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.
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Lipoproteins metabolism for MMBS, Lab. Med. BDSpptx
1. Lipoproteins- Structure, Classification,
Metabolism and Significance
1
Rajendra Dev Bhatt , PhD Scholar
Asst. Professor
Clinical Biochemistry & Laboratory Medicine
Fellow: Translational Research (2018-2022) in CVD in Nepal, NHLBI & NIH, USA
2. īLipids absorbed from the diet and synthesized by the
liver and adipose tissue must be transported between
various cells and organs for utilization and storage.
īLipids 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.
Lipoproteins:
3. General Structure of Lipo proteins
Lipoproteins consist of a nonpolar core and a
single surface layer of amphipathic lipids
Th e 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.
4. General Structure of Lipo proteins
Some apolipoproteins are integral and cannot be removed, whereas
others can be freely transferred to other lipoproteins.
5. Classification of Lipoproteins
Lipoproteins can be classified in three ways-
1) Based on density- They are separated by
Ultracentrifugation. 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
6. Classification of Lipoproteins
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 1.006-
1.019 and the mean diameter ranges between
25- 50nm.
7. Classification of Lipoproteins
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.
8. Classification of Lipoproteins
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.
8
9. Classification of Lipoproteins
9
2) Based on electrophoretic mobilities
īLipoproteins may be separated according to
their electrophoretic properties into - ι, pre β, β,
and broad beta lipoproteins.
īThe mobility of a lipoprotein is mainly
dependent upon protein content.
īThose with higher protein content will move
faster towards the anode and those with
minimum protein content will have minimum
mobility.
11. Classification of Lipoproteins
2) Based on electrophoretic mobilities (contd.)
īHDL are -Îą , VLDL pre- β, LDL-β , and IDL are
broad beta lipoproteins.
īFree fatty acid and albumin complex although not a
lipoprotein is an important lipid fraction in serum
and is the fastest moving fraction.
īChylomicrons remain at the origin since they have
more lipid content.
īVLDLs with less protein content than LDL move
faster than LDL, this is due to nature of apoprotein
present.
12. Classification of Lipoproteins
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.
13. Classification of Lipoproteins
3) Based on nature of Apo- protein content
īOne or more apolipoproteins (proteins or
polypeptides) are present in each lipoprotein.
īThe major apolipoproteins of HDL (Îą-lipoprotein)
are designated A.
īThe main apolipoprotein of LDL (β -lipoprotein)
is apolipoprotein B (B-100), which is found also in
VLDL.
īChylomicons contain a shorten form of apo B (B-
48) that is synthesized in the intestine, while B-100
is synthesized in the liver.
īApo E is found in VLDL, HDL, Chylomicons, and
chylomicron remnants.
14. 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
C- III 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.
15. Lipoproteins Site Of
Synthesis
Destination Major Lipids Biochemical
Functions
Chylomicron
s
Intestine Liver Exogenous
Triacylglycerol
Deliver lipids of
dietary origin to
Liver and
Adiposecytes
VLDLs Liver Extra Hepatic
Tissues
Endogenous
Triacylglycerol
Deliver
endogenously
produced Lipids
to
Extrahepatocytes
LDLs Intravascular by
removal of
triacylglycerol
from VLDL
Extra hepatic
Tissues
Cholesterol Deliver
endogenously
produced
cholesterol to
Extrahepatocytes
HDLs Liver and
intestine
Liver and
steroid-
hormone-
producing
glands
Phospholipid
Cholesterol
Remove and
degrade
Cholesterol.
16. Plasma Lipoproteins
For Triacylglycerol Transport (TAG-rich):
- Chylomicrons: TAG of dietary origin
- VLDL:TAG of Endogenous (hepatic) synthesis
For Cholesterol transport (cholesterol-rich):
LDL: Mainly Free Cholesterol
HDL: Mainly esterified Cholesterol
17. Metabolism of Chylomicrons
Synthesis of Chylomicrons
ī Chylomicrons are the transport form of dietary triglycerides
from intestines to the adipose tissue for storage; and to
muscle or heart for their energy needs.
ī Chylomicrons are formed in the intestinal mucosal cells, and
secreted into the lacteals of lymphatic system.
ī They are rich in triglyceride
ī If lipemic serum is kept overnight in the refrigerator,
chylomicrons rise as a creamy layer to the top, leaving the
subnatant clear
ī When the chylomicrons are synthesised by the intestinal
mucosa, they contain only apo-B-48 and apo-A but apo-C and
apo-E are added from HDL in blood during transport
20. Metabolism of Chylomicrons
ī Main sites of metabolism of chylomicrons are
adipose tissue and skeletal muscle. The half life of
chylomicrons in blood is about 1 hour.
ī The enzyme lipoprotein lipase (LpL) is located at
the endothelial layer of capillaries of adipose tissue,
muscles and heart; but not in liver.
ī Apo C-II present in the chylomicrons activates the
LpL
ī The LpL hydrolyses triglycerides present in
chylomicrons into fatty acids and glycerol.
ī Muscle or adipose tissue cells take up the liberated
fatty acids
21. Metabolism of Chylomicrons cont..
īFollowing injection of heparin, the LpL is
released from the tissues and lipemia is thus
cleared. This is called post-heparin
lipolytic activity.
īLack of Apo C-II leads to decreased activity
of LpL and consequent accumulation of
chylomicrons and VLDL in blood
īInsulin increases LpL activity
īAnd Liver takes up Chylomicron remnants
22.
23. Metabolism of VLDL
Synthesis of VLDL
ī There are striking similarities in the mechanisms of
formation of chylomicrons by intestinal cells and of
VLDL by hepatic parenchymal cells
ī They are synthesized in the liver from glycerol and
fatty acids and incorporated into VLDL along with
hepatic cholesterol, apo-B-100, C-II and E.
ī Apo-B-100 is the major lipoprotein present in VLDL
ī VLDL carries triglycerides (endogenous triglycerides)
from liver to peripheral tissues for energy needs.
ī The half-life of VLDL in serum is only 1 to 3 hours.
25. Metabolism of VLDL ContâĻ
ī When they reach the peripheral tissues, apo-C-II
activates LpL which liberates fatty acids that are
taken up by adipose tissue and muscle.
ī The remnant is now designated as IDL
intermediate density lipoprotein) and contains
less of TAG and more of cholesterol
ī The major fraction of IDL further loses
triglyceride, so as to be converted to LDL
ī This conversion of VLDL to IDL and then to LDL
is referred to as lipoprotein cascade pathway
ī A fraction of IDL is taken up by the hepatic
receptors.
26. Metabolism of LDL
īLDL transports cholesterol from liver to
peripheral tissues.
īThe only apoprotein present in LDL is apo
B100
īMost of the LDL particles are derived from
VLDL, but a small part is directly released
from liver.
īThe half-life of LDL in blood is about 2 days.
27. Metabolism of LDL Cont..
ī LDL is taken up by peripheral tissues by receptor
mediated endocytosis
ī The liver and many extra hepatic tissues express
the IDL(apo B-100, E) receptor.
ī This receptor is defective in
familial hypercholesterolemia.
ī Approximately 30% of LDL is degraded in extra-
hepatic tissues and 70% in the liver.
ī A positive correlation exists between the incidence
of coronary atherosclerosis and the plasma
concentration of LDL cholesterol.
28. LDL transports cholesterol from liver to the
peripheral tissues. The cholesterol thus liberated
in the cell has three major fates.
i. It is used for the synthesis of other steroids
like steroid hormones.
ii. Cholesterol may be incorporated into the
membranes.
iii. Cholesterol may be esterified to a MUFA by
acyl cholesterol acyl transferase (ACAT) for
storage.
iv. The cellular content of cholesterol regulates
further endogenous synthesis of cholesterol
by regulating HMG CoA reductase
29. LDL and Clinical Applications
âĸ LDL concentration in blood has positive correlation
with incidence of cardiovascular diseases
âĸ A fraction of cholesterol is taken up by macrophages,
this is not a regulated pathway.
âĸ Increased levels of LDL or modification of LDL by
glycation (as seen in diabetes mellitus) or oxidation
increases the fraction of cholesterol taken up by
macrophages.
âĸ LDL infiltrates through arterial walls, and is taken up
by macrophages or scavenger cells. This is the starting
event of atherosclerosis leading to myocardial
infarction
30. LDL and Clinical Applications Cont..
īWhen these cells become engorged (swell)
with cholesterol, foam cells are formed, that
get deposited in the sub-endothelial space
triggering formation of athero-matous plaque
īPro-coagulant changes are induced in the
endothelium resulting in increased chances of
thrombosis and coronary artery disease
īSince LDL-cholesterol is thus deposited in
tissues, so known as âbad cholesterolâ
31. Lipoprotein (a)
ī Lipoprotein (a) or Lp(a) should not be confused with
apo-A. Lp(a) is very strongly associated with myocardial
infarction and is sometimes called the âlittle rascalâ.
ī Lp(a), when present, is attached to apo-B-100 by a
disulfide bond.
ī In 40% population, there is no detectable level of Lp(a) in
serum.
ī In 20% of population, the Lp(a) concentration in blood is
more than 30 mg/dl; and these persons are susceptible for
heart attack at a younger age.
ī Apo-A is a constituent of HDL. This "A" is always
written in capital letters. It is seen in all persons. It is anti-
atherogenic.
32. The biochemical analysis of plasma from a patient with
pancreatitis showed hypertriglyceridemia with increased
VLDL and chylomicrons. To further investigate, the patient
was administered heparin intravenously and blood samples
were collected to analyze the lipolytic activity in plasma. The
test showed low LPL activity in post heparinized blood
samples. Identify the probable cause of reaction after an
intravenous heparin injection increased VLDL and
Chylomicrons
A) Deficiency of Apo B
b) Deficiency of Lipoprotein Lipase
c) Deficiency of LDL receptor
d) Deficiency of Apo A-I
Deficiency of Lipoprotein Lipase
33. Familial Hypercholesterolemia is an autosomal
dominant genetic disorder caused by a
mutation of the gene that encodes for:
a) Apolipoprotein E
b) Apolipoprotein B
c) LDL receptor
d) VLDL receptor
LDL receptor
34. The lipoprotein lipase is present in the endothelial
surfaces of adipose tissues in the heart and it is
required for hydrolysis and release of triglycerides
from chylomicrons. Which of the apolipoprotein that
is present in chylomicron serves as the activator of
an enzyme lipoprotein lipase?
a) Apo B100
b) Apo B48
c) Apo CII
d) ApoE
Apo CII
35.
36. Metabolism of HDL
Synthesis of HDL
ī High density lipoproteins transport cholesterol from
peripheral tissues to the liver.
ī HDL is synthesized and secreted from both liver and
intestine .
ī The major apoproteins in HDL are Apo-A1, with
some Apo-A2, Apo-C and Apo-E.
ī 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.
37. Metabolism of HDL cont..
ī 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.
ī The free cholesterol derived from peripheral tissue
cells are taken up by the HDL.
ī The apo-A-l of HDL activates LCAT (lecithin
cholesterol acyl transferase) present in the plasma.
âĸ The LCAT then binds to the HDL which is
components of phospholipid bilayer of the HDL disk.
38. Metabolism of HDL cont..
38
LCAT and the LCAT activator apo A-Iâbind to the
discoidal particles, and the surface phospholipid and
free cholesterol are converted into cholesteryl esters and
lysolecithin .
T h e nonpolar cholesteryl esters move into t h e
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 .
39. Reverse cholesterol transport
Reverse cholesterol
transport is a
mechanism by which
the body removes
excess cholesterol from
peripheral tissues and
delivers them to the
liver, where it will be
redistributed to other
tissues or removed from
the body by the
gallbladder.
39
40. Metabolism of HDL
T h e 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 H D L 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.
I n the tissues, on the other hand, SR-B1 mediates t h e
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 transport
33
41. HDL- cycle
HDL3, generated from discoidal HDL by the action of
LCAT, accepts cholesterol from the tissues via the SR-
B1 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 andforms
pre -HDL after associating with a minimum amount of
phospholipid and cholesterol 34
42. 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
H D L contributes its apo C and E to nascent VLDL a
n
d
chylomicrons for receptor mediated endocytosis
H D L stimulated prostacyclin synthesis by the endothelial
cells, which prevent thrombus formation
H D L also helps in the removal of macrophages.
36
43. Summary of formation and fate
īChylomicrons is a
transporter of dietary
lipids whereas VLDL
is a transporter of
endogenous
lipids(mainly TGs).
īLDL transports
cholesterol to peripheral
cells while HDL
transports cholesterol
from peripheral cells
back to liver
37
44. Clinical Significance of lipoprotein
metabolism
44
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.
45. Fatty Liver (contd.)
Fatty livers fall into two main categories-
A)More synthesis of Triglycerides
īHigh carbohydratediet
īHigh fat feeding
īStarvation
īDiabetes 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 Triglyceride.
40
47. Fatty Liver (contd.)
47
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.
It may be due to â
(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.
48. Fatty Liver (contd.)
48
(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)Deficiency of essential fatty acids can also cause
impaired PL synthesis
49. Fatty Liver (contd.)
âĸ (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.
âĸ 4) Impaired secretion of VLDL- oxidative stress is
a common cause for membrane disruption of
lipoproteins.
49
50. Fatty Liver (contd.)
50
2) Alcoholic fatty liver
īAlcoholism leads to fat accumulation in the liver,
hyperlipidemia, and ultimately cirrhosis.
īThe 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.
51. Fatty Liver and Lipotropic agents
51
Lipotropic agents- Agents such as-
âĸCholine
âĸInositol
âĸMethionine and other essential amino acids,
âĸ Essential fatty acids,
âĸAnti oxidant vitamins,
âĸVitamin B12, folic acid and
âĸSynthetic 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.
52. Primary Disorders of Plasma Lipoproteins
(Dyslipoproteinemias)
âĸ Inherited defects in lipoprotein metabolism lead to
the primary condition of either hypo- or
hyperlipoproteinemia .
âĸ 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.
âĸ All of the primary conditions are due to a defect at a
stage in lipoprotein formation, transport, or
degradation.
52
53. Primary Disorders of Plasma Lipoproteins
(Dyslipoproteinemias)
53
Name Defect Characteristics
Hypolipoproteinemias
Abetalipoproteinemia Rare; blood acylglycerols
low; intestine and liver
accumulateacylglycerols.
Intestinal malabsorption.
No chylomicrons, VLDL,
or LDL are formed
because of defect in the
loading of apo B with
lipid.
All have low or near
absence of HDL.
Hypertriacylglycerolemia
due to absence of apo C-
II, Low LDL levels.
Atherosclerosis in the
elderly.
Familial alpha-
lipoprotein deficiency
Tangier disease
Fish-eye disease
Apo-A-I deficiencies
54. Primary Disorders of Plasma Lipoproteins
(Dyslipoproteinemias)
54
Defect Characteristics
Name
Hyperlipoproteinemia
Familial lipoprotein
lipase deficiency (type I)
Familial
hypercholesterolemia
(type II a)
Hypertriacylglycerolemia
due to deficiency of LPL,
abnormal LPL, or apo C-
II deficiency causing
inactive LPL.
Defective LDL receptors
or mutation in ligand
region of apo B-100.
Slow clearance of
chylomicrons and VLDL.
Low levels of LDL and
HDL. No increased risk
of coronary disease.
Elevated LDL levels and
hypercholesterolemia,
resulting in
atherosclerosis and
coronary disease.
55. Primary Disorders of Plasma Lipoproteins
(Dyslipoproteinemias)- contd.
Name Defect Characteristics
Deficiency in remnant
clearance by the liver is
due to abnormality in
apo E.
Familial type III
hyperlipoproteinemia
(broad beta disease,
remnant removal disease,
familial
dysbetalipoproteinemia)
Familial
Hypertriacylglycerolemia
(type IV)
Overproduction of VLDL
often associated with
glucose intolerance and
hyperinsulinemia.
Hepatic lipase deficiency Deficiency of the enzyme
leads to accumulation of
large triacylglycerol-rich
Increase in chylomicron
and VLDL remnants ,
Causes
hypercholesterolemia,
xanthomas, and
atherosclerosis.
High cholesterol, VLDL,
Subnormal LDL and
HDL. Associated with
Alcoholism, diabetes
mellitus and obesity.
Patients have xanthomas
and coronary heart
disease.
50
56. 1. The class of lipoproteins that is protective
against atherosclerosis is âĻ
a. Low-density of lipoproteins
b. Very low-density lipoproteins
c. High-density lipoproteins
d. Chylomicrons
High-density lipoproteins
57. 2. The highest phospholipids content is found in
a. Chylomicrons
b. VLDL
c. LDL
d. HDL
HDL
58. 3. Activated lecithin cholesterol acyl transferase
is essential for the conversion of ...
a. VLDL remnants into LDL
b. Nascent HDL into HDL
c. HDL2 into HDL3
d. HDL3 into HDL2
HDL3 into HDL2