Synthesis and catabolism of lipoproteins; dyslipoproteinaemia

1. Metabolism of Lipoproteins
R. C. Gupta
Professor and Head
Department of Biochemistry
National Institute of Medical Sciences
Jaipur, India

2. As lipids are hydrophobic, they are not
soluble in the aqueous medium of plasma
For transport in blood, they have to be
made water-soluble
The lipids are solubilized by converting
them into lipoproteins

4. In lipoproteins, more hydrophobic lipids,
e.g. triglycerides and cholesteryl esters,
are present in the interior
These are surrounded by amphipathic
lipids e.g. phospholipids and free
cholesterol

6. The apoproteins present in
lipoproteins are:
• Apo A-I
• Apo A-II
• Apo B-48
• Apo B-100
• Apo C-I
• Apo C-II
• Apo C-III
• Apo D
• Apo E

8. The plasma lipoproteins
are classified into:
Chylomicrons (CM)
Very low density lipoproteins (VLDL)
Low density lipoproteins (LDL)
High density lipoproteins (HDL)

9. Lipoproteins are classified on the basis of
their relative density (specific gravity)
Chylomicrons have the lowest density
High-density lipoproteins have the highest
density

11. CM and VLDL are rich in triglycerides
LDL is rich in cholesterol
HDL is rich in phospholipids and
cholesterol

13. The apoproteins in CM are Apo A-I, A-II,
B-48, C-I, C-II, C-III and E
The apoproteins in VLDL are Apo B-100,
C-I, C-II, C-III and E
The only apoprotein present in LDL is Apo
B-100

14. There are different sub-classes of HDL
e.g. HDL1, HDL2 and HDL3
The apoprotein present in HDL1 is Apo E
HDL2 contains Apo A-I, C-I, C-II, C-III
and E
HDL3 contains Apo A-II and D

15. The common function of all lipoproteins is
to transport lipids in plasma
But each lipoprotein class has a specific
transport function
Functions of lipoproteins

16. Chylomicrons transport dietary triglycerides
from the intestine to peripheral tissues
VLDL transports endogenously synthesized
triglycerides from liver to peripheral tissues
LDL transports cholesterol from liver to
peripheral tissues
HDL transports excess cholesterol from
peripheral tissues to liver

17. Transport of cholesterol from peripheral
tissues to liver is known as reverse
cholesterol transport
This is a mechanism by which HDL
prevents accumulation of cholesterol in
peripheral tissues

18. Chylomicrons (CMs) are synthesized in
the intestinal mucosa
Apoproteins A and B-48 are synthesized
on ribosomes on the rough endoplasmic
reticulum in mucosal cells
These apoproteins enter the lumen of the
endoplasmic reticulum
Metabolism of chylomicrons

19. Apoproteins combine with triglycerides to
form ‘nascent chylomicrons’
Microsomal triglyceride transfer protein
incorporates apoproteins into chylomicrons
The nascent chylomicrons are transported
to Golgi apparatus
They are released from Golgi apparatus
into lacteals as secretory vacuoles

20. After reaching the circulation, nascent
chylomicrons receive apoproteins C and
E from HDL
After acquiring apo C and apo E, nascent
chylomicrons are converted into active
chylomicrons

21. Catabolism of chylomicrons occurs in
extra-hepatic tissues
These tissues possess lipoprotein lipase
which is normally inactive
This enzyme is really present on the
surface of endothelium of capillaries

22. Upon reaching extrahepatic tissues, the
apo C-II and phospholipids present in
chylomicrons activate lipoprotein lipase
Lipoprotein lipase hydrolyses the trigly-
cerides present in the chylomicrons

23. Free fatty acids released from trigly-
cerides are taken up by the tissues
Glycerol released from triglycerides goes
to liver via circulation
The hydrolysis continues until about 90%
of the triglycerides are broken down

24. With the loss of triglycerides, apo A and C
are transferred from chylomicrons to HDL
This converts chylomicrons into 'chylo-
micron remnants'
Chylomicron remnants enter liver cells via
a receptor specific for apo E
Chylomicron remnants are catabolized in
liver

26. Synthesis of VLDL is similar to that of
chylomicrons but the site of synthesis is liver
First, nascent VLDL is synthesized which
contains only apo B-100
It acquires apo C and E in circulation from
HDL, and is converted into VLDL
Metabolism of VLDL

27. VLDL carries the triglycerides of hepatic
origin to extrahepatic tissues
Lipoprotein lipase is activated by apo C-II
and phospholipids present in VLDL
Triglycerides are hydrolysed, and fatty
acids are taken up by the tissues

28. Catabolism of VLDL is also similar to that
of chylomicrons
After hydrolysis of a major portion of
triglycerides, apo C is transferred to HDL
This converts VLDL into VLDL remnants
or IDL (intermediate density lipoproteins)

29. Nearly half of the VLDL remnants are
taken up by liver cells
The uptake is mediated by an apo E-
specific receptor
These VLDL remnants are catabolized

30. The remaining VLDL remnants transfer
their apo E to HDL
This converts VLDL remnants into LDL

32. LDL is synthesized from circulating IDL
The only apoprotein present in LDL is B-100
Apo B-100 is a single long polypeptide chain
which is wrapped around the LDL particle
Only one molecule of apo B-100 is present
in one LDL particle
Metabolism of LDL

33. Reproduced with permission from Danton O’Day

34. LDL is rich in cholesterol and carries
cholesterol to different tissues
Cells that require cholesterol take up the
entire LDL
LDL receptors on the cell recognize apo
B-100 and bind LDL

35. The receptor-LDL complex enters the cell
by endocytosis
The lysosomal enzymes hydrolyse apo B-
100 and cholesteryl esters
Apo B-100 is hydrolysed into amino acids

36. Cholesteryl esters are hydrolysed to form
free cholesterol
Free cholesterol is used by the cell
The receptors which have become free
can return to the cell membrane

37. Synthesis of LDL receptors is subject to
regulation
When the cell needs cholesterol,
synthesis of LDL receptor increases
When the cell has sufficient cholesterol,
synthesis of LDL receptors stops

39. HDL is synthesized in liver and intestine
Newly synthesized HDL is known as
'nascent HDL’
Nascent HDL synthesized in liver
contains apo A-I, C-I, C-II, C-III and E
Metabolism of HDL

40. Nascent HDL formed in the intestine
contains only apo A-I
It acquires apo C and E after entering the
circulation

41. Nascent HDL is disc-shaped, and consists of
a phospholipid bilayer and apoproteins
It is capable of picking up cholesterol and
packing it in its interior
An enzyme, lecithin cholesterol acyl
transferase (LCAT) is also present on the
surface of HDL

42. After entering the circulation, HDL comes in
contact with tissue cells
It interacts with a cellular protein, ATP-
Binding Cassette Transporter A1 (ABCA1)
ABCA1 helps in the transfer of cholesterol
into HDL

43. LCAT is activated by apo A-I present in
nascent HDL
LCAT transfers a fatty acid from lecithin to
cholesterol
This converts them into lysolecithin and
cholesteryl ester respectively
Lysolecithin is released into circulation

44. Cholesteryl esters accumulate in the interior
and push the phospholipids outwards
This converts the disc-shaped particle into
spherical and mature HDL3
HDL3 takes up cholesterol from tissues and
from the circulating LDL and VLDL

45. Addition of cholesterol to HDL3 converts it
into HDL2
HDL2 transfers cholesterol to liver, and is
reconverted into HDL3
The HDL2-HDL3 cycle transports cholesterol
from extra-hepatic tissues to liver

46. Cholesteryl ester transfer protein (CETP)
is a protein secreted by tissues into blood
Most of the CETP in plasma is of hepatic
origin
CETP is also known as plasma lipid
transfer protein
It transfers lipids between different
lipoproteins

47. CETP causes exchange of cholesteryl
esters of HDL with triglycerides of LDL
and VLDL
LDL and VLDL would ultimately carry
these cholesteryl esters to the liver

49. Inherited disorders of lipoprotein
metabolism
Disorders of lipoprotein metabolism
result in dyslipoproteinaemia
Dyslipoproteinaemia comprises:
• Hypolipoproteinaemia
• Hyperlipoproteinaemia

50. This is a group of disorders in which the
concentration of one or more lipoproteins
in plasma is decreased
These disorders include: (i) abetalipo-
proteinaemia, (ii) hypobetalipoproteinaemia
and (iii) hypoalphalipoproteinaemia
Hypolipoproteinaemia

51. Abetalipoproteinaemia is a rare auto-
somal recessive disorder
Incorporation of lipids in the lipoproteins
containing apo B is defective
Hence, CMs, VLDL and LDL are absent
or greatly decreased in plasma
Abetalipoproteinaemia

52. Transport of dietary lipids from intestine
to various tissues is impaired
Availability of fatty acids is decreased
Synthesis of cholesterol, glycolipids and
sphingomyelin is decreased
Serum cholesterol and triglycerides are
very low

53. Many patients with abetalipo-
proteinaemia die in childhood
Those who survive develop:
Steatorrhoea
Intestinal malabsorption
Retinitis pigmentosa
Neurological abnormalities

54. This is an autosomal dominant disorder
The defect is decreased synthesis of apo
B
Plasma LDL and cholesterol are low
Clinical abnormalities are mild and
compatible with life
Hypobetalipoproteinaemia

55. This is an autosomal recessive disorder
of a-lipoprotein (HDL) metabolism
It is also known as Tangier disease as it
was first discovered on the Tangier island
Synthesis of apo A is decreased resulting
in a decreased level of HDL
Hypoalphalipoproteinaemia

56. Decreased HDL level impairs transport
of cholesterol
Cholesterol is deposited in liver, spleen,
tonsils, lymph nodes etc
Risk of atherosclerosis is increased
Mild neurological abnormalities are also
common

57. A classification of hyperlipoproteinaemias
of genetic origin was proposed by
Frederickson and his associates in 1967
It was slightly modified by W.H.O. in 1970
Hyperlipoproteinaemia

58. In W.H.O. classification, hyperlipo-
proteinaemia is divided into six
types on the basis of:
Fasting plasma levels of CM, VLDL,
LDL, HDL, cholesterol and trigly-
cerides (after a 14-hour fast)
Appearance of serum after standing
it for 48 hours (serum storage test)

59. Genetic deficiency of lipoprotein lipase
CM present in fasting plasma
LDL and VLDL normal or slightly raised
Triglycerides greatly increased
Cholesterol normal or slightly raised
Hyperlipoproteinaemia, type I

60. Genetic deficiency of LDL receptors
CM absent in fasting plasma
LDL and cholesterol greatly raised
VLDL and triglycerides normal
Hyperlipoproteinaemia, type IIa

61. Variant of type IIa
CM absent in fasting plasma; LDL and
VLDL raised
Cholesterol and triglycerides increased
Hyperlipoproteinaemia, type IIb

62. Due to abnormal apo E
CM and VLDL remnants not removed;
VLDL and LDL raised
Cholesterol and triglycerides increased
On electrophoresis, pre-b and b-lipo-
proteins fuse to form a broad b band
Hyperlipoproteinaemia, type III

63. Cause not known
VLDL and triglycerides increased
LDL and cholesterol normal or slightly
increased
Hyperlipoproteinaemia, type IV

64. Cause is not known; associated with
diabetes and obesity
CM present in fasting plasma
LDL normal; VLDL, triglycerides and
cholesterol increased
Hyperlipoproteinaemia, type V

66. Serum storage test in different
types of hyperlipoproteinaemia
I IIa IIb III IV V