2. Digestion and Absorption of Lipids
Dietary Lipids include :
Neutral fat (triacylglycerol or triglycerides)
Fatty acids
Phospholipids
Glycolipids
Sterols
Fat soluble vitamins (A, D, E and K).
Digestion and Absorption of Lipids
Dietary Lipids include :
Neutral fat (triacylglycerol or triglycerides)
Fatty acids
Phospholipids
Glycolipids
Sterols
Fat soluble vitamins (A, D, E and K).
3. Digestion in mouth and stomach
Little or no digestion occurs in the mouth or stomach.
4. Digestion in Small Intestine
In duodenum dietary fat is emulsified by bile
salts.
Digestion in Small Intestine
In duodenum dietary fat is emulsified by bile
salts.
5. Hydrolysis of dietary triacylglycerols
Emulsified triacylglycerols hydrolyzed by pancreatic lipase.
6. Hydrolysis of dietary phospholipids
Phospholipids are digested by pancreatic phospholipase-A2
7. Hydrolysis of cholesterol ester
Cholesterol esters hydrolyzed by pancreatic cholesterol
esterase which produces cholesterol plus free fatty acid.
9. These, together with bile salts, form mixed micelles.
Fat soluble vitamins A, D, E and K are also packaged
in these micelles and are absorbed from the micelles
along with the products of dietary lipid.
10. Absorption and transport of lipid from intestinal lumen.
2-MAG: 2-monoacylglycerol;
C: cholesterol;
CE: cholesterol ester;
FA: fatty acid;
LysoPL: lysophospholipid;
TG: triacylglycerol)
Absorption and transport of lipid from intestinal lumen.
2-MAG: 2-monoacylglycerol;
C: cholesterol;
CE: cholesterol ester;
FA: fatty acid;
LysoPL: lysophospholipid;
TG: triacylglycerol)
11.
12. Abnormalities in Lipid Digestion and Absorption
Lipid Malabsorption
Lipid malabsorption results in a loss of lipid as much
as 30 g/day including the fat soluble vitamins and
essential fatty acids in the feces.
Conditions in which the feces contain large amounts
of fat and fatty acids, commonly stearic acid
therefore called steatorrhea, (Greek, steato = fat).
Abnormalities in Lipid Digestion and Absorption
Lipid Malabsorption
Lipid malabsorption results in a loss of lipid as much
as 30 g/day including the fat soluble vitamins and
essential fatty acids in the feces.
Conditions in which the feces contain large amounts
of fat and fatty acids, commonly stearic acid
therefore called steatorrhea, (Greek, steato = fat).
13. Steatorrhea caused by a number of conditions. The
most common causes are:
• Bile salt deficiency occurs in liver disease or due to
obstruction in the bile duct.
• Pancreatic enzyme deficiency occurs in pancreatitis
or cystic fibrosis.
• Defective chylomicron synthesis occurs in
congenital abetalipoproteinemia.
Steatorrhea caused by a number of conditions. The
most common causes are:
• Bile salt deficiency occurs in liver disease or due to
obstruction in the bile duct.
• Pancreatic enzyme deficiency occurs in pancreatitis
or cystic fibrosis.
• Defective chylomicron synthesis occurs in
congenital abetalipoproteinemia.
14. FATTY ACID METABOLISM
Fatty acids are amphipathic compounds containing a
long hydrocarbon chain and a terminal carboxylate
group (R-COOH).
Fatty acids are stored in adipose tissues as
triacylglycerol also called neutral fats or triglyceride.
Fatty acids mobilized from triacylglycerol are oxidized
to meet energy needs of a cell.
FATTY ACID METABOLISM
Fatty acids are amphipathic compounds containing a
long hydrocarbon chain and a terminal carboxylate
group (R-COOH).
Fatty acids are stored in adipose tissues as
triacylglycerol also called neutral fats or triglyceride.
Fatty acids mobilized from triacylglycerol are oxidized
to meet energy needs of a cell.
15. For the utilization of stored fatty acids in the form of
triacylglycerol in adipose tissues requires three stages of
processing:
1. Mobilization of lipid (lipolysis):
In this process, triacylglycerols of adipose tissue degraded to
fatty acids and glycerol and transported to the energy
requiring tissues. Glycerol produced by lipolysis is
metabolized by liver.
For the utilization of stored fatty acids in the form of
triacylglycerol in adipose tissues requires three stages of
processing:
1. Mobilization of lipid (lipolysis):
In this process, triacylglycerols of adipose tissue degraded to
fatty acids and glycerol and transported to the energy
requiring tissues. Glycerol produced by lipolysis is
metabolized by liver.
16. 2. Activation of fatty acids:
In the tissues fatty acids are activated to fatty acyl-CoA and
transported into mitochondria for degradation.
3. Oxidation of fatty acyl-CoA:
Fatty acyl-CoA degraded by oxidation into acetyl-CoA,
which is then oxidized in the citric acid cycle
2. Activation of fatty acids:
In the tissues fatty acids are activated to fatty acyl-CoA and
transported into mitochondria for degradation.
3. Oxidation of fatty acyl-CoA:
Fatty acyl-CoA degraded by oxidation into acetyl-CoA,
which is then oxidized in the citric acid cycle
17. 1. Mobilization of Fatty Acids from Triacylglycerol
(Lipolysis)
1. Mobilization of Fatty Acids from Triacylglycerol
(Lipolysis)
21. Transport of Acyl-CoA into Mitochondria by
Carnitine Transport System
Activated long chain fatty acids are carried across the
inner mitochondrial membrane by carnitine, (β-hydroxy
γ-trimethyl ammonium butyrate).
Carnitine is formed from lysine and methionine in liver
and kidney
Transport of Acyl-CoA into Mitochondria by
Carnitine Transport System
Activated long chain fatty acids are carried across the
inner mitochondrial membrane by carnitine, (β-hydroxy
γ-trimethyl ammonium butyrate).
Carnitine is formed from lysine and methionine in liver
and kidney
22. Activation and transport of fatty acids into mitochondria
by carnitine shuttle.
• CAT-I: carnitine acyltransferase-l;
• CAT-II: carnitine acyltransferase-ll
Activation and transport of fatty acids into mitochondria
by carnitine shuttle.
• CAT-I: carnitine acyltransferase-l;
• CAT-II: carnitine acyltransferase-ll
26. In β-oxidation two carbon units sequentially removed
beginning from the carboxyl end of the fatty acid in the
form of acetyl-CoA.
It is called β-oxidation because oxidation of fatty acids
occurs at the β-carbon atom.
β-oxidation pathway occurs in mitochondria.
In β-oxidation two carbon units sequentially removed
beginning from the carboxyl end of the fatty acid in the
form of acetyl-CoA.
It is called β-oxidation because oxidation of fatty acids
occurs at the β-carbon atom.
β-oxidation pathway occurs in mitochondria.
27.
28. Sequence of Reactions of β-oxidation
Acyl-CoA is degraded by a repeated sequence of four
reactions :
1. Oxidation by FAD
2. Hydration
3. Oxidation by NAD
4. Cleavage.
Sequence of Reactions of β-oxidation
Acyl-CoA is degraded by a repeated sequence of four
reactions :
1. Oxidation by FAD
2. Hydration
3. Oxidation by NAD
4. Cleavage.
34. Energy yield from the β-oxidation of fatty acids
Complete β-oxidation of palmitoyl CoA (16 carbon acid)
occurs through 7 cycles of β-oxidation yielding
8 acetyl-CoA,
7 FADH2
7 NADH
Energy yield from the β-oxidation of fatty acids
Complete β-oxidation of palmitoyl CoA (16 carbon acid)
occurs through 7 cycles of β-oxidation yielding
8 acetyl-CoA,
7 FADH2
7 NADH
35. Therefore the number of ATPs formed:
• 7x 1.5 = 10.5 ATPs from the 7 FADH2
• 7x 2.5= 17.5 ATPs from the 7 NADH
• 80 ATPs from 8 molecules of acetyl-CoA in TCA cycle.
• Total of 108 ATPs.
Therefore the number of ATPs formed:
• 7x 1.5 = 10.5 ATPs from the 7 FADH2
• 7x 2.5= 17.5 ATPs from the 7 NADH
• 80 ATPs from 8 molecules of acetyl-CoA in TCA cycle.
• Total of 108 ATPs.
36. Two high energy phosphate bonds are consumed in the
activation of palmitate, in which ATP is split into AMP
and PPi.
Thus, the net yield from the complete oxidation of
palmitate is 108-2 =106 ATPs
Two high energy phosphate bonds are consumed in the
activation of palmitate, in which ATP is split into AMP
and PPi.
Thus, the net yield from the complete oxidation of
palmitate is 108-2 =106 ATPs
37. Regulation of β-oxidation
Rate limiting step in the β-oxidation pathway is the
formation of acyl-carnitine which is catalyzed by
carnitine-acyl transferase-l (CAT-I).
CAT-I is an allosteric enzyme. Malonyl-CoA is an
inhibitor of CAT-I.
Regulation of β-oxidation
Rate limiting step in the β-oxidation pathway is the
formation of acyl-carnitine which is catalyzed by
carnitine-acyl transferase-l (CAT-I).
CAT-I is an allosteric enzyme. Malonyl-CoA is an
inhibitor of CAT-I.
38. In well-fed state due to increased level of insulin,
concentration of malonyl-CoA increases which inhibits
CAT-I and leads to decrease in fatty acid oxidation.
In starvation, due to increased level of glucagon
concentration of malonyl-CoA decreases and stimulates
the fatty-acid oxidation
In well-fed state due to increased level of insulin,
concentration of malonyl-CoA increases which inhibits
CAT-I and leads to decrease in fatty acid oxidation.
In starvation, due to increased level of glucagon
concentration of malonyl-CoA decreases and stimulates
the fatty-acid oxidation
39.
40. Oxidation of a Fatty Acid with an Odd Number of
Carbon Atoms
Fatty acids, having an odd number of carbon atoms,
are oxidized by the pathway β-oxidation producing
acetyl-CoA until a three-carbon, propionyl-
CoA residue remains.
Oxidation of a Fatty Acid with an Odd Number of
Carbon Atoms
Fatty acids, having an odd number of carbon atoms,
are oxidized by the pathway β-oxidation producing
acetyl-CoA until a three-carbon, propionyl-
CoA residue remains.
41. In the oxidation of odd carbon fatty acids, the
propionyl-CoA and acetyl-CoA, rather than two
molecules of acetyl-CoA are produced in the
final round of degradation.
Propionyl-CoA is converted to succinyl-CoA
constituent of citric acid cycle.
In the oxidation of odd carbon fatty acids, the
propionyl-CoA and acetyl-CoA, rather than two
molecules of acetyl-CoA are produced in the
final round of degradation.
Propionyl-CoA is converted to succinyl-CoA
constituent of citric acid cycle.
53. Acetoacetate and β-hydroxybutyrate are interconverted
by the mitochondrial enzyme β-hydroxybutyrate
dehydrogenase.
Acetoacetate continually undergoes spontaneous
nonenzymatic decarboxylation to yield acetone
The concentration of total ketone bodies in the blood of
well-fed condition does not normally exceed 0.2
mmol/L.
Acetoacetate and β-hydroxybutyrate are interconverted
by the mitochondrial enzyme β-hydroxybutyrate
dehydrogenase.
Acetoacetate continually undergoes spontaneous
nonenzymatic decarboxylation to yield acetone
The concentration of total ketone bodies in the blood of
well-fed condition does not normally exceed 0.2
mmol/L.
55. Ketone bodies are water soluble energy yielding
substances. Acetone is an exception, since it cannot be
metabolized and is readily exhaled through lungs.
Ketone bodies are water soluble energy yielding
substances. Acetone is an exception, since it cannot be
metabolized and is readily exhaled through lungs.
56. Formation of ketone bodies.
Liver is the only organ that synthesizes ketone bodies.
and transferred to other organs as fuel
The synthesis of ketone bodies occurs in mitochondria
of hepatic cells
Formation of ketone bodies.
Liver is the only organ that synthesizes ketone bodies.
and transferred to other organs as fuel
The synthesis of ketone bodies occurs in mitochondria
of hepatic cells
57.
58.
59.
60. Utilization of Ketone Bodies
The site of production of ketone bodies is the liver.
But the liver cannot utilize ketone bodies because it
lacks particular enzyme CoA-transferase which is
required for activation of ketone bodies.
Utilization of Ketone Bodies
The site of production of ketone bodies is the liver.
But the liver cannot utilize ketone bodies because it
lacks particular enzyme CoA-transferase which is
required for activation of ketone bodies.
63. Significance of Ketogenesis
Ketogenesis is a mechanism that allows the liver to
oxidize increasing quantities of fatty acids.
During deprivation of carbohydrate (starvation &
diabetes mellitus) acetoacetate and β-hydroxybutyrate
serve as alternative source of energy for extra hepatic
tissues
Significance of Ketogenesis
Ketogenesis is a mechanism that allows the liver to
oxidize increasing quantities of fatty acids.
During deprivation of carbohydrate (starvation &
diabetes mellitus) acetoacetate and β-hydroxybutyrate
serve as alternative source of energy for extra hepatic
tissues
64. In prolonged starvation 75% of the energy needs of
the brain are supplied by ketone bodies reducing its
need for glucose.
Acetoacetate also has a regulatory role in lipid
metabolism. High levels of acetoacetate in the blood
specify an abundance of acetyl units and lead to a
decrease in the rate of lipolysis in adipose tissue.
In prolonged starvation 75% of the energy needs of
the brain are supplied by ketone bodies reducing its
need for glucose.
Acetoacetate also has a regulatory role in lipid
metabolism. High levels of acetoacetate in the blood
specify an abundance of acetyl units and lead to a
decrease in the rate of lipolysis in adipose tissue.
65. The formation and export of ketone bodies releases
coenzyme-A, allowing continued fatty acid oxidation.
Ketone bodies are water soluble transportable form of
derivatives of acetyl-CoA. They do not need to be
incorporated into lipoproteins or carried by albumins as
do the other lipids.
The formation and export of ketone bodies releases
coenzyme-A, allowing continued fatty acid oxidation.
Ketone bodies are water soluble transportable form of
derivatives of acetyl-CoA. They do not need to be
incorporated into lipoproteins or carried by albumins as
do the other lipids.
66. Regulation of Ketogenesis
The ketone body formation is regulated at three levels:
1. Factors regulating lipolysis
2. Factors regulating β-oxidation of fatty acids
3. Factors regulating oxidation of acetyl-CoA
Regulation of Ketogenesis
The ketone body formation is regulated at three levels:
1. Factors regulating lipolysis
2. Factors regulating β-oxidation of fatty acids
3. Factors regulating oxidation of acetyl-CoA
67. Steps of regulation of
formation of ketone
bodies.
Steps of regulation of
formation of ketone
bodies.
68. Disorders of Ketone Body Metabolism
Ketosis
When the rate of formation of the ketone bodies by liver
exceeds the capacity of the peripheral tissues to use
them up, their levels begin to rise in blood.
An increase in concentration of ketone bodies in blood is
called ketonemia and eventually leads to excretion of
ketone bodies into the urine called ketonuria.
The overall condition (ketonemia and ketonuria) is
called ketosis.
Disorders of Ketone Body Metabolism
Ketosis
When the rate of formation of the ketone bodies by liver
exceeds the capacity of the peripheral tissues to use
them up, their levels begin to rise in blood.
An increase in concentration of ketone bodies in blood is
called ketonemia and eventually leads to excretion of
ketone bodies into the urine called ketonuria.
The overall condition (ketonemia and ketonuria) is
called ketosis.
69. Ketoacidosis
The acidosis caused by over production of ketone bodies
is termed as ketoacidosis.
Acetoacetate and β-hydroxybutyrate when present in
high concentration in blood, are buffered by HCO3
– of
bicarbonate buffer. The excessive use of HCO3
– depletes
the alkali reserve causing ketoacidosis.
Ketoacidosis is seen in type I diabetes mellitus, whereas
in type II diabetes ketoacidosis is relatively rare.
Ketoacidosis
The acidosis caused by over production of ketone bodies
is termed as ketoacidosis.
Acetoacetate and β-hydroxybutyrate when present in
high concentration in blood, are buffered by HCO3
– of
bicarbonate buffer. The excessive use of HCO3
– depletes
the alkali reserve causing ketoacidosis.
Ketoacidosis is seen in type I diabetes mellitus, whereas
in type II diabetes ketoacidosis is relatively rare.
70. Overproduction of ketone bodies in diabetes and starvation.
Drain off oxaloacetate for glucose synthesis, slows
oxidation of acetyl-CoA by citric acid pathway, diverting
acetyl-CoA to the formation of ketone bodies.
Overproduction of ketone bodies in diabetes and starvation.
Drain off oxaloacetate for glucose synthesis, slows
oxidation of acetyl-CoA by citric acid pathway, diverting
acetyl-CoA to the formation of ketone bodies.
74. DE NOVO SYNTHESIS OF FATTY ACIDS
De novo synthesis means new synthesis.
Site : Fatty acid synthesis occurs mainly in the liver,
mammary glands and to a lesser extent, in adipose
tissue, kidney and brain.
Sub-cellular site : Cytosol
DE NOVO SYNTHESIS OF FATTY ACIDS
De novo synthesis means new synthesis.
Site : Fatty acid synthesis occurs mainly in the liver,
mammary glands and to a lesser extent, in adipose
tissue, kidney and brain.
Sub-cellular site : Cytosol
75. Materials required
1) Starting material : Acetyl CoA
2) Enzymes : Fatty acid Synthase & Acetyl CoA
carboxylase.
3) Coenzymes : Biotin &NADP
4) Carbon dioxide
5) ATP : For energy
6) End product : Palmitic acid
1) Starting material : Acetyl CoA
2) Enzymes : Fatty acid Synthase & Acetyl CoA
carboxylase.
3) Coenzymes : Biotin &NADP
4) Carbon dioxide
5) ATP : For energy
6) End product : Palmitic acid
77. Fatty acid synthesis occurs in three phases:
1. Transport of acetyl-CoA from mitochondria to cytosol.
2. Carboxylation of acetyl-CoA to malonyl-CoA.
3. Reactions of fatty acid synthase complex.
Fatty acid synthesis occurs in three phases:
1. Transport of acetyl-CoA from mitochondria to cytosol.
2. Carboxylation of acetyl-CoA to malonyl-CoA.
3. Reactions of fatty acid synthase complex.
84. The fatty acid synthase (FAS) enzyme is a dimmer of
identical subunits (homodimer).
Each subunit contains all of the six enzymes, as well as
an acyl carrier protein (ACP).
Even though each subunit possesses all enzymes
required for fatty acid synthesis, the monomers are not
active.
A dimmer is required for the synthesis.
The fatty acid synthase (FAS) enzyme is a dimmer of
identical subunits (homodimer).
Each subunit contains all of the six enzymes, as well as
an acyl carrier protein (ACP).
Even though each subunit possesses all enzymes
required for fatty acid synthesis, the monomers are not
active.
A dimmer is required for the synthesis.
85. The ACP segment contains the vitamin pantothenic
acid in the form of 4-phosphopantetheine.
4-phosphopantetheine provides the sulfhydryl (–SH)
group to which the growing fatty acid chain is attached
as it is synthesized.
Thus, the function of the ACP in fatty acid biosynthesis
is analogous to the role of coenzyme-A in fatty acid
oxidation.
.
The ACP segment contains the vitamin pantothenic
acid in the form of 4-phosphopantetheine.
4-phosphopantetheine provides the sulfhydryl (–SH)
group to which the growing fatty acid chain is attached
as it is synthesized.
Thus, the function of the ACP in fatty acid biosynthesis
is analogous to the role of coenzyme-A in fatty acid
oxidation.
.
86. Fatty acid synthase has one more sulfhydryl (–SH)
group which is furnished by a specific cysteine residue
of 3-ketoacyl synthase enzyme.
Both –SH groups participate in fatty acid biosynthesis.
Fatty acid synthase has one more sulfhydryl (–SH)
group which is furnished by a specific cysteine residue
of 3-ketoacyl synthase enzyme.
Both –SH groups participate in fatty acid biosynthesis.
87. Reactions de novo fatty acid synthesis
De novo synthesis of fatty acids.
• ACP: acyl carrier protein;
• KS: ketoacyl synthase
Reactions de novo fatty acid synthesis
De novo synthesis of fatty acids.
• ACP: acyl carrier protein;
• KS: ketoacyl synthase
88.
89.
90.
91.
92. Regulation of Fatty Acid Synthesis
The reaction catalyzed by acetyl-CoA Carboxylase is
the rate limiting step in the biosynthesis of fatty acids
and this enzyme is an important site of regulation. The
acetyl-CoA carboxylase is regulated by following
mechanisms
Regulation of Fatty Acid Synthesis
The reaction catalyzed by acetyl-CoA Carboxylase is
the rate limiting step in the biosynthesis of fatty acids
and this enzyme is an important site of regulation. The
acetyl-CoA carboxylase is regulated by following
mechanisms
93. Allosteric Mechanism
Acetyl-CoA carboxylase is an allosteric enzyme,
palmitoyl-CoA, the principle product of fatty acid
synthesis, is a feedback inhibitor of the enzyme and
citrate is an allosteric activator.
Covalent Modification of Enzyme
Acetyl-coA carboxylase is also regulated by covalent
modification. Phosphorylation, triggered by the hormones
glucagon and epinephrine inactivates the enzyme and
thereby reduces fatty acid synthesis.
Allosteric Mechanism
Acetyl-CoA carboxylase is an allosteric enzyme,
palmitoyl-CoA, the principle product of fatty acid
synthesis, is a feedback inhibitor of the enzyme and
citrate is an allosteric activator.
Covalent Modification of Enzyme
Acetyl-coA carboxylase is also regulated by covalent
modification. Phosphorylation, triggered by the hormones
glucagon and epinephrine inactivates the enzyme and
thereby reduces fatty acid synthesis.
94. Regulation of fatty acid synthesis by allosteric mechanism
and covalent modification.
96. Triacylglycerols are esters of the alcohol glycerol and
fatty acids. It contains a glycerol backbone to which 3-
fatty acids are esterified.
97. Triacylglycerol serves as the body’s major fuel
storage reserve.
Human can store only few hundred grams of glycogen
in liver and muscle, hardly enough to supply the body’s
energy needs for 12 hours.
In contrast, the total amount of stored triacylglycerol in
70 kg man is about 15 kg, enough to support basal
energy needs for as long as 12 weeks.
Triacylglycerol serves as the body’s major fuel
storage reserve.
Human can store only few hundred grams of glycogen
in liver and muscle, hardly enough to supply the body’s
energy needs for 12 hours.
In contrast, the total amount of stored triacylglycerol in
70 kg man is about 15 kg, enough to support basal
energy needs for as long as 12 weeks.
98. Triacylglycerols have the highest energy content of all
stored nutrients.
Whenever carbohydrate ingested in excess of the body’s
capacity to store glycogen, the excess is converted to
triacylglycerol and stored in adipose tissue
Triacylglycerols have the highest energy content of all
stored nutrients.
Whenever carbohydrate ingested in excess of the body’s
capacity to store glycogen, the excess is converted to
triacylglycerol and stored in adipose tissue
102. Fate of Triacylglycerol Formed in Liver and
Adipose Tissue
The triacylglycerol stored in adipose tissue are
continually undergoing lipolysis (hydrolysis) and re-
esterification through triacylglycerol cycle
The resultant of these two processes, lipolysis
(breakdown) and re-esterification (synthesis)
determines the level of circulating free fatty acids in the
plasma
Fate of Triacylglycerol Formed in Liver and
Adipose Tissue
The triacylglycerol stored in adipose tissue are
continually undergoing lipolysis (hydrolysis) and re-
esterification through triacylglycerol cycle
The resultant of these two processes, lipolysis
(breakdown) and re-esterification (synthesis)
determines the level of circulating free fatty acids in the
plasma
104. The triacylglycerol stored in adipose tissue undergoes
hydrolysis by a hormone sensitive lipase to form free
fatty acids and glycerol.
Some of the fatty acids released by lipolysis of
triacylglycerol in adipose tissue pass into the
bloodstream, and remainder are used for resynthesis of
triacylglycerol.
The triacylglycerol stored in adipose tissue undergoes
hydrolysis by a hormone sensitive lipase to form free
fatty acids and glycerol.
Some of the fatty acids released by lipolysis of
triacylglycerol in adipose tissue pass into the
bloodstream, and remainder are used for resynthesis of
triacylglycerol.
105. Some of the fatty acids released into the blood are taken
up by several tissues, including muscle, where it is
oxidized to provide energy and some are taken up by the
liver.
Much of the fatty acid taken up by liver is not oxidized
but is recycled to triacylglycerol and exported again into
the blood in the form of VLDL back to adipose tissue,
and reesterified into triacylglycerol
Some of the fatty acids released into the blood are taken
up by several tissues, including muscle, where it is
oxidized to provide energy and some are taken up by the
liver.
Much of the fatty acid taken up by liver is not oxidized
but is recycled to triacylglycerol and exported again into
the blood in the form of VLDL back to adipose tissue,
and reesterified into triacylglycerol
106. The glycerol, released in adipose tissue, cannot be
metabolized by adipocytes because they lack glycerol
kinase.
Rather, glycerol is transported through the blood to the
liver, which can phosphorylate it. The resulting glycerol
phosphate can be used to form triacylglycerol in the
liver or to be converted to DHAP.
The glycerol, released in adipose tissue, cannot be
metabolized by adipocytes because they lack glycerol
kinase.
Rather, glycerol is transported through the blood to the
liver, which can phosphorylate it. The resulting glycerol
phosphate can be used to form triacylglycerol in the
liver or to be converted to DHAP.
107. Regulation of triacylglycerol metabolism
The rate of biosynthesis and degradation of
triacylglycerols depends on the metabolic resources
and requirements of the moment.
The rate of triacylglycerol biosynthesis is regulated
by the action of hormones.
Regulation of triacylglycerol metabolism
The rate of biosynthesis and degradation of
triacylglycerols depends on the metabolic resources
and requirements of the moment.
The rate of triacylglycerol biosynthesis is regulated
by the action of hormones.
108. When the mobilization of fatty acids is required to meet
energy needs, breakdown of triacylglycerol and thus
release of fatty acids from adipose tissue is stimulated by
the hormones glucagon and epinephrine.
Epinephrine, and glucagon, stimulates hormone
sensitive lipase by increasing c-AMP and
phosphorylation.
Simultaneously, these hormonal signals decrease the rate
of glycolysis and increase the rate of gluconeogenesis in
the liver.
When the mobilization of fatty acids is required to meet
energy needs, breakdown of triacylglycerol and thus
release of fatty acids from adipose tissue is stimulated by
the hormones glucagon and epinephrine.
Epinephrine, and glucagon, stimulates hormone
sensitive lipase by increasing c-AMP and
phosphorylation.
Simultaneously, these hormonal signals decrease the rate
of glycolysis and increase the rate of gluconeogenesis in
the liver.
109. Insulin stimulates the conversion of dietary
carbohydrates and proteins to triacylglycerol.
In the presence of insulin, hormone sensitive lipase
is dephosphorylated and becomes inactive and
inhibits breakdown of triacylglycerol.
Insulin stimulates the conversion of dietary
carbohydrates and proteins to triacylglycerol.
In the presence of insulin, hormone sensitive lipase
is dephosphorylated and becomes inactive and
inhibits breakdown of triacylglycerol.
112. Adipose tissues store and supply fatty acids.
Cosmetically adipose tissue is viewed as an enemy;
however its importance in energy homeostasis is
second only to that of the liver.
There are two types of adipose tissue, white and brown,
with different roles.
Human adipose tissue is mostly of the white type.
Adipose tissues store and supply fatty acids.
Cosmetically adipose tissue is viewed as an enemy;
however its importance in energy homeostasis is
second only to that of the liver.
There are two types of adipose tissue, white and brown,
with different roles.
Human adipose tissue is mostly of the white type.
113. White adipose tissue (WAT) is amorphous and widely
distributed in the body: under the skin, around deep
blood vessels, and in the abdominal cavity. White
adipose tissue contains specialized cells, adipocytes that
are devoted solely to the function of storing fat.
The typical adult has 13 kg of adipose tissue. Obesity
results when this amount increases.
White adipose tissue (WAT) is amorphous and widely
distributed in the body: under the skin, around deep
blood vessels, and in the abdominal cavity. White
adipose tissue contains specialized cells, adipocytes that
are devoted solely to the function of storing fat.
The typical adult has 13 kg of adipose tissue. Obesity
results when this amount increases.
114. The adipocytes of WAT are large (diameter 30 to70
μm), spherical cells, completely filled with a single
large lipid droplet that squeezes the mitochondria and
nucleus against the plasma membrane.
The lipid droplet contains triacylglycerols (TAGs) and
cholesterol esters and is coated with a monolayer of
phospholipids. Specific protein perilipin and the
enzymes for synthesis and breakdown of TAGs are
associated with the surface of the droplets.
The adipocytes of WAT are large (diameter 30 to70
μm), spherical cells, completely filled with a single
large lipid droplet that squeezes the mitochondria and
nucleus against the plasma membrane.
The lipid droplet contains triacylglycerols (TAGs) and
cholesterol esters and is coated with a monolayer of
phospholipids. Specific protein perilipin and the
enzymes for synthesis and breakdown of TAGs are
associated with the surface of the droplets.
115. Brown adipose tissue cells have more mitochondria and
a richer supply of capillaries than WAT cells, and it is
the cytochromes of mitochondria and the hemoglobin in
capillaries that give brown adipose tissues its
characteristic brown color.
Brown adipose tissue cells have more mitochondria and
a richer supply of capillaries than WAT cells, and it is
the cytochromes of mitochondria and the hemoglobin in
capillaries that give brown adipose tissues its
characteristic brown color.
117. White Adipose Tissue Metabolism
In adipose tissue triacylglycerol is stored in the
adipocytes.
Like other cell types, adipocytes have an active
glycolytic metabolism, oxidize pyruvate and fatty
acids via the citric acid cycle, and carry out oxidative
phosphorylation.
White Adipose Tissue Metabolism
In adipose tissue triacylglycerol is stored in the
adipocytes.
Like other cell types, adipocytes have an active
glycolytic metabolism, oxidize pyruvate and fatty
acids via the citric acid cycle, and carry out oxidative
phosphorylation.
118. When carbohydrate intake is high, adipose tissue can
convert glucose (via pyruvate and acetyl-CoA) to fatty
acids, convert fatty acids to triacylglycerols, and store
triacylglycerols as large lipid droplets.
When carbohydrate intake is high, adipose tissue can
convert glucose (via pyruvate and acetyl-CoA) to fatty
acids, convert fatty acids to triacylglycerols, and store
triacylglycerols as large lipid droplets.
119. Synthesis and Degradation of triacylglycerol in adipose
tissue
In adipose tissue triacylglycerol is synthesized from acyl
CoA (active form of fatty acids) and glycerol-3-
phosphate.
When, the demand for fuel rises (between meals),
hormone sensitive lipases in adipocytes hydrolyzes
stored triacylglycerols to release free fatty acids, and
glycerol.
Synthesis and Degradation of triacylglycerol in adipose
tissue
In adipose tissue triacylglycerol is synthesized from acyl
CoA (active form of fatty acids) and glycerol-3-
phosphate.
When, the demand for fuel rises (between meals),
hormone sensitive lipases in adipocytes hydrolyzes
stored triacylglycerols to release free fatty acids, and
glycerol.
123. Regulation of adipose tissue metabolism
Lipolysis and reesterification are regulated by many
nutritional, metabolic, and hormonal factors that
influence either, the rate of esterification or the rate of
lipolysis.
Lipolysis is controlled by level of cAMP, thus the
processes which destroy or preserve cAMP have an
effect on
Regulation of adipose tissue metabolism
Lipolysis and reesterification are regulated by many
nutritional, metabolic, and hormonal factors that
influence either, the rate of esterification or the rate of
lipolysis.
Lipolysis is controlled by level of cAMP, thus the
processes which destroy or preserve cAMP have an
effect on
127. Fatty liver
Fatty liver is the excessive accumulation of fat primarily
neutral fat, triacylglycerol in the liver.
Liver contains about 5% fat. In pathological conditions
this may go up to 25–30% and is known as fatty liver or
fatty infiltration of liver.
When accumulation of lipid in the liver becomes chronic,
fibrotic changes occur in cells which may finally lead to
cirrhosis and impairment of liver function.
Fatty liver
Fatty liver is the excessive accumulation of fat primarily
neutral fat, triacylglycerol in the liver.
Liver contains about 5% fat. In pathological conditions
this may go up to 25–30% and is known as fatty liver or
fatty infiltration of liver.
When accumulation of lipid in the liver becomes chronic,
fibrotic changes occur in cells which may finally lead to
cirrhosis and impairment of liver function.
128. Fatty liver occurs in conditions in which there is an
imbalance between hepatic triacylglycerol synthesis
and the secretion of VLDL.
Fatty liver falls into two main categories:
Fatty liver occurs in conditions in which there is an
imbalance between hepatic triacylglycerol synthesis
and the secretion of VLDL.
Fatty liver falls into two main categories:
129. 1. The first type is
associated with the increased levels of plasma free fatty
acids.
The increasing amounts of free fatty acids are taken up by the
liver and esterified to triacylglycerol, but the production of
VLDL does not keep pace with the increasing influx of free
fatty acids, allowing triacylglycerol to accumulate which in
turn causes fatty liver.
This occurs during starvation and feeding high fat diet
1. The first type is
associated with the increased levels of plasma free fatty
acids.
The increasing amounts of free fatty acids are taken up by the
liver and esterified to triacylglycerol, but the production of
VLDL does not keep pace with the increasing influx of free
fatty acids, allowing triacylglycerol to accumulate which in
turn causes fatty liver.
This occurs during starvation and feeding high fat diet
130. 2. The second type of fatty Liver is due to impairment in
the biosynthesis of plasma lipoproteins. This defect may
be due to:
A block in apolipoprotein synthesis
A block in the synthesis of lipoprotein from lipid
and apolipoprotein
Defect in the synthesis of phospholipids that are
found in lipoproteins
A failure in the secretory mechanism itself.
2. The second type of fatty Liver is due to impairment in
the biosynthesis of plasma lipoproteins. This defect may
be due to:
A block in apolipoprotein synthesis
A block in the synthesis of lipoprotein from lipid
and apolipoprotein
Defect in the synthesis of phospholipids that are
found in lipoproteins
A failure in the secretory mechanism itself.
131. Factors that Cause Fatty Liver
1. High fat diet.
2. Starvation or uncontrolled diabetes mellitus
3. Alcoholism
4. High cholesterol diet
5. Use of certain chemicals
Factors that Cause Fatty Liver
1. High fat diet.
2. Starvation or uncontrolled diabetes mellitus
3. Alcoholism
4. High cholesterol diet
5. Use of certain chemicals
133. Lipotropic Factors
The substances that prevent the accumulation of fat in
the liver are known as lipotropic factors.
Dietary deficiency of these factors can result in fatty
liver.
The various lipotropic agents are : choline, methionine
,betaine .
Vitamin B12 and folic acid have also lipotropic effect, as
these are involved in the formation of methionine from
homocysteine.
Lipotropic Factors
The substances that prevent the accumulation of fat in
the liver are known as lipotropic factors.
Dietary deficiency of these factors can result in fatty
liver.
The various lipotropic agents are : choline, methionine
,betaine .
Vitamin B12 and folic acid have also lipotropic effect, as
these are involved in the formation of methionine from
homocysteine.
135. Four main types of lipoproteins are :
1.Chylomicrons
2. Very low density lipoproteins (VLDL)
3. Low density lipoproteins (LDL)
4. High density lipoproteins (HDL)
Four main types of lipoproteins are :
1.Chylomicrons
2. Very low density lipoproteins (VLDL)
3. Low density lipoproteins (LDL)
4. High density lipoproteins (HDL)
138. Metabolism of Lipoproteins
The pathways of lipoprotein metabolism include two
cycles, one exogenous and one endogenous; these cycles
are interconnected and both centered on the Liver.
Metabolism of Lipoproteins
The pathways of lipoprotein metabolism include two
cycles, one exogenous and one endogenous; these cycles
are interconnected and both centered on the Liver.
139. The exogenous pathway involves metabolism of
chylomicrons
1. Dietary lipids are packaged into chylomicrons.
2. Fatty acids from triacylglycerol of chylomicrons are
released by lipoprotein lipase to adipose and muscle
tissues, during transport through capillaries.
3. Chylomicron remnants containing largely protein and
cholesterol are taken by the liver.
4. In the liver, the remnants release their cholesterol
The exogenous pathway involves metabolism of
chylomicrons
1. Dietary lipids are packaged into chylomicrons.
2. Fatty acids from triacylglycerol of chylomicrons are
released by lipoprotein lipase to adipose and muscle
tissues, during transport through capillaries.
3. Chylomicron remnants containing largely protein and
cholesterol are taken by the liver.
4. In the liver, the remnants release their cholesterol
140. The endogenous pathway involves metabolism of
VLDL, LDL and HDL
5. In endogenous pathway lipids synthesized or packaged in
the liver are delivered to peripheral tissues by VLDL.
6. Removal of triacylglycerol from VLDL converts VLDL
to VLDL remnants, also called intermediate density
lipoprotein IDL
The endogenous pathway involves metabolism of
VLDL, LDL and HDL
5. In endogenous pathway lipids synthesized or packaged in
the liver are delivered to peripheral tissues by VLDL.
6. Removal of triacylglycerol from VLDL converts VLDL
to VLDL remnants, also called intermediate density
lipoprotein IDL
141. 7. IDL is either taken up by the liver or further removal of
triacylglycerol from IDL produces low density
lipoprotein (LDL),
8. LDL delivers cholesterol to extrahepatic tissues or
returns to the liver. Approximately 30% of LDL is
degraded in extra hepatic tissues and 70% in the liver.
7. IDL is either taken up by the liver or further removal of
triacylglycerol from IDL produces low density
lipoprotein (LDL),
8. LDL delivers cholesterol to extrahepatic tissues or
returns to the liver. Approximately 30% of LDL is
degraded in extra hepatic tissues and 70% in the liver.
142. 9. High density lipoprotein (HDL), originates in the liver as
small, protein-rich nascent HDL particles
10. Excess cholesterol in lipoproteins and extrahepatic
tissues is transported back to the liver by HDL in reverse
cholesterol transport.
9. High density lipoprotein (HDL), originates in the liver as
small, protein-rich nascent HDL particles
10. Excess cholesterol in lipoproteins and extrahepatic
tissues is transported back to the liver by HDL in reverse
cholesterol transport.
143. The overview of formation and transport of lipoproteins,
showing exogenous and endogenous lipoprotein metabolic
cycle.
The numbered steps are discussed in the text.
(C: cholesterol; CM: chylomicron; CMR: chylomicron
remnant; LPL: lipoprotein lipase; FFA: free fatty acid;
LDL: low density lipoprotein, IDL: intermediate
density lipoprotein)
The overview of formation and transport of lipoproteins,
showing exogenous and endogenous lipoprotein metabolic
cycle.
The numbered steps are discussed in the text.
(C: cholesterol; CM: chylomicron; CMR: chylomicron
remnant; LPL: lipoprotein lipase; FFA: free fatty acid;
LDL: low density lipoprotein, IDL: intermediate
density lipoprotein)
153. Reverse Cholesterol Transport
This is the process whereby excess cholesterol contained
in extra hepatic tissue is taken to the liver, by HDL for
utilization or excretion through bile.
The LCAT esterifies the cholesterol content of HDL &
prevent it from re-entering the cells.
Thus esterification by LCAT serves to trap cholesterol
within the lipoprotein , preventing it from deposition in
the tissues.
Reverse Cholesterol Transport
This is the process whereby excess cholesterol contained
in extra hepatic tissue is taken to the liver, by HDL for
utilization or excretion through bile.
The LCAT esterifies the cholesterol content of HDL &
prevent it from re-entering the cells.
Thus esterification by LCAT serves to trap cholesterol
within the lipoprotein , preventing it from deposition in
the tissues.
154.
155. Significance of reverse cholesterol transport
By reverse cholesterol transport cellular and lipoprotein
cholesterol is delivered back to the liver.
This is important because the steroid nucleus of
cholesterol cannot be degraded; and the liver is the only
organ that can remove excess cholesterol by secreting it in
the bile for excretion in the feces.
Significance of reverse cholesterol transport
By reverse cholesterol transport cellular and lipoprotein
cholesterol is delivered back to the liver.
This is important because the steroid nucleus of
cholesterol cannot be degraded; and the liver is the only
organ that can remove excess cholesterol by secreting it in
the bile for excretion in the feces.
156. Reverse cholesterol transport prevents deposition of
cholesterol in tissues ( anti- atherogenic).
An elevated HDL cholesterol (good cholesterol) level
decreases the risk of coronary heart disease.
Reverse cholesterol transport prevents deposition of
cholesterol in tissues ( anti- atherogenic).
An elevated HDL cholesterol (good cholesterol) level
decreases the risk of coronary heart disease.
157. Diagnostic Importance of Lipoproteins
The blood levels of certain lipoproteins have diagnostic
importance. The ratio of HDL cholesterol to that in the
LDL cholesterol can be used to evaluate susceptibility
to the development of heart disease. For healthy person,
LDL/HDL ratio is 3:5.
Diagnostic Importance of Lipoproteins
The blood levels of certain lipoproteins have diagnostic
importance. The ratio of HDL cholesterol to that in the
LDL cholesterol can be used to evaluate susceptibility
to the development of heart disease. For healthy person,
LDL/HDL ratio is 3:5.
158. Raised plasma LDL-cholesterol concentration is
associated with an increased risk of ischemic heart
disease.
Whereas raised plasma concentration of HDL
cholesterol is associated with a decreased risk of
ischemic heart disease and seems to have protective
effect.
Raised plasma LDL-cholesterol concentration is
associated with an increased risk of ischemic heart
disease.
Whereas raised plasma concentration of HDL
cholesterol is associated with a decreased risk of
ischemic heart disease and seems to have protective
effect.
159. LDL cholesterol is called bad cholesterol because
excess cholesterol is present in the form of LDL.
HDL cholesterol is called good cholesterol
LDL cholesterol is called bad cholesterol because
excess cholesterol is present in the form of LDL.
HDL cholesterol is called good cholesterol
160. Disorders of Lipoprotein Metabolism
Disorders of lipoprotein metabolism are:
• Hyperlipoproteinemia
• Hypolipoproteinemia
• Familial Hypercholesterolemia.
Disorders of Lipoprotein Metabolism
Disorders of lipoprotein metabolism are:
• Hyperlipoproteinemia
• Hypolipoproteinemia
• Familial Hypercholesterolemia.
161. Hyperlipoproteinemia
The causes of hyperlipoproteinemia are complex, and
different disease mechanisms can give rise to similar lipid
patterns. In practice lipoprotein disorders are classified as
follows:
Primary hyperlipoproteinemia when the disorder is not
due to some other disorders.
Secondary hyperlipoproteinemia when the disorder is
manifested due to some other disease.
Hyperlipoproteinemia
The causes of hyperlipoproteinemia are complex, and
different disease mechanisms can give rise to similar lipid
patterns. In practice lipoprotein disorders are classified as
follows:
Primary hyperlipoproteinemia when the disorder is not
due to some other disorders.
Secondary hyperlipoproteinemia when the disorder is
manifested due to some other disease.
162.
163.
164.
165. Hypolipoproteinemia
Hypolipoproteinemia is also classified as:
Primary hypolipoproteinemia is due to reduced synthesis of
protein, e.g.:
–– Abetalipoproteinemia
–– Tangier disease
Secondary hypoliporoteinemia, e.g.:
–– Kwashiorkor in children
–– Severe malabsorption
–– Some forms of chronic liver disease.
Hypolipoproteinemia
Hypolipoproteinemia is also classified as:
Primary hypolipoproteinemia is due to reduced synthesis of
protein, e.g.:
–– Abetalipoproteinemia
–– Tangier disease
Secondary hypoliporoteinemia, e.g.:
–– Kwashiorkor in children
–– Severe malabsorption
–– Some forms of chronic liver disease.
166. Familial Hypercholesterolemia
Hypercholesterolemia is a genetic disorder caused by the
mutation of LDL receptors gene. The molecular defect
of hypercholesterolemia is an absence or deficiency of
functional receptors for LDL (B-100/E).
Familial Hypercholesterolemia
Hypercholesterolemia is a genetic disorder caused by the
mutation of LDL receptors gene. The molecular defect
of hypercholesterolemia is an absence or deficiency of
functional receptors for LDL (B-100/E).
168. Cholesterol is the major sterol in human
Cholesterol is an amphipathic lipid which can be
synthesized by most cells of the body and it is obtained
from the diet in foods of animal origin.
It is not synthesized in plants.
The major source of dietary cholesterol is egg yolk and
meat, particularly liver.
Cholesterol is the major sterol in human
Cholesterol is an amphipathic lipid which can be
synthesized by most cells of the body and it is obtained
from the diet in foods of animal origin.
It is not synthesized in plants.
The major source of dietary cholesterol is egg yolk and
meat, particularly liver.
169. An abnormality in either cholesterol metabolism or
transport through the plasma appears to be related to the
development of atherosclerosis that can lead to
myocardial infarction or stroke.
An abnormality in either cholesterol metabolism or
transport through the plasma appears to be related to the
development of atherosclerosis that can lead to
myocardial infarction or stroke.
171. De Novo Synthesis of Cholesterol
Cholesterol is synthesized by most cells of the body.
Liver and intestine are major site of cholesterol
synthesis.
All 27-carbon atoms of cholesterol are derived from the
acetyl-CoA.
The reactions of cholesterol biosynthesis occurs into 5
stages
De Novo Synthesis of Cholesterol
Cholesterol is synthesized by most cells of the body.
Liver and intestine are major site of cholesterol
synthesis.
All 27-carbon atoms of cholesterol are derived from the
acetyl-CoA.
The reactions of cholesterol biosynthesis occurs into 5
stages
173. The first two stages take place in the cytoplasm and next
three in the endoplasmic reticulum.
1. Condensation of three molecules of acetyl-CoA to
mevalonate
2. Conversion of mevalonate to activated isoprene units
3. Polymerization of six isoprene units to form squalene
4. Cyclization of squalene to form parent steroid
nucleus lanosterol
5. Formation of cholesterol from lanosterol.
The first two stages take place in the cytoplasm and next
three in the endoplasmic reticulum.
1. Condensation of three molecules of acetyl-CoA to
mevalonate
2. Conversion of mevalonate to activated isoprene units
3. Polymerization of six isoprene units to form squalene
4. Cyclization of squalene to form parent steroid
nucleus lanosterol
5. Formation of cholesterol from lanosterol.
178. Energy Cost of Cholesterol Synthesis
Cholesterol biosynthesis is a complex and energy-
expensive process.
ATP is consumed only in the steps that convert
mevalonate to the activated isoprene units.
Three ATP molecules are used to create each of the six
activated isoprenes required to construct squalene, for a
total cost of 18 ATP molecules.
Energy Cost of Cholesterol Synthesis
Cholesterol biosynthesis is a complex and energy-
expensive process.
ATP is consumed only in the steps that convert
mevalonate to the activated isoprene units.
Three ATP molecules are used to create each of the six
activated isoprenes required to construct squalene, for a
total cost of 18 ATP molecules.
179. Regulation of De Novo Synthesis of Cholesterol
Cholesterol biosynthesis is a complex and energy-
expensive process.
Excess cholesterol cannot be catabolized for use as fuel
and must be excreted.
In mammals, cholesterol production is regulated by:
• Intracellular cholesterol concentration
• Supply of ATP, and
• Hormones glucagon and insulin.
Regulation of De Novo Synthesis of Cholesterol
Cholesterol biosynthesis is a complex and energy-
expensive process.
Excess cholesterol cannot be catabolized for use as fuel
and must be excreted.
In mammals, cholesterol production is regulated by:
• Intracellular cholesterol concentration
• Supply of ATP, and
• Hormones glucagon and insulin.
180. The synthesis of mevalonate by HMG-CoA reductase
is the committed step in cholesterol biosynthesis.
Short-term regulation of the activity of existing
HMG-CoA reductase is regulated by reversible
covalent alteration, i.e. by phosphorylation and
dephosphorylation.
Hormone, glucagon stimulates its phosphorylation,
inactivating the enzyme, and insulin promotes
dephosphorylation, activating the enzyme and favoring
cholesterol synthesis.
The synthesis of mevalonate by HMG-CoA reductase
is the committed step in cholesterol biosynthesis.
Short-term regulation of the activity of existing
HMG-CoA reductase is regulated by reversible
covalent alteration, i.e. by phosphorylation and
dephosphorylation.
Hormone, glucagon stimulates its phosphorylation,
inactivating the enzyme, and insulin promotes
dephosphorylation, activating the enzyme and favoring
cholesterol synthesis.
181. In the long-term regulation, the number of molecules of
HMG-CoA reductase is increased or decreased in
response to cellular concentrations of cholesterol.
HMG-CoA reductase in liver is inhibited by mevalonate
and by cholesterol
Mevalonate and cholesterol repress transcription of the
HMGCoA reductase via activation of a transcription
factor, sterol regulatory element-binding protein
(SREBP) and thus decreases the cholesterol synthesis.
In the long-term regulation, the number of molecules of
HMG-CoA reductase is increased or decreased in
response to cellular concentrations of cholesterol.
HMG-CoA reductase in liver is inhibited by mevalonate
and by cholesterol
Mevalonate and cholesterol repress transcription of the
HMGCoA reductase via activation of a transcription
factor, sterol regulatory element-binding protein
(SREBP) and thus decreases the cholesterol synthesis.
182. Small quantities of oxysterols such as 25-
hydroxycholesterol are formed in the liver and act as
regulators of cholesterol synthesis. Oxysterols inhibits
cholesterol synthesis by stimulating proteolysis of
HMG-CoA reductase
Small quantities of oxysterols such as 25-
hydroxycholesterol are formed in the liver and act as
regulators of cholesterol synthesis. Oxysterols inhibits
cholesterol synthesis by stimulating proteolysis of
HMG-CoA reductase
184. Metabolic Fates of Cholesterol
Cholesterol has several metabolic fates.
A small fraction of the cholesterol made in the liver is
incorporated into the membranes of the hepatocytes.
Small quantities of oxysterols such as 25-
hydroxycholesterols are formed in the liver and act as
regulators of cholesterol synthesis. Oxysterols inhibits
cholesterol synthesis by stimulating proteolysis of HMG-
CoA reductase.
Metabolic Fates of Cholesterol
Cholesterol has several metabolic fates.
A small fraction of the cholesterol made in the liver is
incorporated into the membranes of the hepatocytes.
Small quantities of oxysterols such as 25-
hydroxycholesterols are formed in the liver and act as
regulators of cholesterol synthesis. Oxysterols inhibits
cholesterol synthesis by stimulating proteolysis of HMG-
CoA reductase.
185. In other tissues, cholesterol is converted into steroid
hormones in the adrenal cortex and gonads.
Vitamin D hormone is synthesized in liver and kidney,
which regulates calcium and phosphorus metabolism.
Most of the cholesterol is exported in one of the three
forms, as bile acids, biliary cholesterol, or cholesteryl
ester.
In other tissues, cholesterol is converted into steroid
hormones in the adrenal cortex and gonads.
Vitamin D hormone is synthesized in liver and kidney,
which regulates calcium and phosphorus metabolism.
Most of the cholesterol is exported in one of the three
forms, as bile acids, biliary cholesterol, or cholesteryl
ester.
189. Cholesterol is transported in body fluids in the form of
lipoprotein particles.
Cholesterol esters that are resynthesized in the mucosal
cells, together with some unesterified cholesterol are
incorporated into chylomicrons, which transport
cholesterol and other dietary lipids from intestine
Cholesterol is transported in body fluids in the form of
lipoprotein particles.
Cholesterol esters that are resynthesized in the mucosal
cells, together with some unesterified cholesterol are
incorporated into chylomicrons, which transport
cholesterol and other dietary lipids from intestine
190. During circulation, only about 5% of the cholesterol
ester is lost. The rest 95% of the chylomicron
cholesterol is delivered to the liver through LRP (LDL
receptor related protein) receptor in the form of
chylomicron remnants.
Cholesterol in excess of the liver’s own needs is
exported into the blood in the form of VLDL.
During circulation, only about 5% of the cholesterol
ester is lost. The rest 95% of the chylomicron
cholesterol is delivered to the liver through LRP (LDL
receptor related protein) receptor in the form of
chylomicron remnants.
Cholesterol in excess of the liver’s own needs is
exported into the blood in the form of VLDL.
191. Triacylglycerols of VLDL are hydrolyzed by the action
of lipoprotein lipase. The resulting remnants, which are
rich in cholesteryl esters, are called intermediate
density lipoproteins (IDL).
Half of the IDL are taken up by the liver for processing,
and half are converted to low density lipoprotein by the
removal of more triacylglycerol.
Low density lipoprotein is the major carrier of
cholesterol in blood.
Triacylglycerols of VLDL are hydrolyzed by the action
of lipoprotein lipase. The resulting remnants, which are
rich in cholesteryl esters, are called intermediate
density lipoproteins (IDL).
Half of the IDL are taken up by the liver for processing,
and half are converted to low density lipoprotein by the
removal of more triacylglycerol.
Low density lipoprotein is the major carrier of
cholesterol in blood.
192. The role of LDL is to transfer cholesterol to peripheral
tissues through LDL receptors and regulate de novo
cholesterol synthesis
HDL picks up cholesterol from the peripheral tissues and
from other lipoproteins and converts it to cholesterol
esters by LCAT enzyme.
These HDL-cholesterol esters are ultimately returned to
the liver through HDL receptor (SR-B1) for excretion,
where it is degraded or excreted in the bile.
The role of LDL is to transfer cholesterol to peripheral
tissues through LDL receptors and regulate de novo
cholesterol synthesis
HDL picks up cholesterol from the peripheral tissues and
from other lipoproteins and converts it to cholesterol
esters by LCAT enzyme.
These HDL-cholesterol esters are ultimately returned to
the liver through HDL receptor (SR-B1) for excretion,
where it is degraded or excreted in the bile.
196. Excretion of Cholesterol
Cholesterol is excreted in feces
Unlike many other metabolites, cholesterol cannot be
destroyed by oxidation to CO2 and H2O, because of
absence of enzymes capable of catabolizing the
steroid ring.
It is excreted in the bile either as cholesterol or after
conversion to bile acids.
Excretion of Cholesterol
Cholesterol is excreted in feces
Unlike many other metabolites, cholesterol cannot be
destroyed by oxidation to CO2 and H2O, because of
absence of enzymes capable of catabolizing the
steroid ring.
It is excreted in the bile either as cholesterol or after
conversion to bile acids.
197. About 1 gm of cholesterol is eliminated from the body
per day. Roughly, half is excreted in the form of bile
acids and half is in the form of cholesterol.
Moreover, some dietary cholesterol is excreted in feces
without being absorbed.
Some of the cholesterol in the intestine is acted on by
intestinal bacterial enzymes and converted to neutral
sterols, coprostanol, cholestanol and excreted through
feces.
About 1 gm of cholesterol is eliminated from the body
per day. Roughly, half is excreted in the form of bile
acids and half is in the form of cholesterol.
Moreover, some dietary cholesterol is excreted in feces
without being absorbed.
Some of the cholesterol in the intestine is acted on by
intestinal bacterial enzymes and converted to neutral
sterols, coprostanol, cholestanol and excreted through
feces.
198. Disorder of Cholesterol Metabolism
Atherosclerosis
Atherosclerosis is the general term for hardening of
the arteries, due to formation of plaque, results in the
endothelial damage and narrowing of the lumen.
Disorder of Cholesterol Metabolism
Atherosclerosis
Atherosclerosis is the general term for hardening of
the arteries, due to formation of plaque, results in the
endothelial damage and narrowing of the lumen.
199. Atherosclerosis is due to dysregulation of cholesterol
metabolism. As noted earlier, cholesterol cannot be
catabolized by animal cells. Excess cholesterol can
only be removed by excretion or by conversion to
bile salts.
Atherosclerosis is due to dysregulation of cholesterol
metabolism. As noted earlier, cholesterol cannot be
catabolized by animal cells. Excess cholesterol can
only be removed by excretion or by conversion to
bile salts.
200. When the sum of cholesterol synthesized and cholesterol
obtained in the diet exceeds the amount required for the
synthesis of membrane, bile salts, and steroids,
pathological accumulations of cholesterol (plaques) can
obstruct blood vessels, a condition is called
atherosclerosis.
When the sum of cholesterol synthesized and cholesterol
obtained in the diet exceeds the amount required for the
synthesis of membrane, bile salts, and steroids,
pathological accumulations of cholesterol (plaques) can
obstruct blood vessels, a condition is called
atherosclerosis.
202. Factors responsible for development of atherosclerosis
1. Age
2. Sex
3. Genetic factor
4. Hyperlipidemia
5. Lipoprotein(a) (LPa)
6. Level of HDL
7. Hypertension
8. Cigarette smoking
9. Diabetes mellitus
10. Minor or soft risk factors
1. Age
2. Sex
3. Genetic factor
4. Hyperlipidemia
5. Lipoprotein(a) (LPa)
6. Level of HDL
7. Hypertension
8. Cigarette smoking
9. Diabetes mellitus
10. Minor or soft risk factors
203. Age
As age advances, the elasticity of the vessel wall
decreases and formation of plaques progresses. Formation
of plaque leads to narrowing of the lumen .
Sex
Males are affected more than females. Male sex hormone
is atherogenic or conversely that female sex hormones are
protective.
Age
As age advances, the elasticity of the vessel wall
decreases and formation of plaques progresses. Formation
of plaque leads to narrowing of the lumen .
Sex
Males are affected more than females. Male sex hormone
is atherogenic or conversely that female sex hormones are
protective.
204. Genetic factor
Hereditary genetic derangement of lipoprotein metabolism
leads to high cholesterol level.
Hyperlipidemia
Increased levels of serum cholesterol , triacylglycerol, low
density lipoprotein (LDL) are associated with increased risk of
atherosclerosis
Lipoprotein(a) (LPa)
Elevated LPa levels are associated with an increased risk of
coronary heart disease
Genetic factor
Hereditary genetic derangement of lipoprotein metabolism
leads to high cholesterol level.
Hyperlipidemia
Increased levels of serum cholesterol , triacylglycerol, low
density lipoprotein (LDL) are associated with increased risk of
atherosclerosis
Lipoprotein(a) (LPa)
Elevated LPa levels are associated with an increased risk of
coronary heart disease
205. Level of HDL
Low level of HDL is associated with atherosclerosis. HDL
has protective effect against atherosclerosis. HDL participates in
reverse transport of cholesterol
Hypertension
It acts probably by mechanical injury of the arterial wall due to
increased blood pressure.
Cigarette smoking
Cigarettes smoking increase the risk due to reduced level of HDL
and accumulating carbon monoxide that may cause endothelial
cell injury.
Level of HDL
Low level of HDL is associated with atherosclerosis. HDL
has protective effect against atherosclerosis. HDL participates in
reverse transport of cholesterol
Hypertension
It acts probably by mechanical injury of the arterial wall due to
increased blood pressure.
Cigarette smoking
Cigarettes smoking increase the risk due to reduced level of HDL
and accumulating carbon monoxide that may cause endothelial
cell injury.
206. Diabetes mellitus
The risk is due to the coexistence of other risk factors such as
obesity, hypertension, and hyperlipidemia.
Minor or soft risk factors
These include lack of exercise, stress, obesity, high caloric
intake, diet containing large quantities of saturated fats, use
of oral contraceptive, alcoholism etc.
The risk is due to increased LDL and decreased HDL levels.
Diabetes mellitus
The risk is due to the coexistence of other risk factors such as
obesity, hypertension, and hyperlipidemia.
Minor or soft risk factors
These include lack of exercise, stress, obesity, high caloric
intake, diet containing large quantities of saturated fats, use
of oral contraceptive, alcoholism etc.
The risk is due to increased LDL and decreased HDL levels.
