphate
----- FPP. Enzyme is transferase.
Two FPP condense, releasing pyrophosphate,
and form Squalene--- 30 C compound.
18 ATPs are used in this process of squlene
synthesis from isoprenes.
compound Geranyl Pyrophosphate – GPP
(10 C ). Enzyme is transferase.
GPP condenses with one more IPP to form a
15 C compound --- Farnesyl Pyrophosphate
----- FPP. Enzyme is transferase.
Two FPP condense, releasing pyrophosphate,
and form Squalene--- 30 C compound.
18 ATPs are used in this process of squlene
synthesis from isoprenes.
Squalene monooxygenase adds an oxygen
atom to Squqlene.
NADPH reduces this oxygen atom and results
in the addition of an OH group at C3 .
Hydroxylation of OH group to squalene
triggers the cyclization of Squalene and
forms Lanostreol. Enzyme is cyclase.
Lanosterol is the four ringed structure--- first
sterol.
atom to Squqlene.
NADPH reduces this oxygen atom and results
in the addition of an OH group at C3 .
Hydroxylation of OH group to squalene
triggers the cyclization of Squalene and
forms Lanostreol. Enzyme is cyclase.
Lanosterol is the four ringed structure--- first
sterol.
Lanosterol is converted to Cholesterol by a
series of 20 reactions.
During these reactions carbon chain is
shortened from 30 carbons to 27 carbons.
Removal of methyl groups at C4
migration of double bond from C8 to C5.
Reduction of double bond between C24 and
C25.
series of 20 reactions.
During these reactions carbon chain is
shortened from 30 carbons to 27 carbons.
Removal of methyl groups at C4
migration of double bond from C8 to C5.
Reduction of double bond between C24 and
C25.
Cholesterol synthesis has to be tightly
regulated as the imbalance between
synthesis/intake and utilization leads to
accumulation of cholesterol in blood vessels
which have serious consequences ----
atherosclerosis.
HMGCoA reductase is the rate limiting
enzyme and it is the major control point for
cholesterol synthesis.
regulated as the imbalance between
synthesis/intake and utilization leads to
accumulation of cholesterol in blood vessels
which have serious consequences ----
atherosclerosis.
HMGCoA reductase is the rate limiting
enzyme and it is the major control point for
cholesterol synthesis.
1- Intracellular cholesterol levels:-
I/C cholesterol levels bring changes in the
HMGCoA reductase activity. Synthesis of this
enzyme can be increased by the transcription
of the gene that encodes HMGCoA
reductase.
Transcription takes place by the amino
terminal ( SRE )of a protein called SREBP.
.
I/C cholesterol levels bring changes in the
HMGCoA reductase activity. Synthesis of this
enzyme can be increased by the transcription
of the gene that encodes HMGCoA
reductase.
Transcription takes place by the amino
terminal ( SRE )of a protein called SREBP.
.
SREBP lies in ER membrane and is in
complex with a protein called SREBP-
cleavage activating protein ( SCAP).
SCAP acts as cholesterol sensor.
When cholesterol level is high in the cell,
SREBP remains within ER membrane with
SCAP and is inactive.
When cholesterol level decreases, this
complex is released and goes to Golgi app.
complex with a protein called SREBP-
cleavage activating protein ( SCAP).
SCAP acts as cholesterol sensor.
When cholesterol level is high in the cell,
SREBP remains within ER membrane with
SCAP and is inactive.
When cholesterol level decreases, this
complex is released and goes to Golgi app.
In Golgi , SREBP is acted upon by proteases.
This causes the release of the SRE from the
SREBP and this SRE can enter the nucleus.
SRE causes transcription of the gene
encoding HMGCoA reductase.
Synthesis of the enzyme is increased and
leads to more cholesterol synthesis.
This causes the release of the SRE from the
SREBP and this SRE can enter the nucleus.
SRE causes transcription of the gene
encoding HMGCoA reductase.
Synthesis of the enzyme is increased and
leads to more cholesterol synthesis.
2- Regulation by cyclic AMP:-
Covalent regulation. Done through
phosphorylation of HMGCoA Reductase by
cAMP activated protein kinase (AMPK ).
Phosphorylated form of the enzyme is
inactive.
3- Regulation by Phosphoprotein
phosphatase;- It causes dephosphorylation
of the inactive form of enzyme and activates
it.
Covalent regulation. Done through
phosphorylation of HMGCoA Reductase by
cAMP activated protein kinase (AMPK ).
Phosphorylated form of the enzyme is
inactive.
3- Regulation by Phosphoprotein
phosphatase;- It causes dephosphorylation
of the inactive form of enzyme and activates
it.
4- Regulation by hormones:-
- Insulin---- increases HMGCoA reductase
activity and thus increases cholesterol
synthesis.
- Glucagon---- decreases the enzyme and
thus decreases cholesterol synthesis.
5- Cholesterol intake through diet decreases
hepatic synthesis of cholesterol by reducing
activity of the enzyme while intake of
saturated fats increase its synthesis.
- Insulin---- increases HMGCoA reductase
activity and thus increases cholesterol
synthesis.
- Glucagon---- decreases the enzyme and
thus decreases cholesterol synthesis.
5- Cholesterol intake through diet decreases
hepatic synthesis of cholesterol by reducing
activity of the enzyme while intake of
saturated fats increase its synthesis.
6- Inhibition by drugs:-
The statin drugs (simvastatin) resemble
HMGCoA in structure. They act as
competitive inhibitors of HMGCoA reductase
and decrease blood cholesterol levels.
The statin drugs (simvastatin) resemble
HMGCoA in structure. They act as
competitive inhibitors of HMGCoA reductase
and decrease blood cholesterol levels.
Conversion to bile acids and bile salts which
are then excreted in feces.
Secreted in bile, taken to intestines and then
excreted.
Conversion to neutral sterols by bacteria in
intestines and then excreted.
Synthesis of Vit. D .
Synthesis of steroid hormones.
are then excreted in feces.
Secreted in bile, taken to intestines and then
excreted.
Conversion to neutral sterols by bacteria in
intestines and then excreted.
Synthesis of Vit. D .
Synthesis of steroid hormones.
Major part is in esterified form and is
transporeted in lipoproteins. Highest amount
of circulating cholesterol is in the form of LDL
which takes cholesterol from liver to all the
tissues.
transporeted in lipoproteins. Highest amount
of circulating cholesterol is in the form of LDL
which takes cholesterol from liver to all the
tissues.
In adults , normal level is
150– 200 mg/100 ml
Risk of developing cardiovascular diseases
increases when the level is above 200mg/100
ml.
150– 200 mg/100 ml
Risk of developing cardiovascular diseases
increases when the level is above 200mg/100
ml.
Primary Hypercholesterolemia:-
- genetic absence or deficiency of LDL
receptors.
- decreased entery of LDL in target tissues.
- raised plasma LDL levels which means raised
plasma cholesterol.
- increased incidence of ischemic heart
disease and nodules form in skin called
xanthomas.
- genetic absence or deficiency of LDL
receptors.
- decreased entery of LDL in target tissues.
- raised plasma LDL levels which means raised
plasma cholesterol.
- increased incidence of ischemic heart
disease and nodules form in skin called
xanthomas.
Secondary Hypercholesterolemia:-
Primary hypothyroidism
Diabetes mellitus
Nephrotic syndrome
Cholestasis
Drugs
Raised plasma free fatty acids
Primary hypothyroidism
Diabetes mellitus
Nephrotic syndrome
Cholestasis
Drugs
Raised plasma free fatty acids
Composed of neutral lipid core ( TAG and
cholesterol esters )
Shell of amphipathic apolipoproteins,
phospholipid and unesterified cholesterol.
Soluble in aqueous medium
Separated from each other by
electrophoresis or by ultracentrifugation.
cholesterol esters )
Shell of amphipathic apolipoproteins,
phospholipid and unesterified cholesterol.
Soluble in aqueous medium
Separated from each other by
electrophoresis or by ultracentrifugation.
On the basis of density ;-
- chylomicrons
- VLDL
- LDL
- HDL
On electrophoresis–
- chylomicrons at origin
- LDL (beta lipoproteins)
- VLDL ( pre-beta lipoproteins)
-HDL ( alpha lipoproteins)
- chylomicrons
- VLDL
- LDL
- HDL
On electrophoresis–
- chylomicrons at origin
- LDL (beta lipoproteins)
- VLDL ( pre-beta lipoproteins)
-HDL ( alpha lipoproteins)
Serve very important functions
- recognition site for cell-surface receptors
- activators or coenzymes for enzymes of
lipoprotein metabolism
- some are essential structural component of
the lipoprotein particle
- transfer between different types of
lipoproteins and bring about changes.
- Classes from A to E. Some have sub classes.
- recognition site for cell-surface receptors
- activators or coenzymes for enzymes of
lipoprotein metabolism
- some are essential structural component of
the lipoprotein particle
- transfer between different types of
lipoproteins and bring about changes.
- Classes from A to E. Some have sub classes.
Assembled in intestinal mucosal cells.
Contains about 90% TAG
Its apoprotein is apo B-48 which is
synthesized in RER.
These nascent chylomicrons are released in
blood through lymphatic system.
In plasma it receives from HDL two more
apopreoteins i.e apo C-II and apo-E.
Contains about 90% TAG
Its apoprotein is apo B-48 which is
synthesized in RER.
These nascent chylomicrons are released in
blood through lymphatic system.
In plasma it receives from HDL two more
apopreoteins i.e apo C-II and apo-E.
Apo C-II activates the enzyme Lipoprotein
lipase, located on the capillary walls.
Lipoprotein lipase degrades TAG in
chylomicrons and forms free fatty acids and
glycerol.
Synthesis of this enzyme is increased by
insulin ( fed state ). During starvation activity
declines in adipocytes while increases in
cardiac muscles.
lipase, located on the capillary walls.
Lipoprotein lipase degrades TAG in
chylomicrons and forms free fatty acids and
glycerol.
Synthesis of this enzyme is increased by
insulin ( fed state ). During starvation activity
declines in adipocytes while increases in
cardiac muscles.
Degradation of TAG leads to decrease in the
size of chylomicron particles and increases its
density.
apoC-II is returned to HDL leaving behind
chylomicron remnant which has apoE and
apoB48.
Liver cells recognize apoE and rapidly take up
chylomicron remnants.
size of chylomicron particles and increases its
density.
apoC-II is returned to HDL leaving behind
chylomicron remnant which has apoE and
apoB48.
Liver cells recognize apoE and rapidly take up
chylomicron remnants.
In liver cells they are acted upon by lysosomal
enzymes and degradation of all the
components take place , releasing amino
acids, free cholesterol and fatty acids.
The receptor is recycled.
enzymes and degradation of all the
components take place , releasing amino
acids, free cholesterol and fatty acids.
The receptor is recycled.
60% TAG --- carry from liver to the peripheral
tissues --- imbalance results in fatty liver.
20% cholesterol and its esters.
Produced in liver – contain apoB 100
In blood acquire apoC-II and apo E from HDL.
apoC-II activates lipoprotein lipase
Degradation of TAG causes a decrease in the
size of VLDL and increases its density.
apoC and apoE are returned to HDL
tissues --- imbalance results in fatty liver.
20% cholesterol and its esters.
Produced in liver – contain apoB 100
In blood acquire apoC-II and apo E from HDL.
apoC-II activates lipoprotein lipase
Degradation of TAG causes a decrease in the
size of VLDL and increases its density.
apoC and apoE are returned to HDL
apoB-100 remains on the particles.
An exchange of lipids takes place between
VLDL and HDL------ VLDL gives some TAG to
HDL and gets some cholesterol esters from
HDL. Cholesterol ester transfer protein helps
in this exchange.
These modifications result in the formation
of IDL --- transient state
IDL is converted to LDL very rapidly. Some
IDL can be taken up by liver directly.
An exchange of lipids takes place between
VLDL and HDL------ VLDL gives some TAG to
HDL and gets some cholesterol esters from
HDL. Cholesterol ester transfer protein helps
in this exchange.
These modifications result in the formation
of IDL --- transient state
IDL is converted to LDL very rapidly. Some
IDL can be taken up by liver directly.
Composed of 50% Cholesterol and its esters
and only 8% TAG, 20% protein. It has highest
cholesterol content.
Formed in circulation by the degradation and
modification of VLDL.
Smaller diameter and higher density as
compared to VLDL and IDL.
Function is to provide cholesterol to the
peripheral tissues .
and only 8% TAG, 20% protein. It has highest
cholesterol content.
Formed in circulation by the degradation and
modification of VLDL.
Smaller diameter and higher density as
compared to VLDL and IDL.
Function is to provide cholesterol to the
peripheral tissues .
Uptake of LDL into the cells takes place
through LDL receptors on the cell surface
membrane.
LDL receptors recognize apo B-100 on the
surface of LDL particles.
LDL receptors are glycoproteins in nature,
clustered in pits on cell membranes.
A protein, Clathrin, coats the intracellular
side of the pit and stabilizes its shape.
through LDL receptors on the cell surface
membrane.
LDL receptors recognize apo B-100 on the
surface of LDL particles.
LDL receptors are glycoproteins in nature,
clustered in pits on cell membranes.
A protein, Clathrin, coats the intracellular
side of the pit and stabilizes its shape.
LDL particles bind with the receptor. The LDL
and the receptor form a complex. This
complex goes inside the cell by endocytosis
of these vesicles.
Endosomes are formed by the fusion of many
LDL containing vesicles.
The receptors get separated from LDL and go
back to the cell surface pits.
LDL particles get inside the lysosomes.
and the receptor form a complex. This
complex goes inside the cell by endocytosis
of these vesicles.
Endosomes are formed by the fusion of many
LDL containing vesicles.
The receptors get separated from LDL and go
back to the cell surface pits.
LDL particles get inside the lysosomes.
Lysosomal enzymes degrade LDL contents
by hydrolysis.
There is release of free cholesterol, amino
acids, fatty acids and phospholipids.
by hydrolysis.
There is release of free cholesterol, amino
acids, fatty acids and phospholipids.
Cholesterol derived by the degradation of
chylomocrons, IDL and LDL increases
cholesterol level in cell and decreases activity
of HMGCoA reductase.
High cholesterol in cell also inhibits the
synthesis of LDL receptors by decreasing the
expression of LDL receptor gene, so that no
more LDL- cholesterol enters the cells.
chylomocrons, IDL and LDL increases
cholesterol level in cell and decreases activity
of HMGCoA reductase.
High cholesterol in cell also inhibits the
synthesis of LDL receptors by decreasing the
expression of LDL receptor gene, so that no
more LDL- cholesterol enters the cells.
If the cholesterol in the cell derived from the
lipoproteins is not immediately used for
structural and synthetic purposes, it is
converted into esterified form and then
stored in the cell. Enzyme for this
esterification is Acyl CoA-cholesterol
acyltransferase ( ACAT ). Activity of ACAT is
increased by free cholesterol.
lipoproteins is not immediately used for
structural and synthetic purposes, it is
converted into esterified form and then
stored in the cell. Enzyme for this
esterification is Acyl CoA-cholesterol
acyltransferase ( ACAT ). Activity of ACAT is
increased by free cholesterol.
Highest protein content i.e 40%,
30% phospholipid, only 25% cholesterol.
Synthesized in liver and intestines.
Contains apo A 1, apo A II, apo C II, apo E.
Smallest size highest density.
30% phospholipid, only 25% cholesterol.
Synthesized in liver and intestines.
Contains apo A 1, apo A II, apo C II, apo E.
Smallest size highest density.
Newly synthesized HDL is disc shaped and
contains cholesterol, PL, apo-A and apo-E.
It interacts with chylomicra remnants and
acquires cholesterol. It converts free
cholesterol into its esterified form with the
help of plasma enzyme LCAT. This makes
HDL3 .
contains cholesterol, PL, apo-A and apo-E.
It interacts with chylomicra remnants and
acquires cholesterol. It converts free
cholesterol into its esterified form with the
help of plasma enzyme LCAT. This makes
HDL3 .
HDL3 removes free cholesterol from
membranes and other tissues. Again LCAT
gets into action and HDL2 is formed which
has higher content of cholesterol esters.
HDL2 transfers cholesterol esters to VLDL
and receives TAG from VLDL.
membranes and other tissues. Again LCAT
gets into action and HDL2 is formed which
has higher content of cholesterol esters.
HDL2 transfers cholesterol esters to VLDL
and receives TAG from VLDL.
Transfers apoproteins to other lipoproteins.
Takes up lipids from other lipoproteins e.g
VLDL.
Takes up unesterified cholesterol from other
lipoproteins and cell membranes.
Converts free cholesterol into its esterified
form with the help of plasma enzyme
Lecithin-cholesterol acyltransferase (LCAT).
LCAT is activated by apo A1.
Takes up lipids from other lipoproteins e.g
VLDL.
Takes up unesterified cholesterol from other
lipoproteins and cell membranes.
Converts free cholesterol into its esterified
form with the help of plasma enzyme
Lecithin-cholesterol acyltransferase (LCAT).
LCAT is activated by apo A1.
HDL transfers cholesterol esters to other
lipoproteins and also carries cholesterol to
liver for bile acid synthesis , excretion via bile
and hormone synthesis. This is called
“Reverse cholesterol transport”. Uptake of
HDL2 by liver takes place through SR-B1
receptors.
It is also called “Good cholesterol”.
lipoproteins and also carries cholesterol to
liver for bile acid synthesis , excretion via bile
and hormone synthesis. This is called
“Reverse cholesterol transport”. Uptake of
HDL2 by liver takes place through SR-B1
receptors.
It is also called “Good cholesterol”.
A- PRIMARY HYPERLIPOPROTEINEMIAS;-
1-Type-I: Familial lipoprotein lipase deficiency:-
-hypertriglyceridemia
- hyperchylomicronemia--- creamy layer
forms on the top of plasma on stagnation.
- high VLDL
-low LDL and low HDL
1-Type-I: Familial lipoprotein lipase deficiency:-
-hypertriglyceridemia
- hyperchylomicronemia--- creamy layer
forms on the top of plasma on stagnation.
- high VLDL
-low LDL and low HDL
2-Type II: Familial Hypercholesterolemia:-
- a common disorder
- deficiency of LDL receptors and increased
cholesterol synthesis
- high LDL level
- increased incidence of atherosclerosis and
cardiovascular diseases.
- a common disorder
- deficiency of LDL receptors and increased
cholesterol synthesis
- high LDL level
- increased incidence of atherosclerosis and
cardiovascular diseases.
3- Type III: Familial dys-beta-lipoproteinemia:-
-high levels of LDL, VLDL and IDL.
- hypercholesterolemia---- atherosclerosis
- defective form of apo E cannot bind to
receptors---- chylomicrons and IDL cannot be
cleared.
-high levels of LDL, VLDL and IDL.
- hypercholesterolemia---- atherosclerosis
- defective form of apo E cannot bind to
receptors---- chylomicrons and IDL cannot be
cleared.
4- Type IV- Familial Hypertriglyceridemia:-
- increased endogenous synthesis of TAG
- high VLDL level
5- Combined Hyperlipidemias:-
- raised cholesterol and TAG
- high levels of chylomicrons and VLDL
- increased endogenous synthesis of TAG
- high VLDL level
5- Combined Hyperlipidemias:-
- raised cholesterol and TAG
- high levels of chylomicrons and VLDL
6- Wolman’s disease :-
- deficiency of enzyme cholesterol ester
hydrolase in lysososmes
- cholesterol ester storage
- deficiency of enzyme cholesterol ester
hydrolase in lysososmes
- cholesterol ester storage
1- Abetalipoprotenemia:-
- defect in synthesis of apo-B
- low LDL and low cholesterol
- no synthesis of chylomicrons and VLDL,
low TAG
2- Familial alpha lipoprotein deficiency:-
- low apo A
- low HDL
- accumulation of cholesterol esters in
tissues
- defect in synthesis of apo-B
- low LDL and low cholesterol
- no synthesis of chylomicrons and VLDL,
low TAG
2- Familial alpha lipoprotein deficiency:-
- low apo A
- low HDL
- accumulation of cholesterol esters in
tissues
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