2. Lecture Outline
• What are lipoproteins?
• What do they do
• Basic structure
• Lipoprotein metabolism
• Cholesterol homeostasis
• Development of atherosclerosis
• lipoproteins in atherosclerosis
• Role of diet
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3. 2/16/2018 TaufiqMufti 3
LIPOPROTEINS
• globular micelle-like particles
• having non-polar core of triacylglycerols
and cholestrol esters
• surrounded by an amphiphilic coating of
proteins, phospholipids and cholestrol.
4. What do lipoproteins do?
• transport lipid-soluble compounds between tissues
– Substrates for energy (TG)
– Essential components for cells (PL, UC)
– hormones Precursors
– eicosanoids Precursors
– Lipid soluble vitamins
– bile acids Precursors
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5. What are lipoproteins?
Lipoproteins are protein-lipid complexes
• Hydrophobic
core (TG, CE)
• Hydrophilic
surface (UC,
PL)
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11. • Helices
• of apolipoprotiens have hydrophilic and
hydrophobic side chains on opposite sides of the
helical cylinder,
• amphipathic and float on phospholipid surface,
• The charged head groups of lipids presumably bind
to oppositely charged residue on the helix,
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12. apoA-I
• On chylomicrons and HDL.
• 243 residues and 29kD polypeptide.
• 22 residue segments of similar
sequence.
• X-Ray reveals that polypeptide chain
forms a pseudocontinuous α-helix that is
punctuated by kinks at pro residues
spaced about every 22 residues.
• 4 monomers associate to form the
structure.
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15. apoB-100
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• present in LDL
• Has 4536 residue monomers
• largest monomeric protien known.
• Hydrophobic
• Each LDL particle has 1 molecule of apoB-100.
• It covers almost ½ of the particle surface.
16. • Blood stream delivers chylomicrons throughout the
body.
VLDL, IDL, LDL are synthesized by liver
transport endogenous triacylglycerols and
cholestrol TO TISSUES.
HDL transports cholestrol and other lipids
BACK TO LIVER.
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18. Classification of Lipoproteins
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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
12d/2e2/n13sity. 8
19. Classificationof Lipoproteins
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9
Based on electrophoretic mobilities
Lipoproteins may be separated according to their
electrophoretic properties into - α, pre β, β, and
broad beta lipoproteins.
21. Classification
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2) Based on electrophoretic mobilities (contd.)
HDL are -α , VLDL pre- β, LDL-β , and IDL are broad
beta lipoproteins.
VLDLs with less protein content than LDLmove
faster than LDL, this is due to nature of apoprotein
present.
22. Classification
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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.
Chylomiconscontain 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.
24. Functions
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(1) form part of the structure of the lipoprotein, e.g. apo B,
structural component ofVLDL and Chylomicons
(2) cofactors, e.g. C-II for lipoprotein lipase, A-I for lecithin:
cholesterol acyl transferase (LCAT),
(3) inhibitors, eg, apo A-II and apo C- III for lipoprotein
lipase, apo C-I for cholesteryl ester transfer protein
(4) Act as ligands for interaction with lipoprotein receptors
e.g. apo B-100 and apo E for the LDL receptor, apo A-I for
the HDLreceptor.
25. Metabolism of chylomicrons
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Chylomicrons are found in chyle in lymphatic
system
transport of all dietary lipids into the circulation.
1) Synthesis of Apo B48 Chylomicronsin the rough
endoplasmic reticulum (RER).
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As the lipid content increases, density decreases and size increases, Chylomicrons
are least dense but biggest in size, HDL are rich in proteins , hence most dense
but smallest in size.
29. Lipoproteins
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Lipoprotein Apoproteins Function
Chylomicron apoB-48, apoC,apoE TransportTGsform intestine to liver/ other
tissues
VLDL apoB-100, apoC,apoE TransportTGsfrom liver to adipose/muscles.
IDL apoB-48, apoC,apoE Intermediary between VLDLandLDL
LDL apoB-48 Transport cholesterol to peripheraltissues.
HDL apoA, apoC,apoE,
apoD
•Absorb cholesterol form peripheral tissues
and transport it toliver
•Reservoir for exchangeof lipoproteins in
VLDLand Chylomicronmetabolism
30. Apoprotein Lipoprotein Size, kDa Comments
Apo B-48 CM and CR 260 Synthesized in
intestine
Apo B-100 VLDL, LDL, IDL,
HDL
550 Synth in liver,
Apo A-I HDL, CM 28 Activator of LCAT
Apo A-II HDL, CM 17 ?Inhibitor of LCAT
Apo D HDL 19.3 ?lipid transfer protein
Apo C-II VLDL CM, HDL, 8.9 Activator of LPL
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31. Apolipoproteins-A
• Apo AI (liver, small intestine)
– activator of LCAT
• Apo AII (liver)
– inhibitor of hepatic lipase;
– component of ligand for HDL binding
• Apo A-IV (small intestine)
– Activator of LCAT;
– modulator of lipoprotein lipase (LPL)
• Apo A-V (liver)
– Direct functional role is unknown;
– regulates TG levels.
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32. Apolipoproteins-B-E
• Apo B-100 (liver)
– synthesis of VLDL;
– ligand for LDL-receptor
• Apo B-48 (small intestine)
synthesis of chylomicrons
• Apo E (liver, macrophages, brain)
– Ligand for apoE-receptor
– mobilization of cellular cholesterol
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33. Apolipoproteins-C
• Apo C-I (liver)
– Activator of LCAT,
– inhibitor of hepatic TGRL uptake
• Apo C-II (liver)
– Activator of LPL,
– inhibitor of hepatic TGRL uptake
• Apo C-III (liver)
– Inhibitor of LPL,
– inhibitor of hepatic TGRL uptake
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39. Metabolism of chylomicrons
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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.
In Abetalipoproteinemia (a rare disease), lipoproteins containing
apo Bare not formed and lipid droplets accumulate in the intestine
and liver(Due to non formation of VLDL)
40. CHYLOMICRONS:
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• Chylomicrons adhere to endotehlium of
capillarieson skeletal muscles and adipose tissue.
triglyecrols are hydrolysed by action of
“lipoprotein lipase”.
Monoacylglycerols and fatty acids are then taken
up tissues.
41. • hydrolysis of chylomicrons
• loss of its triacylglycerols
• reduced to “ cholestrol enriched chylomicron
remnants.”
• Remnants taken up by the liver.
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42. Chylomicrons vs. VLDL
Made by liver
30-90 nm diameter
Density 0.95-1.006
7-10% protein
56% TAG
20% PL
15% CE
8% C
1% FFA
Made by intestine
90-1000 nm dia
Density <0.95
1-2% protein
88% TAG
8% PL
3% CE
1% C
trace FFA
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44. 2/16/201
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Chylomicrons are acted upon by the enzyme
lipoprotein lipase .
Reaction with lipoprotein lipase results in the
loss of approximately 90% of the triacylglycerol
and loss of apo C
chylomicron remnant is about half the
diameter of the parent chylomicron enriched in
cholesterol and cholesteryl esters
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Chylomicron remnants are taken up by the liver by
receptor-mediated endocytosis, cholesteryl esters
and triacylglycerols are hydrolyzed
Uptake is mediated by apo E
.
Hepatic lipase has a dual role:
(1) it acts as a ligand tofacilitate remnant uptake
(2) it hydrolyzes remnant triacylglycerol and
phospholipid.
47. Metabolism ofVLDL
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Newly secreted or "nascent" VLDLcontain only a
small amount of apolipoproteins C and E, and the full
complement is acquired from HDL
A p o B100 is essential for VLDL formation.
57. VLDL Biogenesis
Cholesterol and
Atherosclerosis, Grundy)
Microsomal
TG transfer
protein
(MTP)
Facilitates the
translocation, folding
of apoB and addition
of lipids to lipid
binding domains
TG and
cholesterol are
synthesized in the
liver as VLDL
which contains
apoB-100
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63. VLDL
Conversion to
LDL
Further action on IDL by
hepatic lipase
loses additional
apolipoproteins (apoE)
becomes and is
converted to LDL
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64. Catabolismof VLDL
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phospholipids and apo C-II are cofactors for lipoprotein
lipase activity
apoA-II and apo C-III are inhibitors.
Triacylglycerol is hydrolyzed to free fatty acids plus
glycerol.
few FFAs return to circulation, but the bulk is
transported into the tissue.
65. Catabolismof VLDL
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loss of 90% of the TAG of VLDLs by lipoprotein lipase
formation of VLDLremnants (IDL )
IDL, VLDL taken up by the liver via the LDL (apo B-100, E) receptor,
Thus, each LDL particle is derived from a single precursor VLDL
particle.
large proportion of IDL forms LDL,
66. Metabolism ofLDL
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LDL(apo B-100, E)receptor is defective in familial
hypercholesterolemia
30% of LDL is degraded in extra-hepatic tissues and
70% in the liver
positive correlation between coronary
atherosclerosis and LDL
67. Modification of LDL
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LDL
Apo B-100
Derivatization:
Aldehydes
Glucosylation
eg. diabetes
Oxidation:
Degradation of
B-100 by reactive
oxygen species
Derivatized
LDL
Oxidized
LDL
68. Metabolism of
VLDL
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The liver and many
extrahepatic 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 ofB-100
containing the LDL
receptor ligand,
and it also takes up
lipoproteins rich in apo E.
80. Statins:
HMG CoAReductase
inhibitorsBileAcid
Seqestrants
•Bind andremove
bile in intestine
•Increases
cholesterol
conversion to bile
FibricAcids
•Reduces
synthesis of VLDL
in liver
•Increases
catabolismof
VLDL
Cholesterol
AbsorptionInhibitor
Ezetimibe:
•Inhibits transporter
protein on surface of
intestinal absorptive
cells.
•Blocksuptake of
dietary cholesterol
in smallintestine.
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82. HDL obtained through degradation of other
lipoproteins.
.
Cholesterol esterifies into Cholesteryl esters by
LCAT.
LCAT is activated by apoA-I.
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83. •
• Liver is the only organ capable of disposing off
cholesterol by conversion to bile acids.
• ½ of VLDL, after degradation into IDLand LDL
enter liver via LDL receptor
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84. •
• HDL bind to a cell receptor SR-BI (scavenger
receptor class B type I ) and tranfers lipids into
the cells.
•
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85. METABOLISM OF
HDL
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TaufiqMufti 85
Synthesis of HDL
H D L is synthesized and secreted from liver and
intestine .
apo C and apo E synthesized in the liver
Nascent HDL consists of discoid phospholipid bilayer
containing apo Aand free cholesterol.
86. METABOLISM OF
HDL
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TaufiqMufti 8686
apo A-I activate LCAT —convert phospholipid and
free cholesterol into cholesteryl esters and
lysolecithin
removal of excess unesterified cholesterol from
lipoproteins and tissues.
87. METABOLISM OF HDL
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TaufiqMufti 87
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
87
88. Reversecholesterol
transport
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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)
88
89. 2/16/2018TaufiqMufti 89
ABCA1 (ATP-binding cassette transporter A1) couple
the hydrolysis of ATP to the binding of a
substrate, enabling it to be transported across
the membrane.
transfers cholesterol from cells to pre -HDL or apo A-
1, which are then converted to HDL3
12/22/13 Biochemistry for medics 35
90. Functions
of HDL
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Scavenging action- HDL scavenges extracholesterol
from peripheral tissues by reverse cholesterol transport
HDL pl us apo E competes with LDL for binding sites
on the membranes and prevents internalization of LDL
cholesterol in the smoothcells of the arterial walls
contributes its apo C and E to nascent VLDL and
chylomicrons for receptor mediated endocytosis
stimulates prostacyclin synthesis by the endothelial
cells, which prevent thrombus formation
removal of macrophages from arterial wall
36
93. Fatty Liver
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Fatty livers fall into two main categories-
A) More synthesis of Triglycerides
High carbohydrate diet
High fat diet
Starvation
Diabetes mellitus
High carbohydrate diet stimulates de novo fatty acid synthesis
40
94. FattyLiver
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94
B) Defective VLDLsynthesis - metabolic block in the
production of plasma lipoproteins, thus allowing
triacylglycerol to accumulate.
due to –
(1) block in apolipoproteins synthesis
a) Protein energy Malnutrition
b) Impaired absorption
c) Inhibitors of endogenous protein synthesis e.g.- Ccl4,
Puromycin, Ethionine
d) Hypobetalipoproteinemia- Defective apo Bgene can
cause impaired synthesis of apo B protein.
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(2) failure in provision of phospholipids
a) deficiency of choline, a lipotropic factor can
cause impaired formation of phosphatidyl choline
(Lecithin)
b)Methionine deficiency causeimpaired choline
synthesis
c)Inositol deficiency
d)Deficiency of essential fatty acids---impaired PL
synthesis
97. 2/16/2
018 TaufiqMufti 97
2) Alcoholicfatty liver
Alcoholism leads to fat accumulation in the
liver, hyperlipidemia, and ultimately cirrhosis.
Changes in [NADH]/ [NAD+] redox potential in
liver
interference with transcription factors regulating
theexpression of the enzymes involved in the
pathways.
98. Metabolism of HDL
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Scavenger receptor B1(SR-B1) are 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,
I n the tissues SR-B1 mediates cholesterol uptake
from the cells by HDL,
transports it to the liver for excretion via the bile
33
99. HDL-cycle
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HDL3 accepts cholesterol, esterified by LCAT,
increasing the size to form less dense HDL2
HDL3 reformed after selective delivery of cholesteryl
ester to the liver or by hydrolysis of HDL2
Free apo A-I is released by these processes and forms
pre -HDL
34
102. ABCA1 Transporter/Receptor
Essential for moving excess intracellular cholesterol
and phospholipid to the plasma membrane.
Acts as a flipase, flipping cholesterol and phospholipid
from inner leaflet of plasma membrane to outer leaflet.
2/16/2018 TaufiqMufti 102
ATP dependent protein.
necessary for removing excess cholesterol from foam cells and
preventing early steps in atherosclerosis.
ApoA-I is required for capturing the cholesterol released from the
foam cell.
103. The Scavenger Receptor
2/16/2018 TaufiqMufti 103
(SR-A1 receptor)
How macrophages deal with oxidized or modified LDL
The scavenger receptor recognizes & internalizes
oxidized
LDL
Accumulation of these modified LDL in the cell leads to the
accumulation of cholesterol droplets in the macrophage and the
formation of foam cells.
118. LDL Cellular Metabolism
Cholesterol and
Atherosaclerosis, LDL are taken up by the LDL Receptor into clathrin-coated pits2/16/2018 118TaufiqMufti
119. LDL Cellular Metabolism
Cholesterol and
Atherosaclerosis,LDL dissociates from the receptor; the receptor recycles to the membrane2/16/2018 119TaufiqMufti
120. LDL Cellular Metabolism
Cholesterol and
Atherosaclerosis, In the lysosome, lipids are deseterified; proteins are hydrolyzed2/16/2018 120TaufiqMufti
121. LDL Cellular Metabolism
Cholesterol and
Atherosaclerosis,
Increase in free cholesterol regulates decrease cholesterol synthesis and
uptake; increase cholesterol esterification
2/16/2018 121TaufiqMufti
126. Intestinal Cholesterol Metabolism
Schmitz et al, JLR 2001
Liberated unesterified
cholesterol and plant sterols
are transported back into the
lumen via ATP-binding
cassette (ABC) proteins G5
and G8 (heterodimers)
Defects in ABCG5 or ABCG8
leads to sitosterolemia
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127. Role of LXR and FXR
When cholesterol accumulates in
cells, cholesterol is oxidized to
create oxysterols
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128. Role of LXR and FXR
Oxysterols activate LXR through
LXR/RXR heterodimers to activate
genes such as the CYP7A1
enzyme that catalyzes the rate-
limiting step in bile acid
biosynthesis
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129. Role of LXR and FXR
In the intestine, LXR also activates
ABC-1 to remove cholesterol
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130. Role of LXR and FXR
In the intestine, FXR activates
expression of I-BABP, a
protein that increases the
transport of bile acids back to
the liver from the intestine,
reducing their excretion.
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131. Role of LXR and FXR
The FXR receptor is activated by bile
acids. In the liver, activation of FXR-
RXR heterodimers by bile acids results
in the feedback inhibition of CYP7A
expression and reduced biosynthesis
of bile acids.
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134. Reverse Cholesterol Transport - Peripheral Cells
Von Eckardstein et al, ATVB
Aqueous Diffusion:
Slow, unregulated, dictated by
membrane composition
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135. Reverse Cholesterol Transport - Peripheral
Cells
Von Eckardstein et al, ATVB
SR-BI: Binding of HDL to SR-BI
leads to reorganization of
cholesterol within the plasma
membrane and facilitates
cholesterol efflux
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136. Reverse Cholesterol Transport -
Peripheral Cells
Von Eckardstein et al, ATVB
ABC1: Fast and involves the
translocation of cholesterol from
intracellular compartments to the
plasma membrane via signal
transduction processes
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138. Evolution and Progression of
Coronary Atherosclerosis
I nt imal I njury
Fat t y St reak
Lipid-Rich
Plaque
Plaque
Disrupt ion Thrombus Lysis Response
Fibr om uscular
Occlusion
Occlusive
Thrombus
0
20 40 50 60
Age (y ears )
Atherogenic Ris k Fac tors Throm bogenic Ris k Fac tors
Adapted from Fuster, 19922/16/2018 138TaufiqMufti
139. Endothelial Dysfunction
• Increased endothelial
permeability to lipoproteins and
plasma constituents mediated
by NO, PDGF, AG-II,
endothelin.
• Up-regulation of leukocyte
adhesion molecules (L-selectin,
integrins, etc).
• Up-regulation of endothelial
adhesion molecules (E-selectin,
P-selectin, ICAM-1, VCAM-1).
• Migration of leukocytes into
artery wall mediated by oxLDL,
MCP-1, IL-8, PDGF, M-CSF.
Ross, NEJM; 19992/16/2018 139TaufiqMufti
140. Formation of Fatty Streak
• SMC migration stimulated by
PDGF, FGF-2, TGF-B
• T-Cell activation mediated by
TNF-a, IL-2, GM-CSF.
• Foam-cell formation
mediated by oxLDL, TNF-a,
IL-1,and M-CSF.
• Platelet adherence and
aggregation stimulated by
integrins, P-selectin, fibrin,
TXA2, and TF.
Ross, NEJM; 19992/16/2018 140TaufiqMufti
141. Formation of Advanced, Complicated Lesion
• Fibrous cap forms in response
to injury to wall off lesion from
lumen.
• Fibrous cap covers a mixture of
leukocytes, lipid and debris
which may form a necrotic core.
• Lesions expand at shoulders by
means of continued leukocyte
adhesion and entry.
• Necrotic core results from
apoptosis and necrosis,
increased proteolytic activity
and lipid accumulation.
Ross, NEJM; 19992/16/2018 141TaufiqMufti
142. Development of Unstable Fibrous
Plaque
• Rupture or ulceration of fibrous
cap rapidly leads to thrombosis.
• Occurs primarily at sites of
thinning of the fibrous cap.
• Thinning is a result of continuing
influx of and activation of
macrophages which release
metalloproteinases and other
proteolytic enzymes.
• These enzymes degrade the
matrix which can lead to
hemorrhage and thrombus
formation
Ross, NEJM; 19992/16/2018 142TaufiqMufti
143. Plaque Rupture with Thrombus
Thrombus Fibrous cap
1 mm
Lipid core
Illustration courtesy of Frederick J. Schoen, M.D., Ph.D.
Lipids Online2/16/2018 143TaufiqMufti
144. Growth Factors and Cytokines
Involved in Atherosclerosis
Growth Factor/Cytokine Abbr. Source Target
Epidermal growth factor EGF P EC, SMC
Acidic fibroblast growth factor aFGF EC ,M, SMC EC
Basic fibroblast growth factor bFGF EC ,M, SMC EC, SMC
Granulocyte macrophage colony stimulating factor GM-CSF EC ,M, SMC, T EC, M
Heparin-binding EGF-like growth factor HB-EGF EC ,M, SMC SMC
Insulin-like growth factor-I IGF-I EC ,M, SMC, P EC, SMC
Interferon IFN- T, M SMC
Interleukin–1 IL-1 P, EC, M, SMC, T EC, M, SMC
Interleukin-2 IL-2 T EC, M, T
Interleukin-8 IL-8 EC ,M, SMC, T EC, T
Macrophage colony stimulating factor M-CSF EC ,M, SMC, T M
Monocyte chemotactic protein-1 MCP-1 EC ,M, SMC M
Platelet-derived growth factor PDGF EC ,M, SMC, P EC, M, SMC
RANTES SIS T M, T
Transforming growth factor- TGF- M EC
Transforming growth factor- TGF- EC ,M, SMC, T, P M, SMC
Tumor necrosis factor- TNF- EC ,M, SMC, T EC
Tumor necrosis factor- TNF- T EC, M, SMC
Vascular endotholelial growth factor VEGF EC ,M, SMC EC
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146. CHD Mortality is Correlated with Plasma
Cholesterol Levels
LaRosa et al, 1990
140 160 180 200 220 240 260 280 300
Plasma Cholesterol (mg/dl)
0
2
4
6
8
10
12
14
16
18
CHDDeathRate/1000
Six Year CHD Mortality from
MRFIT
Desirable
Borderline
High HIGH
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147. Role of LDL in Atherosclerosis
Steinberg D et al. N Engl J Med 1989;320:915-924.
Endothelium
Vessel Lumen
LDL
LDL Readily Enter the Artery Wall Where They May be Modified
LDL
Intima
Modified LDL
Modified LDL are Proinflammatory
Hydrolysis of Phosphatidylcholine
to Lysophosphatidylcholine
Other Chemical Modifications
Oxidation of Lipids
and ApoB
Aggregation
Lipids Online2/16/2018 147TaufiqMufti
148. Role of LDL in Atherosclerosis
LDL
LDL
Navab M et al. J Clin Invest 1991;88:2039-2046.
Endothelium
Vessel Lumen
Intima
Monocyte
Modified LDL
MCP-1
Lipids Online2/16/2018 148TaufiqMufti
149. Role of LDL in Atherosclerosis
LDL
LDL
Steinberg D et al. N Engl J Med 1989;320:915-924.
Endothelium
Vessel Lumen
Intima
Monocyte
Modified LDL
Modified LDL Promote
Differentiation of
Monocytes into
Macrophages
MCP-1
Macrophage
Lipids Online2/16/2018 149TaufiqMufti
150. Role of LDL in Atherosclerosis
LDL
LDL
Nathan CF. J Clin Invest 1987;79:319-326.
Endothelium
Vessel LumenMonocyte
Modified LDL
Macrophage
MCP-1
Adhesion
Molecules
Cytokines
Intima
Lipids Online2/16/2018 150TaufiqMufti
151. Role of LDL in Atherosclerosis
LDL
LDL
Endothelium
Vessel LumenMonocyte
Macrophage
MCP-1
Adhesion
Molecules
Steinberg D et al. N Engl J Med 1989;320:915-924.
Foam Cell
Modified LDL
Taken up by
Macrophage
Intima
Lipids Online2/16/2018 151TaufiqMufti
152. Role of LDL in Atherosclerosis
Endothelium
Vessel LumenMonocyte
Macrophage
MCP-1Adhesion
Molecules
Foam Cell
IntimaModified
RemnantsCytokines
Cell Proliferation
Matrix Degradation
Doi H et al. Circulation 2000;102:670-676.
Growth Factors
Metalloproteinases
Remnant Lipoproteins
Remnants
Lipids Online2/16/2018 152TaufiqMufti
153. LDL and Atherosclerosis
Fitting the pieces together
2/16/2018 TaufiqMufti 153
Artery
wall
Elevated LDL: Increased residence time in plasma
Increased modification/oxidation of LDL
Monocyte
Endothelial
cells
oxLDL
oxLDL (stimulates cytokine secretion)
Macrophage
Macrophage foam cell
Smooth muscle cell
proliferation
154. SYNTHESIS OF
CHOLESTEROL
SYNTHESIS OF
LDL RECEPTORS
CHOLESTEROL
ESTERS
MEMBRANES
STEROIDS
BILE ACIDS
HMG CoA
Reductase
EXCESS
CHOLESTEROL
LDL
LDL
Receptors
DNA
RNA
INHIBITS
INHIBITS
ACAT
ACTIVATES
LDL DELIVERS CHOLESTEROL TO CELLS
2/16/2018 TaufiqMufti 154
162. Hypolipoproteinemias
2/16/20
18 TaufiqMufti 162
Name Defect Characteristics
Abetalipoproteinemi
a
Rare; blood acylglycerols
low; intestine and liver
accumulate acylglycerols.
Intestinal malabsorption.
No chylomicrons, VLDL,
or LDL formed
defect in apo B
loading
Low/ absent 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
163. Hyperlipoproteinemia
2/16/20
18 TaufiqMufti 163
Defect CharacteristicsName
Familial lipoprotein
lipase deficiency
(type I)
Familial
hypercholesterolemia
(type II a)
Hypertriacylglycerolemia
due to deficiency of LPL,
apo C- II deficiency
Defective LDL receptors
mutation of apo B-100.
Slow clearance of
chylomicrons and VLDL.
Low LDL and HDL.
No CHD
Elevated LDL
hypercholesterolemia,
atherosclerosis
CHD
164. Dyslipoproteinemias
2/16/2018 TaufiqMufti 164
Name Defect Characteristics
Deficiency in remnant
clearance by the liveris
due to abnormality in
apo E.
Familial type III
hyperlipoproteinemia
(broad beta 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
TG rich LDL,VLDL
remnants
Increase in CM and VLDL
remnants , Causes
hypercholesterolemia,
xanthomas, and
atherosclerosis.
High cholesterol, VLDL,
LDL and HDL. Due to
Alcoholism, DM obesity.
Patients have xanthomas
and coronary heart disease.
12/22/13 50
166. Seven Countries Study: CHD Events
are
Correlated with Saturated Fat
0 5 10 15 20
% Calories from Saturated Fat
0
1
2
3
4
5
CHDDeathsandMI/100
R = 0.84
V
M
C
D
G
S
W
B
Z
U
N
E
K
Keys, 19702/16/2018 166TaufiqMufti
168. Thrombogenic Risk Factors May be as
Important as Lipid Risk Factors
• Fibrinogen: Upper tertile for fibrinogen
associated with 2.3-fold increase in risk for
myocardial infarction.
• Factor VII: 25% increase in factor VIIc is
associated with a 55% increase in risk of a fatal
CHD events within 5 years.
2/16/2018 168TaufiqMufti
