BY

Dr.Liniyanti D.Oswari, MNS, MSc.

 To understand the lipid & lipoprotein
metabolism in the body.
 Recognize the significance of dyslipidemia in
Atherosclerosis on CVD & CHD, including the
role of HDL-C as a protective risk factor for
CVD &CHD
 Recognize the relationship dyslipidemia with
central obesity & Insulin resistance
 Examine recent clinical trials of dyslipidemia
as it relates to the prevention and treatment
of CVD & CHD
 Clusters of lipids associated with
proteins that serve as transport vehicles
for lipids in the lymph and blood
 Chylomicrons
 VLDL – Very low density lipoprotein
 IDL – Intermediate density
lipoprotein
 LDL – Low density lipoprotein
 HDL – High density lipoprotein
 Distinguished by size
and density
 Each contains
different kinds and
amounts of lipids and
proteins
◦ The more lipid, the
lower the density
◦ The more protein, the
higher the density
 Class Size (nm) Lipids Major
Apoproteins
Chylomicra 100-500 Dietary TG B-48,C-II,E

VLDL 30-80 Endogenous B-100,C-II,E

TG
IDL 25-50 CEs & TGs B-100, E

LDL 18-28 CEs B-100

HDL 5-15 CEs A,C-II,E

Lp (a) 25-30 CEs B-100 &

glycoproteins
Lipid Chylomicron VLDL IDL LDL HDL
Cholesterol 9 22 35 47 19

Triglyceride 82 52 20 9 3

Phospholipid 7 18 20 23 28
 Made by intestinal cells
 Most of lipid is triglyceride
 Little protein
◦ ApoA-I, ApoA-II, ApoB-48, ApoC
 Deliver fatty acids via lipoprotein lipase

 Chylomicron remnants
 Lipoprotein particle that remains after a
chylomicron has lost most of its fatty acids
◦ Taken up by liver
◦ Contents reused or recycled
 Liver
◦ Synthesizes & metabolizes lipids
◦ “Central command center” for relation of lipid
metabolism
◦ Makes additional lipoproteins
12
13
Cholest
AA Vessel wall
FA
P,
glycerol
 Exogenous
Dietary
cholesterol Fecal bile acids
(~300–700 mg/day) Intestine and neutral
sterols
Biliary
cholesterol ~700 mg/day
(~1000 mg/day)

Liver
Synthesis
(~800 mg/day)

Extrahepatic
tissues

Endogenous
Adapted from Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Glew RH. In Textbook
of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:728-777; Ginsberg HN, Goldberg IJ. In
Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138-2149; Shepherd J Eur Heart J
Suppl 2001;3(suppl E):E2-E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-
Liss, 2002:1082-1150.
 Cholesterol is obtained from endogenous and exogenous
sources. Endogenous cholesterol is synthesized in all tissues,
but primarily the liver, intestine, adrenal cortex, and reproductive
tissues, including the placenta. Exogenous cholesterol is
absorbed by the intestine from dietary and biliary sources and
transported to the liver.1,2 In individuals eating a relatively low-
cholesterol diet, the liver produces about 800 mg of cholesterol
per day to replace bile salts and cholesterol lost in the feces.2
Depending on diet, people typically consume 300 to 700 mg of
cholesterol daily.3,4 Approximately 1000 mg of cholesterol is
secreted by the liver into the bile. Thus, approximately 1300 to
1700 mg of cholesterol per day passes through the intestines,4
of which about 700 mg per day is absorbed.5 Because plasma
cholesterol levels are maintained within a relatively narrow range
in healthy individuals, a reduction in the amount of dietary
cholesterol leads to increased synthesis in the liver and
intestine.2
 1000 mg

Inhibitors

Resins

Plant stanols NPC1L1

(Ezetimibe)
 Cholesterol that is absorbed from the intestinal lumen
comes from two sources: dietary cholesterol and
biliary cholesterol (which is by far the greater of the
two in quantity).
 Cholesterol is emulsified by bile acids and packaged
in lipid micelles.
 These lipid micelles are transported to the brush
border of jejunal enterocytes.
 At the brush border of the enterocyte, the cholesterol
is released from the lipid micelle and then enters the
enterocyte.
 Made by liver
 Contains large amounts of triglyceride
 Delivers fatty acids to cells
 More dense than chylomicrons
 A bit more protein (8%)
◦ ApoB-100, ApoC, ApoE
1- Assembly and
secretion
3
2- Hydrolysis by LPL
3- Direct uptake by 1
hepatocyte
4- Flux of pathway 2
into LDL
4
 Lipoprotein that results from loss of fatty
acids from VLDL
 Major lipid is cholesterol esters
 Proteins similar to VLDL but greater
percentage (15%)
◦ ApoB-100, ApoC, ApoE
 Taken up by liver or remain in circulation
 Converted to low-density lipoproteins (LDL)
 “Bad” cholesterol; major lipid in LDL
 Delivers cholesterol from liver to cells
◦ Cell membranes
◦ Hormone production
 Protein (21%)
◦ ApoB-100
◦ Binds to specific LDL receptor
 LDL receptors
◦ Membrane-bound proteins that bind LDL,
causing them to be taken up & dismantled
 Increase LDL  Decrease LDL
◦ SFAs ◦ High PUFA diet
◦ Trans fatty acids ◦ Ω-3 fatty acids
◦ High cholesterol ◦ Dietary fiber
intake ◦ Lifestyle factors
◦ Lifestyle factors ◦ Genetics
◦ Genetics
 Insulin resistance
Increased
increased NEFA and VLDL
glucose flux to liver

IR impairs
LDLR
Insulin resistance
Insulin
and decreased FCHL
resistance
apo-B and DM II
degradation decreased
LPL Metabolic
syndrome
 Direct Association
 Indirect

◦ Longer residence time in
plasma than normal sized
LDL due to decreased Association
recognition by receptors in ◦ Inverse relationship
liver with HDL
◦ Enhanced interaction with ◦ Marker for atherogenic
scavenger receptor
promoting foam cell TG remnant
formation accumulation
◦ More susceptible to ◦ Insulin resistance
oxidation due to decreased
antioxidants in the core
◦ Enter and attach more easily
to arterial wall
◦ Endothelial cell dysfunction
 “Good” cholesterol; major lipid is
phospholipid
 Lipoprotein made by liver that circulates
in the blood to collect excess cholesterol
from cells
 Lowest lipid-to-protein ratio
◦ Protein (50%)
 ApoA, ApoC, ApoE
 Reverse cholesterol transport
◦ Salvage excess cholesterol from cells
◦ Transported back to liver
 HMG-CoA reductase-reduces HMG-CoA to mevalonic
acid in the rate-limiting step of cholesterol
biosynthesis (mainly liver and intestine)
 Lipoprotein Lipase- digests TG core of CMC and VLDL

 Hepatic Lipase-conversion of IDL to LDL

 CETP-transfers cholesteryl esters from HDL to other
lipoproteins in exchange for TG
 LCAT(lecithin cholesterol acyl transferase) conversion
of cholesterol to cholesterol esters
 Apolipoprotein A-major protein of HDL activating
many reactions
 Apo-B-major protein of VLDL, IDL, and LDL

 Apo-CII and Apo E obtained from HDL by CMC and

VLDL for activation of LPL and receptor recognition
respectively
 Why Does HDL-C Protect?

Endothelial repair
Protection against
Anti-inflammatory oxidation

Anti-thrombotic Modulation of
HDL-C endothelial function

Cholesterol Cholesterylester Reverse Cholesterol

acceptor donor Transport (RCT)

Protection of the vessel wall

 What raises HDL?
◦ Uncertain if low carbohydrate diets offer
protection
◦ High MUFA intake
◦ Lifestyle factors ( Exercise)

 Genetic factors influence HDL

 Reverse cholesterol transport

 Maintenance of endothelial function

 Protection against thrombosis

◦ With Apo A-I inhibits generation of calcium-
induced procoagulant activity on erythrocytes
by stabilizing cell membrane

 Low blood viscosity via permitting red cell

deformability

 Anti-oxidant properties-may be related to

enzymes called paraoxonase
 Elevated triglycerides
 Post-prandial lipemia
 Small dense LDL (type B)
Elevated LDL
 Low HDL cholesterol
 Elevated Total
Cholesterol

Nature Medicine 2002

Fat Cells Liver
FFA
CE
IR TG VLDL (CETP) HDL
Apo B (hepatic lipase)
TG
VLDL
CE (CETP) TG Apo A-1

Insulin SD Kidney
LDL
LDL
(lipoprotein
or
hepatic lipase)
Increased Decreased
 Apo B  HDL
 Triglycerides  Apo A-I
 VLDL
 LDL and Small
Dense LDL
 VLDL1 gives rise to
small dense LDL
 Increase TG/Chol
content through
CETP
 Increase
delipidation by
hepatic lipase
  HDL-3, larger with apo
A, C-II, & C-III
 HDL-2, largest, with
additional apo E.
Best negative correlate
CAD
 Other functions
attributed to HDL:
inhibits monocyte
chemotaxis, LDL
oxidation

Tulenko 2002 J Nuclear Cardiology 9:638

Low HDL-cholesterol
Increased catabolism of small dense HDL
Low HDL cholesterol by both content and #
particles
CETP
inhibitors
 High triglycerides
 Post-prandial
lipemia
Fibrate
 Small dense LDL
(type B)
Niacin
Statin
 Low HDL
cholesterol
CETP

ABCA-1
 Familial Hypercholesterolemia – High LDL-C
(Type IIA)
 Polygenic Familial Hypercholesterolemia
 Familial Combined Hyperlipidemia – High LDL-
C and/or high TG levels
 Familial Dyslipidemias –High TG and low HDL
 Familial Dysbetalipoproteinemia (Type III)
Fredrickson-Levy-Lees Classification
Type Lipoprotein Elevation
I Chylomicrons
IIa LDL
IIb LDL + VLDL
III IDL (LDL1)
IV VLDL
V VLDL + Chylomicrons
IDL, intermediate-density lipoprotein
LDL, low-density lipoprotein
VLDL, very-low-density lipoprotein
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th
47
Edition: http://www.accesspharmacy.com
 Lipid Phenotype Plasma Lipid Levels Lipoprotein Phenotype Clinical Signs
[mmol/L (mg/dL)] Elevated
Isolated hypercholesterolemia
Familial Heterozygotes TC = LDL IIa Usually develop
hypercholesterolemi 7–13 (275–500) xanthomas in adulthood
a and vascular disease at
30–50 years
Homozygotes TC LDL IIa Usually develop
>13 (>500) xanthomas in adulthood
and vascular disease in
childhood
Familial defective Heterozygotes TC = LDL IIa
Apo B-100 7–13 (275–500)
Polygenic TC = 6.5–9 (250– LDL IIa Usually asymptomatic
hypercholesterolemi 350) until vascular disease
a develops; no xanthomas
Isolated hypertriglyceridemia
Familial TG = 2.8–8.5 (250– VLDL IV Asymptomatic; may be
hypertriglyceridemia 750) associated with increased
risk of vascular disease
Familial LPL TG >8.5 (750) Chylomicron I, V May be asymptomatic;
deficiency s, VLDL may be associated with
pancreatitis, abdominal
pain,
hepatosplenomegaly
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th
Familial Apo C-II TG >8.5 (>750)
Edition: http://www.accesspharmacy.com
Chylomicron I, V As above 48
 Lipid Phenotype Plasma Lipid Levels Lipoprotein Phenotype Clinical Signs
[mmol/L (mg/dL)] Elevated

Hypertriglyceridemia and hypercholesterolemia

Combined TG = 2.8–8.5 (250– VLDL, LDL IIb Usually asymptomatic

hyperlipidemia 750); TC = 6.5–13 until vascular disease
(250–500) develops; familial
form may present as
isolated high TG or
isolated high LDL
cholesterol
Dysbetalipo- TG = 2.8–8.5 (250– VLDL, IDL; III Usually asymptomatic
proteinemia 750); TC = 6.5–13 LDL normal until vascular disease
(250–500) develops; may have
palmar or
tuboeruptive
xanthomas

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th
49
Edition: http://www.accesspharmacy.com
 Many genetic abnormalities & environmental
factors lead to lipoprotein abnormalities
 Current laboratory values can not define
underlying abnormality
 2˚ hyperlipidemia should be initially
managed by correcting underlying
abnormality when possible

50 50
 Genetic disorder resulting in production of
faulty HDL particles that cannot take up
cholesterol from cells
 High risk for developing cardiovascular
disease
•Can see the platelet
aggregation in response to the
foam cell chemicals and tissue
damage
•The platelets will activate the
coagulation cascade, resulting
in the production of fibrin
strands which trap platelets,
red and white blood cells over
the area = thrombus
•In larger vessels, it takes
longer to develop a thrombus
big enough to completely
block the vessel… so you get
warning signs (TIA, UA) of
stroke and MI
•This process happens
everywhere (brain, heart)
Image courtesy of the Internet Stroke Center at Washington University - www.strokecenter.org
Image courtesy of the Internet Stroke
Center at Washington University -
www.strokecenter.org
 General term for all diseases of the heart and
blood vessels
◦ Atherosclerosis is the main cause of CVD
 Atherosclerosis leads to blockage of blood
supply to the heart, damage occurs (coronary
heart disease, CHD)
◦ Cardio = heart
◦ Vascular = blood vessels

Lipoproteins and cardiovascular disease

(CVD) risk
- LDL is positively associated with CVD

- HDL is negatively associated with CVD

 Age
Men: 45 years
Women: 55 years or premature menopause without estrogen replacement
therapy

Family history of premature CHD (definite myocardial infarction or sudden

death before age 55 years in father or other male first-degree relative, or
before age 65 years in mother or other female first-degree relative)

Cigarette smoking
Hypertension (140/90 mm Hg or taking antihypertensive medication)
Low HDL cholesterol (<40 mg/dL)b

aDiabetes regarded as coronary heart disease (CHD) risk equivalent.

bHDL cholesterol >60 mg/dL counts as "negative" risk factor; its presence removes one risk

factor from the total count.

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th
55
Edition: http://www.accesspharmacy.com
  Athrogenesis

MVS 110: Lecture #11

1. Vasodilatory Endothelial Dysfunction:
Brachial Ultrasound Flow-Mediated Dilation.
2. Atherosclerosis Burden/End-organ Damage:
Carotid IMT, # plaques (based on carotid US),
IVUS, EBCT, advanced CT, MRI
3. General Inflammatory Marker:
hs-C Reactive Protein
4. Markers of Inflamed Endothelium:
ICAM, VCAM, e-Selectin, vWf
5. Other: Homocysteine
 L-Selectin, Monocyte
Integrins
VCAM-
LDL E-Selectin, 1,
P-Selectin ICAM-1

MCP-1
Intima
OxLDL
M-CSF

Other Macrophage
inflammator Activation & Division
y triggers

Media
Smooth Muscle Cell
Migration
Libby et al. Circulation 2002;105:1135-1143.
Oxidation of low-density lipoprotein (LDL) initiates the
atherosclerotic process in the vessel wall by acting as a
potent stimulus for the induction of inflammatory gene
products in vascular endothelial cells. By activating the
nuclear factor B (NFB) transcription factor, oxidized
LDL (oxLDL) stimulates increased expression of cellular
adhesion molecules. There are several different types of
adhesion molecules with specific functions in the
endothelial–leukocyte interaction: The selectins tether
and trap monocytes and other leukocytes. Importantly,
vascular cell adhesion molecules (VCAMs) and
intercellular adhesion molecules (ICAMs) mediate firm
attachment of these leukocytes to the endothelial layer.
OxLDL also augments expression of monocyte
chemoattractant protein 1 (MCP-1) and macrophage-
colony stimulating factor (M-CSF). MCP-1 mediates
the attraction of monocytes and leukocytes and their
diapedesis through the endothelium into the intima.
M-CSF plays an important role in the transformation of
monocytes to macrophage foam cells. Macrophages
express scavenger receptors and take up and
internalize oxLDL in their transformation into foam
cells. Migration of smooth muscle cells (SMCs) from
the intima into the media is another early event
initiating a sequence that leads to formation of a
fibrous atheroma.
 Proinflammatory Risk
Factors

Primary Pro-inflamatory Cytokines

(eg, IL-1, TNF-a)
IL-6
“Messenger”
Cytokine
ICAM-1
Selectins, HSPs, etc. CRP
SAA
Liver
Endothelium
and other cells

Circulation
HSPs=heat shock proteins; SAA=serum amyloid-A.
Adapted from Libby and Ridker. Circulation. 1999;100:1148-1150.
  Total cholesterol: <200 mg/dL
 LDL cholesterol: <130 mg/dL
 HDL cholesterol: >35 mg/dL
 Triglycerides: <200 mg/dL

Desirable Blood Cholesterol

Normal = < 200 mg/dl (5.2 mmol/L)
Borderline = 200-239 mg/dl or (5.2-6mmol/L)
Hypercholesterolemia>240 mg/dl or > 6mmol/L)
 LDL-C = (Past) < 130 mg/dl (2001 < 100)

 LDL-C=total cholesterol - (HDL-C + .2TG)

 HDL-C = (Past) >35 mg/dl (2001) > 40)

 HDL-C = > 60 mg/dl will negate one risk factor
 Normal TG = < 200 mg/dl
 Borderline high = 200-400 mg/dl
 High = 400-1000 mg/dl
 Very High = > 1000 mg/dl
 Life style is a Driver of CVD
Physical Excessive
Life style intervention inactivity food intake
Smoking Stress

Obesity
Hypertension
Risk factor Diabetes
modification Dyslipidaemia

Atherosclerosis Atherosclerosis

Arterial & venous

Chronic Arrhythmia
thrombosis/
heart failure cardiac & cerebral events
At least 3 of
Abdominal obesity: waist circumference > 102 cm (M)
> 88 cm (F)
Hypertriglyceridemia > 150 mg/dl
Low HDL cholesterol< 40 mg/dl (M)
< 50 mg/dl (F)
Hypertension (> 130/85 mm Hg)
Impaired Fasting Glucose or Type 2 diabetes (> 100
mg/dl)
(ATP III. JAMA 285:2486, 2001)
 Type 2 Diabetes
Insulin
Central obesity Resistance Dyslipidemia
Hypertension
Pathophysiology of the metabolic syndrome leading
to atherosclerotic CV disease
Environmental factors
Genetic variation

Abdominal obesity
Adipokines Cytokines

Adipocyte Inflammatory markers Monocyte/

Insulin resistance macrophage
 Tg Metabolic syndrome  HDL
 BP

Atherosclerosis

Plaque rupture/thrombosis
Reilly & Rader 2003;
Eckel et al 2005 Cardiovascular events
 Treatment
◦ NCEP ATP-III guidelines
 Modification of lipids and major risk factors
 See Table 15.9
◦ Medications
 See Table 15.10
◦ Procedures
 Angioplasty
 CABG
 Nicotinic Acid (Niaspan) (muka merah panas)
 Bile Acid Sequestrants (cholestyramine and
colestipol) (otot-otot pegal)
 HMG CoA Reductase Inhibitors (lovastatin,
pravastatin, simvastatin) (kadar kolestertol tinggi)
 Fibric Acid Derivatives (Clofibrate, gemfibrozil)
(kadar trigliserid tinggi)
 Probucol
 Nutrition Therapy
◦ Therapeutic Lifestyle Changes (TLC) developed
as component of ATP-III
 Modifications in fat, cholesterol
 Rich in fruits, vegetables, grains, fiber
 Limit sodium to 2400 mg
 Include stanol esters
 See the next Table for summary
Nutrient Recommended
Intake
 Saturated fat < 7% of total calories
 Polyunsaturated fat Up to 10% of total
calories
 Monounsaturated fat Up to 20% of total
calories
 Total fat 25-30% of total calories
 Carbohydrates 50-60% of total calories
 Fiber 20-30 grams/day
 Protein Approx. 15% of total
calories
 Limit Cholesterol intake <200 mg/day
 Total calories Balance energy intake and
expenditure to maintain
desirable body weight/
prevent weight gain
*Avoid Trans Fats.
 Nutrition Therapy - Other
◦ Increase sources of soluble fiber
◦ Increase intake of plant sterols

◦ Weight loss – BMI 18.5-24.9

◦ Regular physical activity
 Coronary
Angioplasty

 Coronary Bypass
Surgery (CABG)
 Fish Oil (source of omega-3 polyunsaturated fatty acids)
◦ Salmon, flaxseed, canola oil, soybean oil and nuts
◦ At high doses > 6 grams/day reduces TG by inhibition of VLDL-TG
synthesis and apolipoprotein B
◦ Possibly decreases small LDL (by inhibiting CETP)
◦ Several studies have shown lower risk of coronary events
◦ 2 servings of fish/week recommended??
◦ Pharmacologic use restricted to refractory hypertriglyceridemia
◦ Number of undesirable side effects (mainly GI)
 Soy
◦ Source of phytoestrogens inhibiting LDL oxidation
◦ 25-50 grams/day reduce LDL by 4-8%
◦ Effectiveness in postmenopausal women is questionable
 Garlic
◦ Mixed results of clinical trials
◦ In combination with fish oil and large doses (900-7.2 grams/d), decreases
in LDL observed
 Cholesterol-lowering Margarines
◦ Benecol and Take Control containing plant sterols and stanols
◦ Inhibit cholesterol absorption but also promote hepatic cholesterol synthesis
◦ 10-20% reduction in LDL and TC however no outcome studies
◦ AHA recommends use only in hypercholesterolemia pts or those with a cardiac
event requiring LDL treatment
 Other agents include soluble fiber, nuts (esp. walnuts),
green tea
 Overall a combination diet with multiple cholesterol-
lowering agents causes much more significant LDL
reductions
 Fiber: Decreases LDL; increases HDL
◦ Carrots/Grapefruit: Fiber and pectin (whole fruits most
beneficial)
 Avocado: monounsaturated fat
 Beans: High in fiber, low fat; contain lecithin
 Phytosterols: sesame, safflower, spinach, okra,
strawberries, squash, tomatoes, celery, ginger.
 Shiitake mushrooms: contain lentinan (25% reduction in
animal studies)
 Garlic, onion oil: lowers chol. 10-33%
 Omega 3 fish oils
 Red Yeast Rice: a natural substance that inhibits HMG-
CoA reductase. Same ingredient in Lovastatin.