2. Learning objectives
At the end of this chapter the students will able to
Differentiate the structure and composition of lipids.
Outline the sequence of reactions involved in oxidation of fatty acids
in the mitochondrion.
Explain the rationale for the pathway of ketogenesis and identify the
major intermediates and products of this pathway.
Describe the synthesis of fatty acids and triglycerides
Describe Cholesterol synthesis, transport, & excretion
Discuss the composition, functions and metabolism of lipoproteins.
2
3. Chemistry of lipids
Lipids are a heterogeneous group of water- insoluble
(hydrophobic) Organic molecules.
Hydrophobicity is due to the long – hydrocarbon chains.
Includes fats, oils, steroids, waxes, and related
compounds, which are related more by their physical than
by their chemical properties
They have the common property of being:
(a) relatively insoluble in water and
(b) soluble in no polar solvents such as ether and
chloroform.
3
5. Lipids are classified as simple or complex
1. Simple lipids: Esters of fatty acids with various alcohols.
a. Fats: esters of fatty acids with glycerol. Oils are fats in the liquid
state.
b. Waxes: esters of fatty acids with higher molecular weight
monohydric alcohols.
2. Complex lipids: Esters of fatty acids containing other groups in
addition to an alcohol and a fatty acid .
a. Phospholipids: Lipids containing, in addition to fatty acids and an
alcohol, a phosphoric acid residue.
They frequently have nitrogen containing bases and other
substituents
5
6. eg, in-glycerophospholipids the alcohol is glycerol and in
-sphingophospholipids the alcohol is sphingosine.
b, Glycolipids (glycosphingolipids):
- Lipids containing a fatty acid, sphingosine, and carbohydrate.
c, Other complex lipids:
-Lipids such as sulfolipids and aminolipids. Lipoproteins may also
be placed in this category.
3. Precursor and derived lipids:
-These include fatty acids, glycerol, steroids, other alcohols, fatty
aldehydes, and ketone bodies, lipid-soluble vitamins, and hormones.
6
7. Fatty Acids
• Fatty acids are carboxylic acids with hydrocarbon
Side chains. They are the simplest form of lipids.
• Fatty acids are aliphatic carboxylic acids named after the
corresponding hydrocarbons.
• They are not found free in nature but found as esterified forms
• Most of the fatty acids that occur in nature are of even no of carbon
atoms. Palmitic acid (16 C) & Stearic acid (18 C) are most common.
• Fatty acids are of 2 types:-
Saturated (containing no double bonds) & Unsaturated FAs
(containing one or more double bonds) . Both occur almost equally in
nature.
Unsaturated FAs
Monounsaturated Polyunsaturated
7
8. Cont…
Eg :- CH3 (CH2)7 CH2CH2 (CH2)7 COOH stearic acid
(saturated fatty acid)
Eg :- CH3 (CH2)7 CH=CH (CH2)7 COOH oleic acid
(Unsaturated fatty acid)
• There are two systems of numbering the carbon atoms in a
fatty acid
n 3 2 1
CH3 (CH 2)n CH = CH CH2 CH2 CH2 COOH
ω β α
• Fatty acids can be represented as shown below
Eg. C18:1, ∆9 or 18:1(9) C18 indicates 18 carbons, 1 indicates
the number of double bonds, delta 9(∆9) indicates the position
of double bond between 9th and 10th carbon atoms.
8
9. Cont…
• The double bonds in a fatty acid can also be referenced relative
to the ω (methyl) end of the chain.
• Arachidonic acid is referred to as an ω-6 fatty acid because
the terminal double bond is six bonds from the ω end
• Another ω-6 fatty acid is the essential linoleic acid 18:2(9,12).
In contrast, α-linolenic acid, 18:3(9,12,15), is an essential ω-3
fatty acid.
9
12. According to Biological Value
1. Essential Fatty Acids.
• They can not be synthesized by mammals and must be
obtained from plant sources.
• They are polyunsaturated fatty acids (PUFA).
e.g. Linoleic acid (ω6) and linolenic acid (ω3).
*Arachidonic acid is semi essential fatty acid because it can be
synthesized from the above two essential fatty acids
particularly linoleic acid (ω6).
12
13. Functions of EFA
The fluidity of membrane depends on length and degree of
unsaturated fatty acids (Phospholipids).
In case of deficiency of EFA, other fatty acids replace them in the
membrane; as a result membrane gets modified structurally and
functionally.
They are required for the synthesis of PL, cholesterol ester and
lipoproteins
Poly unsaturated fatty acids are released from membranes, diverted
for the synthesis of prostaglandins, leukotriens and thromboxanes
They act as fat mobilizing agents in liver and protect liver from
accumulating fats (fatty liver). 13
14. Omega-3 Fatty Acids
• Group of polyunsaturated fatty acids
• Essential–must be obtained in the diet
• Component of cell membranes
• Mediate inflammation, regulate blood clotting and contraction/relaxation of
arterial walls
• May be helpful in relieving symptoms in rheumatoid arthritis and age-
related macular degeneration
14
16. An imbalance of omega-6 and omega-3 PUFAs in the diet is
associated with an increased risk of cardiovascular disease. The
optimal dietary ratio of omega-6 to omega-3 PUFAs is between
1:1 and 4:1
2. Non Essential Fatty Acids.
They can be synthesized by mammals, so it is not essential to
take them in diet.
They include saturated fatty acids and mono- unsaturated fatty
acids.
16
17. The major lipids
Triacylglycerols (TAG)
They are esters of the trihydric alcohol glycerol and fatty
acids. Stored in adipocytes
They are the main storage forms of fatty acids
Fig:TAGl 17
Figur.TAG
4/8/2023
18. Waxes
Esters of long-chain (C14 to C36) saturated and
unsaturated fatty acids with long-chain (C16 to C30)
alcohols
Certain skin glands of vertebrates secrete waxes
Many tropical plants are coated with a thick layer of
waxes
Biological waxes find a variety of applications in the
pharmaceutical, cosmetic, and in the manufacture of
lotions.
18
19. Phosphatidate and its derivatives
Phosphatidate is the parent compound for the formation of the
different glycerophospholipids.
To the phosphate group different head alcohol may be attached.
If choline is attached it is called phosphatidyl choline (lecithin), if
ethanolamine is attached it is called phosphatidyl ethanolamine.
The second largest membrane lipids are sphingolipids, which
contain two non-polar and one polar head groups.
Their alcohol is the amino alcohol sphingosine.
19
22. Phospholipids
Are the main lipid constituents of membranes.
Phospholipids are of more general term, Any lipid containing
phosphorus
If the alcohol attached is glycerol the PL is
glycerophospholipid.
If the alcohol is sphingosine it is sphingolipid.
Regarded as derivatives of phosphatidic acid, in which the
phosphate is esterified with the -OH of a suitable alcohol.
22
23. Phosphoglycerides
Phosphoglycerides contain:
– Glycerol
– Fatty acid
– Phosphoric acid with an amino alcohol
Have hydrophobic and hydrophilic domains
Suspended in water, they spontaneously rearrange into ordered
structures
– Hydrophobic group to center
– Hydrophilic group to water
– Basis of membrane structure
23
24. Steroids
Play many physiologically important roles
Cholesterol is probably the best known steroid because of its
association with atherosclerosis.
However, biochemically it is also of significance because it is
the precursor of a large number of equally important steroids
like bile acids, adreno-cortical hormones, sex hormones,
vitamin D…
All of the steroids have a similar cyclic nucleus .
24
25. Metabolism of lipids
Digestion & absorption of lipids
The digestion of lipids begins in the stomach, catalyzed by an acid-
stable lipase that originates from glands at the back of the tongue
(lingual lipase) and gastric mucosa(gastric lipase ) in lipid digestion of
neonates,, for whom milk fat is the primary source of calories.
TAG molecules, (SCFA,and MCFA; less than 12 carbons), are the
primary target of this enzyme.
Produce DAG and free fatty acids.
25
26. Cont…
Emulsification of dietary lipids in the small intestine
(duodenum)
Fats or lipids are water-insoluble and tend to
coalesce(compacted togethter ) into droplets in water,
So a critical first step in processing dietary fats is
emulsification.
26
4/8/2023
27. Cont…
Emulsification increases the surface area of the hydrophobic
lipid droplets
So that the digestive enzymes which work at the interface of
the droplet and the surrounding aqueous duodenal contents can
act effectively.
Emulsification is accomplished by two complementary
mechanisms namely,
– The use of the detergent ( amphipathic ) surface active
properties of bile salts and mechanical mixing of
peristalsis. 27
28. Lipolytic enzymes in intestines
• Pancreatic lipase with co-lipase- The major end products of the
digestion of TAG are 2-MAG and fatty acids.
• The binding of co-lipase to the triacylglycerol molecules at the
oil water interface is obligatory for the action of lipase.
• The co-lipase is secreted by the pancreas as an inactive and
activated by trypsin.
• Cholesterol esterase- Cholesterol ester may be hydrolyzed to
free cholesterol and fatty acid.
• Phospholipase A2- The action of phospholipase A2 produces
lysophospholipid and a fatty acid
28
29. Absorption of lipids by intestinal mucosal cells:
A. By Mixed micelle formation = Bile salts, together with free FAs,
free cholesterol, fat-soluble vitamins and 2 MAG form clusters of
amphipathic lipids that coalesce with their hydrophobic groups on the
inside and their hydrophilic groups on the outside of the cluster, and
which are soluble in the aqueous environment of the intestinal lumen.
The micelles get access into enterocytes.
In these cells, fatty acids are activated into acyl CoA.
B. Short and medium chain-length fatty acids do not require the
assistance of a micelle for absorption by the intestinal mucosa.
29
30. Triacylglycerol and cholesteryl ester resynthesis
The mixture of lipids absorbed by the enterocytes migrates to the
SER where biosynthesis of complex lipids takes place.
The long-chain FA are first converted into their activated form by
fatty acyl coenzyme A (CoA) synthetase (thiokinase),
Free glycerol absorbed from intestinal lumen directly enters into
the bloodstream.
So free glycerol is not available for re-esterification.
But the cells can derive glycerol phosphate from glucose by
glycolysis, and add 3 molecules of acyl groups to synthesize TAG.
30
31. .
Figure: Assembly and secretion of chylomicrons by intestinal mucosal
cells via exocytosis.
[Note: Short- and medium-chain-length fatty acids do not require
incorporation into chylomicrons and directly enter into the blood.] CoA =
coenzyme A; AMP = adenosine monophosphate; PPi = pyrophosphate
31
32. Lipid malabsorption (steatorrhea):
Is the loss of > 6g of fat together with fat soluble vitamins
(A,D,E,K) and essential fatty acids
In steatorrhoea, the stool is bulky, greasy and offensive.
Almost all nutrients absorption is impaired because fat coats of
chyme particles in the intestinal lumen and prevents their
interaction with digestive enzymes resulting in failure of
digestion and absorption of chyme constituents.
32
33. Cont….
• Steatorrhea may be due to
A defect in the secretion of bile or pancreatic juice into the
intestine
Impairment in the lipid absorption by the intestinal cells.
• Steatorrhea is commonly seen in disorders associated with
pancreas, biliary obstruction, severe liver dysfunction etc
33
34. Use of dietary lipids by the tissues
• Triacylglycerols (TAGs) in chylomicrons are broken primarily in the
skeletal muscles and adipose tissue by lipoprotein lipase to glycerol and
free fatty acids.
lipoprotein lipase
Triacylglycerol →→→→ + 3 RCOOH
•lipoprotein lipase is found on the luminal surface of endothelial cells of
the capillary beds of the peripheral tissues.
•Its deficiency in familial lipoprotein lipase deficiency results in massive
chylomicronemia.
35. Fate of free-fatty acids
Directly enter adjacent muscle cells or adipocytes.
Alternatively, free fatty acids may be transported in blood in
association with serum albumin ,until they are taken by cells.
Most cells can oxidize fatty acids to obtain energy (ATP).
However, the brain and other nervous tissues, erythrocytes and
the adrenal medulla cannot use plasma free- fatty acids for
fuel, regardless of the blood levels of fatty acids.
Adipocytes can also re-esterify free-fatty acids to produce
triacylglycerol molecules, which are stored until the fatty acids
are needed 35
36. Fate of glycerol
Glycerol is used by the liver to produce glycerol-3-phosphate,
which can enter glycolysis or gluconeogenesis by oxidation to
dihydroxyacetone phosphate.
Fate of chylomicron remnants
After removal of most of its triacylglycerol (TAG) content are
taken up by the liver where , they are hydrolyzed to their
component parts. 36
37. Cont…
This is due to the presence of apolipoprotein E on the surface
of chylomicrons which has apolipoprotein E receptors in
hepatic cells plasma membranes.
Deficiency of apolipoprotein E, leads to familial type III
hyperlipoproteinemia, which leads to defective removal of
chylomicron remnants from the plasma, and they accumulate
in plasma.
37
38. Biosynthesis and storage of fatty acids
Fatty acids are synthesized by an extramitochondrial system, which
is responsible for the complete synthesis of palmitate from acetyl-
CoA in the cytosol.
In humans , fatty acid synthesis occurs primarily in the liver and
lactating mammary glands and, to a lesser extent, in adipose
tissue, brain, lung.
In most mammals, glucose is the primary substrate for lipogenesis,
but in ruminants it is acetate, the main fuel molecule produced by
the diet.
38
39. Cont…
The design strategy for fatty acid synthesis is this:
1. Fatty acid chains are constructed by the addition of two-carbon
units derived from acetyl-CoA.
2. The acetate units are activated by formation of malonyl-CoA (at
the expense of ATP).
3. The addition of two-carbon units to the growing chain is driven
by decarboxylation of malonyl-CoA.
4. The elongation reactions are repeated until the growing chain
reaches 16 carbons in length (palmitic acid) and
5. Other enzymes then add double bonds and additional carbon
units to the chain 39
40. Cont…
Its cofactor requirements include (NADPH, ATP, Mn2+, biotin,
and HCO3 − (as a source of CO2).
Acetyl-CoA is the immediate substrate, and free palmitate is the
end product
Carbohydrates, protein, and other molecules obtained from
the diet in excess of the body's needs for these compounds can be
converted to FA to stored as TAG
Fatty acids are constructed by stepwise addition of two-carbon
units by a large multi-enzyme complex located in the cytoplasm of
all cells. 40
41. Cont…
Steps of de-novo synthesis of fatty acids in the cytosol
A) Production of cytosolic acetyl CoA:
1.The source of mitochondrial acetyl CoA is the oxidation of
pyruvate, degradation of fatty acids, ketone bodies or amino
acids.
2. The Coenzyme A portion of acetyl CoA cannot cross the
mitochondrial membrane Only the acetyl portion is transported
to the cytosol in the
form of citrate.
41
Production of
cytosolic acetylCoA
4/8/2023
42. Cont…
B) Carboxylation of cytosolic acetyl CoA to Malonyl
CoA
Production of Malonyl-CoA Is the Initial & Controlling Step in
Fatty Acid Synthesis.
Bicarbonate as a source of CO2 is required in the initial reaction
for the carboxylation of acetyl-CoA to malonyl- CoA in the
presence of ATP and acetyl-CoA carboxylase.
Acetyl-CoA carboxylase has a requirement for the vitamin biotin
multienzyme protein containing a variable number of identical
subunits, each containing biotin, biotin carboxylase, biotin
carboxyl carrier protein, and transcarboxylase, as well as a
regulatory allosteric site.
42
45. TAG synthesis and storage
They are the major energy reserve of the body
Stored within white adipocytes
In both liver (the primary site of TAG synthesis) and adipose tissue,
glycerol 3-phosphate can be produced from dihydroxyacetone phosphate
(DHAP).
DHAP is reduced by glycerol 3-phosphate dehydrogenase to glycerol 3-
phosphate.
A second pathway found in the liver, but not in adipose tissue, uses
glycerol kinase to convert free glycerol to glycerol 3-phosphate
Glycerol 3-phosphate is the initial acceptor of fatty acids during TAG
synthesis
45
47. 47
Oxidation of Fatty Acids
β-oxidation of fatty acids.
The major pathway for catabolism of saturated fatty acids
mitochondrial pathway called β- oxidation, in which two-
carbon fragments are successively removed from the
carboxyl end of the fatty acyl CoA, producing acetyl CoA.
Steps of β- oxidation of fatty acids:
1. activation and Transport of fatty acids into the
mitochondria:
After a fatty acid is taken up by a cell, it is activated to the
fatty acyl CoA derivative by fatty acyl CoA synthetase
(thiokinase) in the cytosol, with the consumption of 2
ATP molecules.
48. Activation of fatty acids takes place on the outer
mitochondrial membrane
48
49. Cont…
2. Because β- oxidation occurs in the mitochondria, the fatty
Acid CoA must be transported across the inner mitochondrial
membrane , which is impermeable to the bulky, polar molecules
such as coenzyme A.
Therefore a specialized carrier in this membrane transports the
Fatty acid group from the cytosol into the mitochondrial matrix.
This carrier is carnitine, and the transport process is called the
carnitine shuttle.
49
51. 51
Cont….
β-Oxidation pathway
1. Oxidation of the fatty acyl CoA to enoyl CoA forming a trans 2-
double bond on the fatty acyl chain and producing FADH2
(catalyzed by acyl CoA dehydrogenase).
2. Hydration of the trans 2-enoyl CoA to form 3-hydroxyacyl CoA
(catalyzed by enoyl CoA hydratase).
3. Oxidation of 3-hydroxyacyl CoA to 3-ketoacyl CoA producing
NADH (catalyzed by hydroxyacyl CoA dehydrogenase).
4. Cleavage, or thiolysis, of 3-ketoacyl CoA by a second CoA
molecule, giving acetyl CoA and an acyl CoA shortened by two
carbon atoms (catalyzed by-ketothiolase)
53. Energy calculation in β-oxidation of FAs
• If we have a fatty acid with even number of carbon steps ;
1 .find the number of acetyl COA ,NADH and FADH2 produced
-acetyl-coA = n/2
-NADH = (n/2)-1
-FADH2= (n/2)-1
2. How many ATP produced by each component
1 acety COA= produced 12 ATP ,1NADH produced = 3ATP
1FADH2= 2ATP
3.Finaly calculate total ATP and net ATP
e.g= fatty acid with carbon number 16
1. acetylCOA=16/2 = 8 , NADH= (16/2)-1 = 7 FADH2= (16/2)-
1= 7
2. 8x12 + 7x3 + 7x2= 131
3. Total ATP= 131 Net ATP 131-2= 129
53
54. 54
Ketogenesis & Ketolysis
• Ketone bodies : an alternative fuel for cells.
Liver mitochondria have the capacity to divert any excess acetyl CoA
derived from fatty acid or pyruvate oxidation into ketone bodies.
The compounds categorized as ketone bodies = acetoacetate, 3-
hydroxybutyrate and acetone (a volatile non- metabolizable side
product).
They are transported in the blood to peripheral tissues, where they can
be reconverted to acetyl CoA and oxidized by the TCA cycle.
55. 55
Cont…..
Ketone bodies are soluble in aqueous solution, and therefore, do not
need to be incorporated in lipoproteins or carried by albumin as do
other lipids.
Synthesis of ketone bodies by the liver.
Note that HMG CoA synthase , is the rate- limiting step in the
synthesis of ketone bodies and is present in significant quantities only
in the liver.
HMG CoA is also a structural intermediate in the catabolism of the
amino acid leucine and a precursor of cholesterol
57. 57
Cont…..
Although the liver constantly produces low levels of ketone bodies,
Their production becomes much more significant during starvation
and uncontrolled diabetics and hyperemesis gravidarum.
The liver actively produces ketone bodies, but it cannot itself use
them as fuels.
58. 58
Ketolysis (ketone body utilization)
Ketone bodies are used in extrahepatic tissues such as the skeletal
and cardiac muscle and the renal cortex, in proportion to their
concentration in blood.
Even the brain can utilize ketone bodies for fuel if the level rises
sufficiently, this is important during prolonged periods of fasting.
The liver lacks succinyl CoA : acetoacetate CoA transferase (
thiophorase ), and therefore is unable to use acetoacetate as a fuel.
Red blood cells cannot efficiently oxidize acetoacetate and 3-
hydroxybutyrate because they lack mitochondria.
60. 60
Cholesterol metabolism
Cholesterol(the characteristic steroid alcohol of animal tissues),is
an animal sterol which occurs either free or as fatty esters.
The liver plays a central role in the regulation of the body’s
cholesterol balance ; e.g. Cholesterol enters the liver’s cholesterol
pool from a number of sources including:
a. Dietary cholesterol.
b. Cholesterol synthesized by the extrahepatic tissues.
c. De novo synthesized cholesterol by the liver itself
61. Cont….
Cholesterol is eliminated from the liver:
a. As unmodified cholesterol dissolved in bile acid .
b. modified cholestrol by intestinal bacteria
c. As bile salts secreted into the intestinal lumen
61
63. Cholesterol synthesis
Cholesterol synthesis occurs in the cytoplasm with enzymes in
both the cytosol and the endoplasmic reticulum.
All nucleated cells can synthesize cholesterol, including arterial
walls
Synthesized from acetyl COA
The largest contributions to the body’s cholesterol are made by:
Liver(mainly), Intestine, Adrenal cortex, Reproductive tissues (
ovaries and testes), Placenta.
63
64. 64
Cont….
A. Synthesis of HMG CoA
The first two reactions in cholesterol synthetic pathway are similar
to those in the pathway that produces ketone bodies; they result in
the production of HMG CoA (β- hydroxy-β- methylglutaryl CoA).
First, thiolase catalyzes the condensation of two acetyl CoA
molecules to form acetoacetyl CoA.
Next, HMG CoA synthase catalyzes the addition of a third
molecule of acetyl CoA producing HMG CoA.
66. Cont….
B. Synthesis of mevalonate
The next step is the formation of mevalonic acid . This step is
catalyzed by HMG CoA reductase and is the rate-limiting step in
cholesterol synthesis It occurs in the endoplasmic reticulum, uses
2 molecules of NADPH as the reducing agent, and releases CoA,
making the reaction irreversible.
66
4/8/2023
67. Cont…
C. Synthesis of cholesterol
Mevalonate thus formed is then converted to squalene through
various steps.
Squalene, with the formation of various intermediates finally
give rise to the end product cholesterol.
67
4/8/2023
68. 68
Regulation of cholesterol synthesis
HMG CoA reductase is the rate –limiting enzyme in
cholesterol synthesis, and is subject to different kinds of metabolic control:
1. Feed back inhibition: Cholesterol is a feed back inhibitor of
HMG CoA reductase, thus decreasing further cholesterol synthesis.2.
Hormonal regulation
Glucagon favors the formation of the inactive (phosphorylated)
form of HMG CoA reductase and hence, decreases the rate of
cholesterol synthesis.
In contrast, insulin favors the formation of the active
(dephosphorylated) form of HMG CoA reductase and results in an
increase in the rate of cholesterol synthesis.
69. 69
Structure and function of Lipoproteins
Plasma lipoproteins
• The plasma lipoproteins are spherical macromolecular complexes
of lipids and specific proteins (apolipoproteins or apoproteins).
four main Lipoprotein particles include:
a. Chylomicrons (CM).
b. Very low density lipoproteins (VLDL)
c. Low density lipoproteins (LDL).
d. High density lipoproteins (HDL).
Lipoproteins function both to keep lipids soluble as they transport
them in plasma, and to provide an efficient mechanism for
delivering their lipid contents to the tissues.
They differ in lipid and protein composition, size, density and site
of origin
71. Chylomicrons
Made by: the small intestines in the fed state,
Rich in TAG(90%)
Mature chylomicron contains apo B-48, C-II and E
Function: Deliver TAG ’s from small intestine to the liver,
adipose tissue for storage; and to muscle or heart for their energy
needs.
Metabolism: The enzyme lipoprotein lipase (LpL) is located at
the endothelial layer of capillaries of adipose tissue, muscles and
heart; but not in liver.
71
72. Cont…
Apo C-II present in the chylomicrons activates the LpL.
The LpL hydrolyzes triglycerides present in chylomicrons into
fatty acids and glycerol.
Muscle or adipose tissue cells take up the liberated fatty acids.
As the TAG content is progressively decreased, the chylomicrons
shrink in size.
These remnants containing apo B-48 and apo E are taken up by
hepatic cells by receptor mediated endocytosis.
Apo E binds the hepatic receptors
72
73. Synthesis of VLDL
They are synthesized in the liver and some times in the intestine
from glycerol and fatty acids and incorporated into VLDL along
with hepatic cholesterol, apo-B-100, C-II and E.
Apo-B-100 is the major lipoprotein present in VLDL when it is
secreted.
ApoE and C-II are obtained from HDL in plasma.
Function - transport of endogenously synthesized triacylglycerol
from the liver to other body cells.
73
74. Cont…
When they reach the peripheral tissues, apo C-II activates LpL which
liberates fatty acids that are taken up by adipose tissue and muscle.
The remnant is now designated as IDL (intermediate density lipoprotein)
and contains less of TAG and more of cholesterol.
The major fraction of IDL further loses triglyceride, so as to be converted
to LDL (low density lipoprotein).
This conversion of VLDL to IDL and then to LDL is referred to as
lipoprotein cascade pathway.
A fraction of IDL is taken up by the hepatic receptors.
74
75. Low Density Lipoprotein (LDL)
Arise from: VLDL once it has lost a lot of its TG’s,
Secreted into: the bloodstream, Rich in: Cholesterol
Function: Deliver cholesterol from liver to other body cells.
The LDL is taken up by peripheral tissues by receptor mediated
endocytosis.
LDL receptors are present on all cells but most abundant in
hepatic cells
The level of intracellular cholesterol is regulated through
cholesterol-induced suppression of LDL receptor synthesis and
cholesterol-induced inhibition of cholesterol synthesis. 75
76. Cont…
However, the effect of cholesterol-induced suppression of LDL
receptor synthesis is to decrease the rate at which LDLs and
IDLs are removed from the serum.
This can lead to excess circulating levels of cholesterol.
The excess cholesterol tends to be deposited within the
arteries, leading to atherosclerosis.
4/8/2023 76
77. Metabolism of HDL
Made in: the Liver and Small Intestine
Secreted into: the bloodstream
Function: Pick up cholesterol from body cells and take it back
to the liver = “reverse cholesterol transport”
Potential to help reverse heart disease
The major apoproteins in HDL are Apo A1, with some Apo A2,
Apo C and Apo E.
HDL serves as a plasma reservoir of Apo C and Apo E which can
be transferred to VLDL and chylomicrons and back
77
78. Cont…
HDL are synthesized in the liver as discoidal particles –nascent
HDL.
They contain free cholesterol and phospholipids (mostly
lecithin) and apoproteins.
The plasma enzyme lecithin-cholesterol acyltransferase (LCAT)
catalyses the esterification of free cholesterol (by fatty acid of
lecithin) present in the extrahepatic tissues and transfers to the
HDL.
Apoprotein A promotes the activity of LCAT.
HDL also accepts free cholesterol from other lipoproteins in
circulation and cell membrane of peripheral tissues.
78
79. Cont…
Any free cholesterol taken up by HDL undergoes LCAT-
catalysed esterification.
Due to the addition of cholesterol, HDL particles become
spherical.
Mature HDL spheres are taken up by liver cells by apo A-l
mediated receptor mechanism
When HDL3 remains in circulation, the cholesterol ester from
HDL is transferred to VLDL, IDL and LDL by a Cholesterol
Ester Transfer Protein (CETP).
79
81. Factors Associated with CVD
Mostly cardio vascular disease is associated with Atherosclerosis
Cause; Dietary
1. Elevated levels of LDL (bad cholesterol)
--More LDL around to potentially oxidize and accumulate
in artery wall
2. Low levels of HDL
--HDL carries cholesterol from artery walls back to the
liver
3. Low levels of antioxidant vitamins like-Vit. E, Vit. C,
Beta-carotene
4. Low levels of other dietary antioxidants
81
