LIPOPROTEIN METABOLISM

Metabolism of chylomicrons
Synthesis
1. In the smooth endoplasmic reticulum of intestinal
mucosal cells trigly cerides (TG) and cholesterol (C)
formed from dietary fat are coated with phospholipids
(PL) and apoA-I, A-II and apo B-48 to generate
chylomicrons.
2. These chylomicrons then emerge from enterocyte into
lymphatics.
3. Chylomicron that enters lymphatics from intestine is
called as nascent chylomicron.
4. Through the thoracic duct nascent chylomicrons
enters blood.
5. In the circulation nascent chylomicrons combines with
apo C and apo E to form mature chylomicrons.
Formation and secretion of chylomicrons
The TAG is produced in the
(SER) of intestinal epithelial cells
from the digestive products, FAs,
and 2-MAGs.

The protein is synthesized in the

rough endoplasmic reticulum
(RER).

 The major apoprotein in

chylomicrons is B-48.

Assembly of the lipoproteins

occurs in both the ER and the
Golgi complex.
 Degradation (Fate of chylomicrons )
• Chylomicrons are synthesized in intestinal epithelial
cells, secreted into the lymph, pass into the blood,
and become mature chylomicrons.
• On capillary walls in adipose tissue and muscle,
lipoprotein lipase (LPL) activated by ApoCII digests
the triacylglycerols (TG) of chylomicrons to fatty
acids and glycerol.
• Fatty acids (FA) are oxidized in muscle or stored in
adipose cells as triacylglycerols.
• The remnants of the chylomicrons are taken up by the
liver by receptor-mediated endocytosis.
• Lysosomal enzymes within the hepatocyte digest the
remnants, releasing the products into the cytosol.
Degradation (Fate of chylomicrons )
 Metabolism of VLDL
Synthesis
1. Liver mainly synthesizes VLDL.
2. In hepatocytes, synthesized triglycerides
combines with phospholipids, cholesterol and
apo B-100 to generate VLDL.
3. This VLDL is called as nascent VLDL.
4. Nascent VLDL are secreted into hepatic
sinusoids and from there they enters
circulation.
5. Addition of apo C and apo E in the circulation
generates mature VLDL from nascent VLDL.
 Degradation
1. VLDL are rapidly removed from circulation by
extra hepatic tissues.
2. Action of lipoprotein lipase on VLDL results in
the loss of triglycerides and apo C.
3. Free fatty acids and glycerol are metabolized.
4. Loss of triglycerides and apo C results in the
formation of intermediate density lipoproteins
(IDL) or VLDL remnants.
5. Only one IDL particle is formed from each of
VLDL particle.
6. In humans, most of the VLDL remnants are taken
up by the liver and converted to LDL. Uptake is
through the apo E receptor mechanism.
7. However, LDL may be generated in the circulation
from IDL by removing apo E
Degradation
 Metabolism of VLDL

Hepatic triacylglycerol lipase (HTGL),

 Metabolism of LDL

Synthesis
1. Liver directly produces LDL. It is also formed
from IDL in the circulation.
2. In the liver, synthesized cholesterol
combines with triglycerides, phospholipids
and apoproteins to generates LDL.

Apo B is the only apoprotein used for LDL

formation.
 Degradation
 Each day, 50% of LDL is removed from circulation. Extra
hepatic tissues removes half of this and remainder is
removed by liver.

The uptake of LDL by extra hepatic tissues is mediated by cell

surface receptor. Apo B-100 of LDL is recognized by the
receptor
and LDL binds to the receptor. Then the LDL particles are
taken up by endocytosis.

With in the cells LDL are broken down by lysosomal enzymes.

Cholesterolesters and apo proteins are hydrolyzed by

lysosomal hydrolases. Free cholesterol released may be
reesterified. It regulates intra cellular cholesterol synthesis.

Uptake of LDL by liver is mediated through a specific LDL

receptor. In the liver, free cholesterol released may be
esterified and apoprotein is hydrolyzed to amino acids.
 METABOLISM OF HDL

Synthesis
1. Liver mainly synthesizes HDL and
intestine synthesizes to some extent.
2. HDL secreted by liver (intestine) is called
as nascent HDL and is composed of
cholesterol,phospholipid and apo A, apo C
and apo E.
3. In plasma cholesterol of HDL is esterified by
LCAT. (Apo A-I activates LCAT)
4. LCAT system is also involved in the removal
of free cholesterol from extra hepatic tissues.
Degradation
1. The exact fate of HDL remains uncertain. It
is a subject of intensive research.
2. However, three fates for HDL have been
identified.
3. HDL may transfer cholesterolesters to other
lipoproteins like VLDL, LDL.
 It is called as cholesterolester transfer protein.
The cholesterolester of LDL or VLDL is taken
up by liver. Thus HDL mainly function as tissue
cholesterol scavenging agent.
 Since HDL removes free cholesterol from extra
hepatic cells the incidence of atherosclerosis
or coronary artery disease (CAD) is inversely
related to plasma HDL concentration.
4. Some HDL is taken up by liver directly through
apo E receptor and is metabolized.
5. Some HDL is converted to HDL2 and taken up
by liver. Hepatic lipase releases free
cholesterol from HDL2 for uptake into the liver.
METABOLISM OF HDL
 Medical Importance

• Plasma lipoproteins are altered in several

diseases.
 Lipoproteinemias
(Dyslipoproteinemias)
 They are groups of genetic disorders associated
with increased or decreased lipoproteins in
plasma.
 They are mainly due to defects in either
production, transport or catabolism of
lipoproteins.
 They are of two types.
1. Hypolipoproteinemias: in which plasma
lipoprotein is decreased.
2. Hyperlipoproteinemias: in which plasma
lipoprotein is increased.
 HYPOLIPOPROTEINEMIAS
A beta lipoproteinemia
1. This condition is due to block in apo B
production.
2. Since apo B is required for VLDL and
chylomicron their formation is affected.
Further LDL formation is also affected.
Hence, LDL, chylomicrons and VLDL are absent
in plasma.
3. Plasma triglyceride and cholesterol levels are
low.
4. Triglycerides accumulates in liver and intestine
due to lack of chylomicrons and VLDL.
 Bassen-Kornzweig syndrome

1. It resembles abeta lipoproteinemia.

2. Plasma triglyceride and cholesterol levels

are low and they accumulates in tissues.

3. Characteristic symptoms are

acanthocytosis (spike like projections on
erythrocytes),
A typical retinitis and extensive demyelination.
Familial hypo beta lipoproteinemia

1. The condition is characterized by low LDL

and normal chylomicron levels in plasma.

2. It is not a serious condition. Affected

individuals are normal and healthy.

3. Plasma cholesterol level is low.

 Familial alpha-lipoprotein deficiency
(Tangier disease)
1. It was first identified in Tangier island. The
condition is characterized by the absence of
HDL in plasma.
2. HDL formation is impaired due to lack of apo
C-II.
3. Cholesterolesters accumulate in the tissues
and plasma, cholesterol level is low.
4. Symptoms are hepato splenomegaly due to
accumulation of cholesterol and orange
yellow tonsils.
 HYPER LIPOPROTEINEMIAS
(LIPIDEMIAS)
Type-I hyper lipoproteinemia
1. Lipoprotein lipase is deficient in this condition.
2. It is a rare condition and deficiency of lipoprotein
lipase is due to decreased formation of apo C-II,
which is required for its activity.
3. LPL deficiency impairs chylomicron clearance
from plasma. As a result,chylomicron
accumulates in plasma (hyper chylomicronemia).
4. Plasma triglycerides and cholesterol levels are
elevated.
5. Xanthomas (collection of lipids in skin or tendon
sheaths), abdominal pain are common symptoms
in this condition.
Type-II hyper lipoproteinemia or Familial
hyper cholesterolemia
1. It is most common among others.
2. It is due to slow clearance of LDL from
circulation owing to defective LDL receptors.
3. Plasma LDL, triglycerides and cholesterol
level are elevated.
4. Severe xanthomas and deposition of lipid in
tissues are major features.
Hence, this condition is associated with
atherosclerosis and coronary artery disease.
5. Feeding of diet containing PUFA is beneficial
to these individuals.
 Wolman disease
1. It is a rare genetic disorder.
2. Lysosomal acid lipase, which hydrolyzes
cholesterolester and triglyceride is absent in
this condition.
3. Plasma LDL level is elevated,
cholesterolester accumulates in tissues.
4. It is fatal condition and death can occur in
the first six months of life.
 Familial hyper lipoproteinemia (Broad
beta disease)
1. It is a rare condition, in which chylomicron
catabolism is impaired.
2. In this condition production of apo E is defective
and conversion of VLDL remnants to LDL is also
impaired.
3. Hence, both chylomicrons and VLDL remnants are
more in plasma and condition is referred as
remnant disease. Plasma cholesterol and
triglceride levels are elevated.
4. Symptoms are xanthomas and atherosclerosis.
 Familial hyper triacylglycerolemia

1. The condition is characterized by

increased triglycerides and cholesterol in
blood (Endogenous hyperlipidemia).
2. The biochemical defect in this disorder is
not clear.
3. The condition may progress to
atherosclerosis.
 Familial hyper lipoproteinemia

1. In this condition, both chylomicrons and

VLDL are elevated in plasma.
2. Apo B is over produced and plasma
cholesterol and triglyceride levels are
elevated.
3. Xanthoma is the main symptom.
 LCAT deficiency
1. A familial deficiency of this enzyme has been
reported.
2. Lecithin and cholesterol levels are high in plasma.
3. Symptoms are accumulation of free cholesterol
in erythrocytes, corneal infiltration, hemolytic
anemia and kidney damage.

 In addition to the above, hyper lipoproteinemias

also manifest as secondary complication of
diseases like diabetes, atherosclerosis, excessive
use of oral contraceptives, hypothyroidism and
nephrotic syndrome.
 Fatty livers
1. Liver contains about 5% lipid. Of this, about
1/4 is triglyceride.
2. Extensive accumulation of lipid in the liver
leads to condition known as fatty liver.
 In the fatty livers, the lipid content
increases to 25-30%.
 Further, triglycerides and fatty acid may
occupy entire cytoplasm of hepatocyte.
 Several factors causes
accumulation of lipid in liver
1. Raised plasma free fatty acid level
2. Metabolic block in the production of
lipoproteins
3. Toxic substances :Several hepato toxic
agents like carbon tetrachloride, chloroform,
phosphorus, lead, arsenic,alcohol and orotic
acid causes fatty liver.
4. Substances, which inhibit protein synthesis
like puromycin and ethionine, a methionine
analog also cause fatty liver.
 Medical Importance

Effect of fatty liver

• When accumulation of lipid in liver

becomes chronic, fibrotic changes takes
place in hepatocytes, which progress to
cirrhosis and finally impaired liver function.