2. Learning objectives
• To identify components of blood lipids
• To understand the properties of major lipoproteins
• To understand the functions of lipoproteins
• To apply the knowledge acquired to the system in
normal and disease conditions
3. Introduction
• Lipids are defined as organic compounds that are
poorly soluble in water but miscible in organic
solvents
• they are structural components in cells and are
involved in metabolic and hormonal pathways
• Since lipids are insoluble in water, they need the
help of carriers in plasma. Therefore, they form
complexes with specific proteins to form
lipoproteins
• Lipids and proteins associate non-covalently to form
lipoproteins, which function in the blood plasma as
transport vehicles for triacylglycerols and cholesterol
4. Composition of plasma Lipoproteins
Lipoproteins composed of lipids and proteins.
Lipid Components are:
• a neutral lipid core – triacylglycerols (TAG), and
cholesterol esters(CE), surrounded by a shell of
protein, phospholipid (PL) and non-esterified
(free) cholesterol (NEC)
• Non polar core of triacylglycerols and cholesteryl
esters forms the hydrophobic layer
• Surrounding coating of protein, phospholipid
and free cholesterols forms the hydrophilic layer
5. Composition of plasma Lipoprotein cont’d
Sources of blood lipids:
• The TAG and cholesterol carried by the
lipoproteins are obtained from;
i) the diet (exogenous source) or
ii) de novo synthesis (endogenous source)
Lipoprotein particles undergo continuous
metabolic processing, so that they have
variable properties and compositions
• Total plasma lipid is 400-600 mg/dl. Out of this,
40% is cholesterol; 30% is phospholipids; 20% is
triglycerides
6. Composition of plasma Lipoprotein cont’d
• The protein component of lipoproteins are
called apolipoproteins or apoproteins
• At least nine apolipoproteins are distributed
in significant amounts in different human
lipoproteins .
• Most of them are water-soluble and associate
rather weakly with lipoproteins
• Hence, they readily transfer between
lipoprotein particles via the aqueous phase
7. Composition of plasma Lipoprotein cont’d
Sources of apoproteins:
• All apoproteins are mainly synthesized in the
liver;
• but small quantities are produced from almost all
organs
• Intestinal cells produce small quantities of apo-A
The Apoproteins primarily function to:
• solubilise the lipid part, of the lipoprotein
8. Composition of plasma Lipoprotein cont’d
• Apo-B-100: It is a component of LDL; it binds to LDL
receptor on tissues .
• Apo-B-100 is one of the biggest proteins, having 4536
amino acids, with a molecular weight of 550 kDa. It is
synthesized in the liver
• Apo-B-48: It is synthesized in intestinal cells. It is the
structural component of chylomicrons
• Apo-C-II: It activates lipoprotein lipase
• Apo-E: It is an arginine-rich protein. It is present in
chylomicrons, LDL and VLDL.
• Astrocytes also makes apo-E; it is involved in cellular
transport of lipids in centra nervous system(CNS)
9. Figure 1. Apo- B-100 and Apo-B-48 are produced from the
same gene. In liver, the mRNA is translated as usual (B-100). But
in intestine, a particular cytosine residue is de-aminated, to
become uracil. So, a stop codon is generated in the middle, and
a short protein is produced in intestine (B48). Apo-B-48 is only
48% of the size of B-100
10. Classification of lipoproteins
• Classified into five broad categories on the basis
of their functional and physical
properties(densities & electrophoretic mobility) :
1. Chylomicrons, contain apoprotein B-48;
transport exogenous (externally supplied; )
dietary triacylglycerols and cholesterol from the
intestines to the tissues
2. Very low density lipoproteins VLDL or pre-β
lipoproteins. Main apoprotein is B-100
3. Intermediate density lipoproteins IDL or broad β
lipoprotein
4. Low density lipoproteins LDL or beta-
lipoproteins. Major apoprotein in LDL is B- 100
11. Classification of lipoproteins cont’d
• Very low density lipoproteins (VLDL),
intermediate density lipoproteins (IDL), and low
density lipoproteins are a group of related
particles that transport endogenous (internally
produced) triacylglycerols and cholesterol from
the liver to the tissues (the liver synthesizes
triacylglycerols from excess carbohydrates)
5. High density lipoproteins (HDL)or alpha
lipoproteins; major apoprotein in HDL is apo-A
• transport endogenous cholesterol from the
tissues to the liver
13. Figure 3. Comparison of sizes of lipoproteins. Lipoprotein
densities increase with decreasing particle diameter because the
density of their outer coating is greater than that of their inner core
17. Figure 7. LDL, the major cholesterol carrier of the bloodstream. This spheroidal
particle consists of some 1500 cholesteryl ester molecules surrounded by an
amphiphilic coat of 800 phospholipid molecules, 500 cholesterol molecules, and a
single 4536-residue molecule of apolipoprotein B-100.
18. Figure 8. Schematic illustration of low-density lipoprotein (LDL) metabolism and the
role of the liver in its synthesis and clearance. Lipolysis of very-low-density lipoprotein
(VLDL) by lipoprotein lipase in the capillaries releases triglycerides, which are then
stored in fat cells and used as a source of energy in skeletal muscles.
19. Characteristics of Apolipoproteins
Apoproteins Components MW Source Functions
Apo A-I HDL-2 29 Intestine;
Liver
Activation of LCAT; ligand for HDL
receptor; antiatherogenic
Apo A -II HDL-3 17 Intestine;
Liver
Inhibits LCAT; stimulate lipase
Apo-B-100 LDL, VLDL 513 Liver Binds LDL receptors; cholesterol
clearance
Apo B-48 Chylomicron 241 Intestine Cholesterol clearance
Apo C-I Chylomicron, VLDL 6.6 Liver Activation of LCAT
Apo C-II Chylomicron, VLDL
LDL
8.9 Liver Activate extrahepatic LPL in vessel
walls ; clearance of TAG from
chylomicron and VLDL
Apo-C-III Chylomicron, VLDL
LDL
8.8 Liver Inhibit LPL; antiatherogenic
Apo E LDL,VLDL
Chylomicron
19 Liver Arginine rich; ligand for hepatic
uptake
Apo Lp(a) Lp(a) 34 Liver Attached to B-100; impairs
fibrinolysis; atherogenic
20. Functions of lipoproteins
Chylomicrons are the transport form of dietary
triglycerides from intestines to the adipose tissue for
storage; and to muscles(skeletal and cardiac) for their
energy needs
• The retinol is transported in chylomicrons to the liver
for esterification and storage in the satellite cells
VLDL carries triglycerides (endogenous triglycerides)
from liver to peripheral tissues for energy
• About 75% of the plasma cholesterol is incorporated
into the LDL particles.
LDL transports cholesterol from liver to the peripheral
tissues
21. Functions of lipoprotein cont’d
• The cholesterol thus liberated in the cell has three
major fates:
i. It is used for the biosynthesis of other substances/
compounds like steroid hormones, bile acid and bile
salts
ii. Cholesterol may be incorporated into the plasma and
subcellular organelle membranes
iii. Cholesterol may be esterified to a monounsaturated
fatty acids MUFA by acyl cholesterol acyl transferase
(ACAT) for storage
• The cellular content of cholesterol regulates further
endogenous synthesis of cholesterol by regulating
HMG CoA reductase
22. Functions of lipoprotein cont’d
Transport of lipids:
Mechanisms of Lipid transport
1) transport of exogenous (dietary) lipids
2) transport of endogenous lipids from the liver
3) HDL and reverse cholesterol transport
• Transport of exogenous (dietary) lipids: all dietary
fat (exception of medium chain TG) is efficiently
carried into circulation via lymphatic drainage from
the intestinal mucosa
• TG & cholesterol combined with apo A & apo B-48
in the intestinal mucosa to form chylomicrons
23. Functions of Lipoprotein cont’d
• Apo-A-I, activates lecithin-cholesterol acyl
transferase (LCAT); It is the ligand for HDL receptor; It
is anti-atherogenic
• Ligand is an ion, molecule or functional group that
binds to another chemical entity to form a larger
complex
• HDL particle contribute apo C-ll to the chylomicrons
during transportation; apo C-ll is required for the
activation of lipoprotein lipase within the capillary
endothelium of adipose, heart and skeletal muscle
tissues
• Both phospholipids and apo C-II are required as
cofactors for lipoprotein lipase activity
24. Functions of Lipoprotein cont’d
• Free fatty acids FFA are oxidized, reesterified for
storage as TG; or released into the circulation bound
to albumin for transport to the liver
• HDL contribute apoE to the chylomicron remnant,
apoE facilitates binding of the particle to the hepatic
LDL receptors
• Within the hepatocytes, chylomicrons has several
fates: incorporated into membranes; resecreted as
lipoprotein back to the circulation or secreted as bile
acids
• All dietary fats are disposed of within 8 hrs after last
meal; elevated lipid level after meal is a risk factor for
atherosclerosis
25. Functions of Lipoprotein cont’d
• Transport of endogenous lipids from the Liver: the
formation and secretion of VLDL from the liver and its
catabolism to IDL & LDL particles describe the
endogenous lipid pathway; Fatty acids used in the
formation is derived primarily by uptake from the
circulation
• VLDL, transported away from the liver , rapidly as it’s
synthesized
• VLDL, consist of TG,CE,PL and apoB-100
• Nascent VLDL remnant, secreted into the circulation
combined with apoprotein C’s and apoE
26. Figure 9. Model for plasma triacylglycerol and cholesterol transport in humans.
27. Functions of lipoprotein cont’d
• HDL and Reversed cholesterol transport : as the
hepatic secretion of lipid particles into bile is the only
mechanism by which cholesterol can be removed
from the body, transport of excess cholesterol from
the peripheral cells back to liver is important
• The transport is mediated by HDL; HDL is laden with
apoA-1, containing lipoprotein which is
nonatherogenic
• Cholesterol-poor nascent HDL particles secreted by
the liver and small intestine, are esterified to more
mature HDL-2 particles by the action of lecithin
cholesterol acyl transferase LCAT
28. Functions of lipoprotein cont’d
• LCAT , facilitates movement of chylomicrons and
VLDL into the HDL core
• HDL-2, transfer cholesteryl ester back to apoB
mediated by cholesteryl ester transfer protein
(CETP) or the cholesterol-rich particle, removed
from plasma by endocytosis, completing reverse
cholesterol transport
31. Clinical correlates
• ApoB deficiency= abetalipoproteinemia
• Apo-E has I, II, III and IV isoforms, (independent
alleles in the genes).
• Apo E-IV isoform is implicated in the development
of senile dementia and Alzheimer's disease.
• Apo-E is also associated with lipoprotein
glomerulopathy
• Individual with the deficiency of either apo-E or
hepatic triacylglycerol lipase (HTGL) accumulate IDL
in the plasma
• Low HDL due to genetic deficiency of apoA-1 or
secondary to increased plasma TG
32. Clinical correlates cont’d
DISORDER LIPOPROTEIN
ELEVATED
GENETICS CLINICAL FINDINGS
Familial
hypercholesterolemia
LDL AD Tendon Xanthoma,
CHD
Familial defective Apo
B-100
LDL AR Tendon xanthomas
Familial
dysbetahypercholeste
rolemia
LDL, TG AD Tubereruptive
xanthoma,
peripheral vascular
diseases
Familial hepatic lipase
deficiency
VLDL AR CDH
37. • LDL reacts with receptors on various cells, is taken up by
endocytosis, and is digested by lysosomal enzymes. (Step 6)
• a. Cholesterol, released from cholesterol esters by a
lysosomal esterase, can be used for the synthesis of cell
membranes or for the synthesis of bile salts in the liver or
steroid hormones in endocrine tissue.
• b. Cholesterol inhibits HMG-CoA reductase (a key enzyme in
cholesterol biosynthesis) and, thus, decreases the rate of
cholesterol synthesis by the cell.
• c. Cholesterol inhibits synthesis of LDL receptors
(downregulation) and, thus, reduces the amount of
cholesterol taken up by cells.
• d. Cholesterol activates acyl:cholesterol acyltransferase
(ACAT), which converts cholesterol to cholesterol esters for
storage in cells.
38. • LDL reacts with receptors on various cells, is taken up by
endocytosis, and is digested by lysosomal enzymes. (Step 6)
• a. Cholesterol, released from cholesterol esters by a
lysosomal esterase, can be used for the synthesis of cell
membranes or for the synthesis of bile salts in the liver or
steroid hormones in endocrine tissue.
• b. Cholesterol inhibits HMG-CoA reductase (a key enzyme in
cholesterol biosynthesis) and, thus, decreases the rate of
cholesterol synthesis by the cell.
• c. Cholesterol inhibits synthesis of LDL receptors
(downregulation) and, thus, reduces the amount of
cholesterol taken up by cells.
• d. Cholesterol activates acyl:cholesterol acyltransferase
(ACAT), which converts cholesterol to cholesterol esters for
storage in cells.
