Lipoproteins

Because lipids are hydrophobic and essentially insoluble in the

water, therefore, they must be transported through the
bloodstream (aqueous medium) packaged as lipoproteins as
macromolecules which are more water soluble than fatty
substances. Each lipoprotein particle is composed of a core of
hydrophobic lipids such as cholesterol esters and TGs surrounded
by a shell of polar lipids (the phospholipids), which allows a
hydration shell to form around the lipoprotein. Free cholesterol
molecules are dispersed throughout the lipoprotein shell to
stabilize it in a way that allows it to maintain its spherical shape.
The major carriers of lipids are chylomicrons, VLDL, and HDL.
Metabolism of VLDL will lead to IDL and LDL, while metabolism of
chylomicrons leads to chylomicron remnant formation.

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Through this carrier mechanism, lipids leave their tissue of origin, enter

the bloodstream, and are transported to the tissues, where their

components will be either used in synthetic or oxidative process or stored

for later use.

The apoproteins not only add structural stability of the particle but have

other functions as well:

1. By entering into the “polar” surface layer they make the lipoprotein
molecules water miscible (hydrophilic).
2. They activate certain enzymes required for normal lipoprotein
metabolism – Activators—C-II for lipoprotein lipase ,A-1 for lecithin—
cholesterol acyl transferase (LCAT)
– Inhibitors—Apo-A-II and Apo-C III for lipoprotein lipase, Apo-C1 for
cholesteryl ester transferase protein.
3. They act as ligands on the surface of the lipoprotein that target
specific receptors on peripheral tissues that require lipoprotein
delivery for their innate cellular function. They act as ligands for
interaction with lipoprotein receptors in tissues, e.g. Apo B-100 and
apo-E for the LDL receptor and apo-Al for the HDL receptor.

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Lipoproteins can be classified according to their:
1. Hydrated density

2. Electrophoretic mobility

3. Apo-lipoprotein content.

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1. Classification as per hydrated density: Pure fat is less dense
than water. As the proportion of lipid to protein in lipoprotein
complexes increases, the density of the macro-molecule
decreases. Use of the above property has been made in
separating various lipoproteins in plasma by ultracentrifugation
which separate them into four major density classes:
a. Chylomicrons: Density lowest-floats

b. Very low-density lipoproteins (VLDL)

c. Low density lipoproteins (LDL) with their sub-classis

.IDL (intermediate density lipoprotein).

d. High Density lipoproteins (HDL) with their sub-classis

HDL-2 and HDL-3.
2. Classification Based on Electrophoretic Mobility. The most
widely used and simplest classification for lipoproteins is based on
the separation of major four classes by electrophoresis. The most
frequently employed electrophoretic media are “paper” and
‘agarose’. Plasma lipoproteins separated by this technique are
classified in relation to comparable migration of serum proteins.
On electrophoresis, the different fractions according to mobility
appear at:
The origin is chylomicrons,

Migrating into β-globulin region is called β-lipoproteins

(LDL)

Migrating into Pre-β-globulin region, called as pre-β-

lipoproteins (VLDL).

Migrating to “α1-globulin region called α-lipoproteins (HDL)

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 Migration in electrophoresis

Classification Based on Apo-lipoproteins. In this classification, .3

Lipoproteins are designated by their “apo-lipoprotein” composition. At
present, five major lipoprotein families have been identified

Types of Apoproteins Present in Various Lipoprotein Tin

As stated above, lipoproteins are characterized by the presence of one or
more proteins or polypeptides known as apoproteins. According to ABC
nomenclature:
1. HDL: Two major apoproteins of HDL are designated as apo-A-I and
apo-A-II. In addition to above, HDL also contains apo-C-I, C-II and
C-III. HDL-3 is characterized by having apo-D and HDL may also
acquire arginine-rich apo-E.

2. LDL: The main apoprotein of LDL is apo-B100, which is also present

in VLDL.

3. Chylomicrons: Principal apoprotein of chylomicrons is apo-B-48. In

addition, chylomicrons also contain apo-A (AI and AII) and apo-C (C-
II and C-III). Apo- C seems to be freely transferable between
chylomicrons and VLDL on one hand and HDL on the other.

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4. VLDL and LDL: Principal apoproteins of VLDL, IDL and LDL is
apo-B- 100. They also contain apo-C (C-I, C-II and C-III), and apo-E.
IDL carries some apo-E apoprotein.
.Apo-E: Arginine rich apo-E, isolated from VLDL

:Chylomicrons

Chylomicrons are assembled in the intestinal mucosa as a means to

transport dietary cholesterol and TGs to the rest of the body.
Chylomicrons are, therefore, the molecules formed to mobilize dietary
exogenous lipids. The predominant lipids of chylomicrons are TGs
(which contain long chain fatty acids). The apolipoproteins that
predominate before the chylomicrons enter the circulation include apoB-
48 and apoA . ApoB-48 combines only with chylomicrons, The surface is
a layer of phospholipids, with head groups facing the aqueous phase.
Triacylglycerols sequestered in the interior (yellow) make up more than
80% of the mass. Nascent chylomicrons formed in the intestinal mucosa
are secreted into the lymphatic system and enter the circulation at the left
subclavian vein through the thoracic duct. In the bloodstream,
chylomicrons acquire apoC-II and apoE from plasma HDLs. In the
capillaries of adipose tissue and muscle, the fatty acids of chylomicrons
are removed from the TG by the action of lipoprotein lipase (LPL), which
is found on the surface of the endothelial cells of the capillaries. The
apoC-II in the chylomicrons activates LPL in the presence of
phospholipids and returns to HDL. The free fatty acids are then absorbed
by the tissues and the glycerol backbone of the TG is returned, via the
.blood, to the liver and kidneys

Chylomicron remnants: containing primarily cholesterol, apoE and

apoB-48 are then delivered to and taken up by the liver through
interaction with the chylomicron remnant receptor. The recognition of

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chylomicron remnants by the hepatic remnant receptor requires apoE.
Chylomicrons function to deliver dietary TG to adipose tissue and muscle
and dietary cholesterol to the liver for bile acid biosynthesis and the
.excess amount is excreted in bile

Lipoprotein Lipase:
Removal of fatty acids from chylomicrons and from VLDL requires
lipoprotein lipase, an enzyme located on the capillary walls. Lipoprotein
lipase requires Apo-CII and phospholipid as activators; VLDL and
chylomicrons have Apo-C-II, allowing the lipoprotein lipase to hydrolyze
the TG in these particles.

:Very Low-Density Lipoprotein (VLDL)

The dietary intake of both fat and carbohydrate, in excess of the needs of
the body, leads to their conversion into TGs in the liver. These TGs are
packaged into VLDLs and released into the circulation for delivery to the
various tissues (primarily muscle and adipose tissue) for storage or
production of energy through oxidation. VLDLs are, therefore, the
molecules formed to transport endogenously derived TGs to extra-
hepatic tissues. In addition to TGs, VLDLs contain some cholesterol and
cholesteryl esters and the apoproteins, apo-B-100, apo-C-I, apo-C-II, apo-
C-III and apo-E. Like nascent chylomicrons, newly released VLDLs
acquire apoCs and apoE from circulating HDLs.
The fatty acid portion of VLDLs is released to adipose tissue and
muscle in the same way as for chylomicrons, through the action of
lipoprotein lipase; glycerol is also released as mentioned above. The
action of lipoprotein lipase coupled to a loss of certain apoproteins (the
apo-Cs) converts VLDLs to intermediate density lipoproteins (IDLs),
also termed VLDL remnants. The apo-Cs are transferred to HDLs. The

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predominant remaining proteins are apo-B-100 and apo-E. Further loss of
. TGs converts IDLs to LDL

:Intermediate Density Lipoproteins, IDLs

IDLs are formed as TGs are removed from VLDLs and are enriched in
cholesterol (45%) which they deliver to peripheral tissues or to the liver.
The fate of IDLs is either conversion to LDLs or direct uptake by the
liver. Conversion of IDLs to LDLs occurs as more TGs are removed. The
liver takes up IDLs after they have interacted with the LDL receptor to
.form a complex, which is endocytosed by the cell

:Low Density Lipoproteins, LDLs

IDL is converted to LDL, largely by the liver, by removal of additional
TGs. In addition to its formation from VLDL, some LDL is produced and
released by the liver. LDL is a major transport form of cholesterol and
cholesteryl esters to extrahepatic tissues. LDL has specific cell surface
receptors. The receptor-LDL complex is transported to lysosomes, for
degradation of the particle, while most of the LDL receptors are recycled
to the cell surface. High levels of LDL-cholesterol are associated with
elevated risk of heart disease; therefore LDL-cholesterol is the “bad
cholesterol”.

-:High-Density Lipoproteins, HDLs

HDLs are synthesized de novo in the liver and small intestine, as
primarily protein-rich disc-shaped particles. The primary apoproteins of
HDLs are apo-A-I, apo-C-I, apo-C-II and apo-E. In fact, a major function
of HDLs is to act as circulating stores of apo-C-I, apo-C-II and apo-E.
HDLs are converted into spherical lipoprotein particles through the
accumulation of cholesteryl esters. This accumulation converts nascent

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HDLs to HDL2 and HDL3. Any free cholesterol presents in chylomicron
remnants and VLDL remnants (IDLs) can be esterified through the action
of the HDL-associated enzyme, lecithin: cholesterol acyltransferase,
LCAT. LCAT is synthesized in the liver generating a cholesteryl ester
and lysolecithin. The activity of LCAT requires interaction with apo-A-I,
which is found on the surface of HDLs,

Cholesterol-rich HDLs return to the liver, where they are endocytosed.

Hepatic uptake of HDLs, or reverse cholesterol transport, may be
mediated through an HDL-specific apo-A-I receptor or through lipid-lipid
interactions.

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 Lipoprotein (a) [LP(a)]
It is a special type of lipoprotein not present in all people. Normal LP (a)
is not present in the serum in detectable amounts. In 20 per cent of
normal individuals, if present, it is found to be more than 30 mg/dl. When

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present, it is attached to apo-B100 by a disulfide bond. The persons
having LP (a) are more susceptible to heart attack at the
younger age group of 30 to 40 years. LP (a) inhibits
fibrinolysis. Levels more than 30 mg/dl increases the risk of
myocardial infarction by 3 times and when the increased LP (a)
level is associated with increased LDL, the risk for myocardial
infarction increases further.
Treatment of

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