Lipoproteins- structure, classification, metabolism and clinical significance

Lipoproteins- Structure, classification,
metabolism and significance

Biochemistry for Medics
www.namrata.co
12/22/13

Biochemistry for medics

1

Lipids absorbed from the diet and synthesized by the

liver and adipose tissue must be transported between
various cells and organs for utilization and storage.
Lipids are insoluble in water, the problem of
transportation in the aqueous plasma is solved by
associating nonpolar lipids (triacylglycerols and
cholesteryl esters) with amphipathic lipids
(phospholipids and cholesterol) and proteins to make
water-miscible lipoproteins.

General Structure of Lipo proteins
Lipoproteins consist of a nonpolar core and a single

surface layer of amphipathic lipids
The nonpolar lipid core consists of mainly
triacylglycerol and cholesteryl ester and is
surrounded by a single surface layer of
amphipathic phospholipid and cholesterol
molecules
These are oriented so that their polar groups face
outward to the aqueous medium.
The protein moiety of a lipoprotein is known as an
apolipoprotein or apoprotein.

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General Structure of Lipo proteins

Some apolipoproteins are integral and cannot be removed, whereas others
can be freely transferred to other lipoproteins.
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4

Classification of Lipoproteins
Lipoproteins can be classified in three ways1) Based on density- They are separated by
Ultracentrifugation. Depending upon the floatation
constant (Sf), Five major groups of lipoproteins have
been identified that are important physiologically and
in clinical diagnosis.
(i) Chylomicons, derived from intestinal absorption of
triacylglycerol and other lipids; Density is generally
less than 0.95 while the mean diameter lies between
100- 500 nm
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1) Based on density (contd.)

(ii) Very low density lipoproteins (VLDL), derived
from the liver for the export of triacylglycerol;
density lies between 0.95- 1.006 and the mean
diameter lies between 30-80 nm.
(iii) Intermediate density lipoproteins (IDL) are
derived from the catabolism of VLDL,with a density
ranging intermediate between Very low density and
Low density lipoproteins i.e. ranging between 1.0061.019 and the mean diameter ranges between 2550nm.
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Based on density (contd.)
iv) Low-density lipoproteins (LDL), representing a
final stage in the catabolism of VLDL; density lies
between 1.019-1.063 and mean diameter lies between
18-28 nm
(iv) High-density lipoproteins (HDL), involved in
cholesterol transport and also in VLDL and
chylomicron metabolism. Density ranges between
1.063-1.121 and the mean diameter varies between 5-15
nm.
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Lipoproteins with high lipid content will have low density, larger
size and so float on centrifugation. Those with high protein
content sediment easily, have compact size and have a high
density.
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2) Based on electrophoretic mobilities
Lipoproteins may be separated according to their
electrophoretic properties into - α, pre β, β, and
broad beta lipoproteins.
The mobility of a lipoprotein is mainly dependent
upon protein content.
Those with higher protein content will move faster
towards the anode and those with minimum protein
content will have minimum mobility.
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9


Lipoproteins may be separated according to their
electrophoretic properties into - α, pre β, β, and broad
beta lipoproteins.
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2) Based on electrophoretic mobilities (contd.)
HDL are -α , VLDL pre- β, LDL-β , and IDL are broad
beta lipoproteins.
Free fatty acid and albumin complex although not a
lipoprotein is an important lipid fraction in serum
and is the fastest moving fraction.
Chylomicrons remain at the origin since they have
more lipid content.
VLDLs with less protein content than LDL move
faster than LDL, this is due to nature of apoprotein
present.
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As the lipid content increases, density decreases and size increases, that
is why Chylomicrons are least dense but biggest in size, while HDL are
rich in proteins , hence most dense but smallest in size.
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3) Based on nature of Apo- protein content
 One or more apolipoproteins (proteins or polypeptides)
are present in each lipoprotein.
 The major apolipoproteins of HDL (α-lipoprotein) are
designated A.
 The main apolipoprotein of LDL (β -lipoprotein) is
apolipoprotein B (B-100), which is found also in VLDL.
 Chylomicons contain a truncated form of apo B (B-48)
that is synthesized in the intestine, while B-100 is
synthesized in the liver.
 Apo E is found in VLDL, HDL, Chylomicons, and
chylomicron remnants.
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Functions of Apo proteins
(1) They can form part of the structure of the
lipoprotein, e.g. apo B, structural component of VLDL
and Chylomicons
(2) They are enzyme cofactors, e.g. C-II for lipoprotein
lipase, A-I for lecithin: cholesterol acyl transferase
(LCAT), or enzyme inhibitors, eg, apo A-II and apo CIII for lipoprotein lipase, apo C-I for cholesteryl ester
transfer protein
(3) They act as ligands for interaction with lipoprotein
receptors in tissues, e.g. apo B-100 and apo E for the
LDL receptor, apo A-I for the HDL receptor.
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Metabolism of chylomicrons
 Chylomicrons are found in chyle formed only by the

lymphatic system draining the intestine.
 They are responsible for the transport of all dietary lipids
into the circulation.
Synthesis of Chylomicrons
1) Synthesis of Apo B48
 Chylomicrons contain Apo B48, synthesized in the
rough endoplasmic reticulum (RER).
 The synthesis of apo B48 is the result of RNA editing
process.
 Coding information can be changed at the mRNA level
by RNA editing.
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The synthesis of apo B48 is the result of RNA editing
process.
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In liver, the single apo B gene is transcribed into an mRNA
that directs the synthesis of a 100-kDa protein, apoB100.
In the intestine, the same gene directs the synthesis of the
primary transcript; however, a Cytidine deaminase
converts a CAA codon in the mRNA to UAA at a single
specific site.
Rather than encoding glutamine, this codon becomes a
termination signal, and a 48-kDa protein (apoB48) is the
result.
ApoB100 and apoB48 have different functions in the two
organs
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Apolipoprotein B,
synthesized in the
RER, is incorporated
into lipoproteins in the
SER, the main site of
synthesis of
triacylglycerol.
After addition of
carbohydrate residues
in G, they are released
from the cell by reverse
pinocytosis.
Chylomicrons pass
into the lymphatic
system.

Clinical Significance- In Abetalipoproteinemia (a rare disease),
lipoproteins containing apo B are not formed and lipid droplets
accumulate in the intestine and liver(Due to non formation of VLDL)
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18

Synthesis of Chylomicrons (contd.)
2) Synthesis of lipids and formation of lipoprotein
Long-chain fatty acids are esterified to yield to triacylglycerol in
the mucosal cells and together with the other products of lipid
digestion, are incorporated into lipoproteins in the SER, the
main site of synthesis of triacylglycerol.
3) Addition of Carbohydrate-Carbohydrate residues are added
in the golgi apparatus.
4) Release of Chylomicrons- After addition of carbohydrate
residues in golgi apparatus, they are released from the cell by
reverse pinocytosis.
5) Transportation of Chylomicrons- Chylomicrons pass into the
lymphatic system and eventually enter the systemic circulation.

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Catabolism of Chylomicrons
Chylomicrons are acted upon by the enzyme

lipoprotein lipase .
Reaction with lipoprotein lipase results in the
loss of approximately 90% of the triacylglycerol of
chylomicrons and in the loss of apo C (which
returns to HDL) but not apo E, which is retained.
The resulting chylomicron remnant is about
half the diameter of the parent chylomicron and
is relatively enriched in cholesterol and
cholesteryl esters because of the loss of
triacylglycerol.
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Chylomicron remnants are taken up by the liver by

receptor-mediated endocytosis, and the cholesteryl
esters and triacylglycerols are hydrolyzed and
metabolized.
Uptake is mediated by apo E .
Hepatic lipase has a dual role: (1) it acts as a ligand to
facilitate remnant uptake and (2) it hydrolyzes
remnant triacylglycerol and phospholipid.
The products released are re utilized for the synthesis
of VLDL.
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Metabolism of VLDL
There are striking similarities in the mechanisms of

formation of chylomicrons by intestinal cells and of
VLDL by hepatic parenchymal cells
Apart from the mammary gland, the intestine and
liver are the only tissues from which particulate lipid
is secreted.
Newly secreted or "nascent" VLDL contain only a
small amount of apolipoproteins C and E, and the full
complement is acquired from HDL in the circulation
Apo B 100 is essential for VLDL formation.
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23

Metabolism of VLDL

VLDL are secreted into the space of Disse and then into
the hepatic sinusoids through fenestrae in the
endothelial lining. for medics
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24
Biochemistry

Catabolism of VLDL
Catabolism of VLDL is similar to chylomicrons
Both phospholipids and apo C-II are required as

cofactors for lipoprotein lipase activity, while apo A-II and
apo C-III act as inhibitors.
Hydrolysis takes place while the VLDLs are attached to
the enzyme on the endothelium.
Triacylglycerol is hydrolyzed progressively through a
diacyl glycerol to a monoacylglycerol and finally to free
fatty acids plus glycerol.
Some of the released free fatty acids return to the
circulation, attached to albumin, but the bulk is
transported into the tissue .
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Catabolism of VLDL
 Reaction with lipoprotein lipase results in the loss of approximately

90% of the triacylglycerol of VLDLs and in the loss of apo C (which
returns to HDL) but not apo E, which is retained.
 These changes occurring to VLDL, lead to the formation of VLDL
remnants or IDL (intermediate-density lipoprotein)
 After metabolism to IDL, VLDL may be taken up by the liver directly
via the LDL (apo B-100, E) receptor, or it may be converted to LDL.
 Only one molecule of apo B-100 is present in each of these lipoprotein
particles, and this is conserved during the transformations.
 Thus, each LDL particle is derived from a single precursor VLDL
particle.
 In humans, a relatively large proportion of IDL forms LDL, accounting
for the increased concentrations of LDL in humans compared with
many other mammals.
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Metabolism of LDL
The liver and many extra hepatic tissues express the LDL

(apo B-100, E) receptor.
It is so designated because it is specific for apo B-100 but
not B-48, which lacks the carboxyl terminal domain of B100 containing the LDL receptor ligand, and it also takes
up lipoproteins rich in apo E.
This receptor is defective in familial
hypercholesterolemia.
Approximately 30% of LDL is degraded in extra-hepatic
tissues and 70% in the liver.
A positive correlation exists between the incidence of
coronary atherosclerosis and the plasma concentration
of LDL cholesterol.
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Metabolism of VLDL
The liver and many

extrahepatic tissues
express the LDL (apo B100, E) receptor.
It is so designated
because it is specific for
apo B-100
 but not B-48, which
lacks the carboxyl
terminal domain of B-100
containing the LDL
receptor ligand,
 and it also takes up
lipoproteins rich in apo E.
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28

Metabolism of HDL
Synthesis of HDL
HDL is synthesized and secreted from both liver and
intestine .
However, apo C and apo E are synthesized in the liver
and transferred from liver HDL to intestinal HDL
when the latter enters the plasma.
A major function of HDL is to act as a repository for
the apo C and apo E required in the metabolism of
chylomicrons and VLDL.
Nascent HDL consists of discoid phospholipid bilayer
containing apo A and free cholesterol.
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Metabolism of HDL
LCAT and the LCAT activator apo A-I—bind to the

discoidal particles, and the surface phospholipid and
free cholesterol are converted into cholesteryl esters
and lysolecithin .
The nonpolar cholesteryl esters move into the
hydrophobic interior of the bilayer, whereas
lysolecithin is transferred to plasma albumin.
Thus, a nonpolar core is generated, forming a spherical,
pseudomicellar HDL covered by a surface film of polar
lipids and apolipoproteins.
This aids the removal of excess unesterified cholesterol
from lipoproteins and tissues .
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Metabolism of HDL
Role of LCAT
LCAT( Lecithin Cholesterol Acyl Transferase) enzyme
catalyzes the esterification of cholesterol to form
Cholesteryl ester. The reaction can be represented as
followsLecithin + Cholesterol
Lysolecithin +
Cholesteryl Ester

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31

Reverse cholesterol transport
The cholesterol

efflux is brought
about by
esterification of
cholesterol under
the effect of LCAT.
The cholesteryl

ester rich HDL
(HDL2) gains entry
through Scavenger
receptor (SR-B1)

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Metabolism of HDL
The class B scavenger receptor B1 (SR-B1) has been

identified as an HDL receptor with a dual role in
HDL metabolism.
 In the liver and in steroidogenic tissues, it binds HDL
via apo A-I, and cholesteryl ester is selectively
delivered to the cells, although the particle itself,
including apo A-I, is not taken up.
In the tissues, on the other hand, SR-B1 mediates the
acceptance of cholesterol from the cells by HDL,
which then transports it to the liver for excretion via
the bile (either as cholesterol or after conversion to
bile acids) in the process known as reverse
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cholesterol transport

HDL- cycle
HDL3, generated from discoidal HDL by the action of

LCAT, accepts cholesterol from the tissues via the SRB1 and the cholesterol is then esterified by LCAT,
increasing the size of the particles to form the less
dense HDL2.
HDL3 is then reformed, either after selective delivery of

cholesteryl ester to the liver via the SR-B1 or by
hydrolysis of HDL2 phospholipid and triacylglycerol by
hepatic lipase. This interchange of HDL2 and HDL3 is
called the HDL cycle.
Free apo A-I is released by these processes and forms
pre -HDL after associating with a minimum amount of
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Metabolism of HDL
 A second important mechanism for reverse

cholesterol transport involves the ATP-binding
cassette transporter A1 (ABCA1).
ABCA1 is a member of a family of transporter proteins
that couple the hydrolysis of ATP to the binding of a
substrate, enabling it to be transported across the
membrane.
ABCA1 preferentially transfer cholesterol from cells to
poorly lipidated particles such as pre -HDL or apo A-1,
which are then converted to HDL3 via discoidal HDL
Pre -HDL is the most potent form of HDL inducing

cholesterol efflux from the tissues.

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Functions of HDL
Scavenging action- HDL scavenges extra cholesterol

from peripheral tissues by reverse cholesterol
transport
HDL, with the help of apo E competes with LDL for
binding sites on the membranes and prevents
internalization of LDL cholesterol in the smooth cells
of the arterial walls
HDL contributes its apo C and E to nascent VLDL and
chylomicrons for receptor mediated endocytosis
HDL stimulated prostacyclin synthesis by the
endothelial cells, which prevent thrombus formation
HDL also helps in the removal of macrophages from
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36
Biochemistry
the arterial walls . for medics

Summary of formation and fate of
lipoproteins
Chylomicrons is a

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transporter of
dietary lipids
whereas VLDL is a
transporter of
endogenous
lipids(mainly TGs).
 LDL transports
cholesterol to
peripheral cells while
HDL transports
cholesterol from
peripheral cells back
37
to liver.

Role of HDL in receptor mediated
endocytosis

HDL contributes its apo C and E to nascent VLDL and
chylomicrons for receptor mediated endocytosis
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Clinical Significance of lipoprotein
metabolism
Fatty Liver
is an abnormal accumulation of certain fats
(triglycerides) inside liver cells.
Hepatic triacylglycerol synthesis provides the
immediate stimulus for the formation and secretion
of VLDL.
 Impaired VLDL formation or secretion leads to
nonmobilization of lipid components from the liver,
results in fatty liver.
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Fatty Liver (contd.)
Fatty livers fall into two main categoriesA)More synthesis of Triglycerides
High carbohydrate diet
High fat feeding
Starvation
Diabetes mellitus
High carbohydrate diet stimulates de novo fatty acid
synthesis by providing excess of Acetyl CoA and high
fat feeding provides more flux of fatty acids from the
diet that can be esterifies to provide excess
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triglycerides.Biochemistry for medics

40

B) Defective VLDL synthesis -The second type of fatty liver is
usually due to a metabolic block in the production of plasma
lipoproteins, thus allowing triacylglycerol to accumulate.
The lesion may be due to –
(1)A block in apolipoproteins synthesis
a) Protein energy Malnutrition
b) Impaired absorption
c) Presence of inhibitors of endogenous protein synthesis e.g.Carbon tetra chloride, Puromycin, Ethionine , Heavy metals etc.
d) Hypobetalipoproteinemia- Defective apo B gene can cause
impaired synthesis of apo B protein.
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(2) A failure in provision of phospholipids that are
found in lipoproteins
a)A deficiency of choline, a lipotropic factor can
cause impaired formation of phosphatidyl choline
(Lecithin),a glycerophospholipid.
b)Methionine deficiency can also cause impaired
choline synthesis
c) Inositol deficiency
d)Deficiency of essential fatty acids can also cause
impaired PL synthesis
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(3) Impaired Glycosylation- Orotic acid also causes
fatty liver; it interferes with glycosylation of the
lipoprotein, thus inhibiting release, and may also
impair the recruitment of triacylglycerol to the
particles. In conditions of orotic aciduria(disorder of
pyrimidine nucleotide biosynthesis), fatty liver can be
observed.
4) Impaired secretion of VLDL- oxidative stress is a
common cause for membrane disruption of
lipoproteins.
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2) Alcoholic fatty liver
Alcoholism leads to fat accumulation in the liver,
hyperlipidemia, and ultimately cirrhosis.
 The fatty liver is caused by a combination of impaired
fatty acid oxidation and increased lipogenesis, which
is thought to be due to changes in the [NADH]/
[NAD+] redox potential in the liver,
 and also to interference with the action of
transcription factors regulating the expression of the
enzymes involved in the pathways.
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Fatty Liver and Lipotropic agents
Lipotropic agents- Agents such as Choline
Inositol
 Methionine and other essential amino acids,
 Essential fatty acids,
Anti oxidant vitamins,
 Vitamin B12, folic acid and
 Synthetic antioxidants which have the apparent
effect of removal of fats from the liver cells, and thus
prevent the formation of fatty liver are called
lipotropic agents. for medics
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Biochemistry

46

Primary Disorders of Plasma Lipoproteins
(Dyslipoproteinemias)
Inherited defects in lipoprotein metabolism lead to

the primary condition of either hypo- or
hyperlipoproteinemia .
 In addition, diseases such as diabetes mellitus,
hypothyroidism, nephrotic syndrome, and
atherosclerosis are associated with secondary
abnormal lipoprotein patterns that are very similar to
one or another of the primary inherited conditions.
All of the primary conditions are due to a defect at a
stage in lipoprotein formation, transport, or
degradation.
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47

Name

Defect

Characteristics

Abetalipoproteinemia

No chylomicrons, VLDL,
or LDL are formed
because of defect in the
loading of apo B with
lipid.

Rare; blood acylglycerols
low; intestine and liver
accumulate acylglycerols.
Intestinal malabsorption.

Familial alphalipoprotein deficiency

All have low or near
absence of HDL.

Hypertriacylglycerolemia
due to absence of apo CII, Low LDL levels.
Atherosclerosis in the
elderly.

Hypolipoproteinemias

Tangier disease
Fish-eye disease
Apo-A-I deficiencies
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48

Name

Defect

Characteristics

Familial lipoprotein
lipase deficiency (type I)

due to deficiency of LPL,
abnormal LPL, or apo CII deficiency causing
inactive LPL.

Slow clearance of
chylomicrons and VLDL.
Low levels of LDL and
HDL. No increased risk
of coronary disease.

Familial
hypercholesterolemia
(type II a)

Defective LDL receptors
or mutation in ligand
region of apo B-100.

Elevated LDL levels and
hypercholesterolemia,
resulting in
atherosclerosis and
coronary disease.

Hyperlipoproteinemia

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(Dyslipoproteinemias)- contd.
Name

Defect

Characteristics

Familial type III
hyperlipoproteinemia
(broad beta disease,
remnant removal disease,
familial
dysbetalipoproteinemia)

Deficiency in remnant
clearance by the liver is
due to abnormality in
apo E.

Increase in chylomicron
and VLDL remnants ,
Causes
hypercholesterolemia,
xanthomas, and
atherosclerosis.

Familial
(type IV)

Overproduction of VLDL
often associated with
glucose intolerance and
hyperinsulinemia.

High cholesterol, VLDL,
Subnormal LDL and
HDL. Associated with
Alcoholism, diabetes
mellitus and obesity.

Hepatic lipase deficiency

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Deficiency of the enzyme Patients have xanthomas
leads to accumulation of and coronary heart
large triacylglycerol-rich disease.
HDL and VLDL remnants
50

Atherosclerosis
Read the details at

http://www.namrata.co/atherosclerosis-a-review-power-poin

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51

For further details
Refer

A Case Oriented Approach Towards Biochemistry
by: Namrata Chhabra, Sahil Chhabra
http://www.jaypeedigital.com/BookDetails.aspx?id=9789350
And visit our web sitehttp://www.namrata.co/category/metabolism-lipids/subject

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52

Lipoproteins- structure, classification, metabolism and clinical significance

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