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For

Medical Student Block 7


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
Acyl-Cholesterol Acyl Transferase (ACAT)
Cholesterol

COOH HO Cholesterol
Ester

COO

Lecithin-Cholesterol Acyl Transferase (LCAT)


Lysolecithin COO COO

COO COO

+ N OPOO + N OPOO
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 Chylomicro VLDL IDL LDL HDL
n
Cholesterol 9 22 35 47 19

Triglyceride 82 52 20 9 3

Phospholipi 7 18 20 23 28
d
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
Transports exogeneous ( dietary ) triglycerides
90 - 95 % by weight is triglycerides(dominant)
Absent from fasting plasma
Removed from the plasma within 6 hours by the
liver
Inadequate clearance produces a creamy layer on
the plasma
16
17
Cholest
AA Vessel
wall
FA
P,
glycerol
Exogenous
Dietary
cholesterol Fecal bile
(~300700 mg/day) Intestine acids
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 Harrisons 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.
Exogeneous Pathway
Transport of dietary lipids, mostly the chylomicrons
transportation of triglycerides to the liver

Endogeneous Pathway
Transportation of lipids from the liver to the tissues
( VLDL & LDL )

Effects of hormones
Insulin
Remember, insulin always decreases plasma glucose
Inactivates lipase decreases lipolysis and the catabolism of
triglycerides to fatty acids / glucose
Stimulates lipogenesis ( fatty acid conversion to triglycerides )
Insulin helps make fat
In diabetes mellitus, insulin deficiency promotes the release of
fatty acids and their conversion to triglycerides by the liver

24
Made by liver
Transports endogeneous triglycerides from
liver to tissues
50 - 65 % by weight is triglycerides
Excess dietary carbohydrates are converted
to triglycerides by the liver

Delivers fatty acids to cells


More dense than chylomicrons
A bit more protein (8%):ApoB-100, ApoC, ApoE
Dietary Carbohydrate Increases
VLDL Production

Plasma
Dietary Triglyceride
Carbohydrate (VLDL)
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)
Synthesized in the liver
Approximately 50 % by weight cholesterol
Most atherogenic lipoprotein Bad
Cholesterol
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 -3 fatty acids
High cholesterol Dietary fiber
intake Lifestyle
Lifestyle factors factors
Genetics Genetics
Insulin resistance
Increased
increased NEFA VLDL
and glucose flux to
liver

IR impairs
LDLR
Insulin
Insulin
resistance and FCHL
resistance
decreased apo- and
B degradation DM II
decreased
LPL Metabolic
syndrome
Direct Association Indirect
Longer residence time in
plasma than normal sized LDL Association
due to decreased recognition
by receptors in liver Inverse
Enhanced interaction with relationship
scavenger receptor with HDL
promoting foam cell Marker for
formation
atherogenic TG
More susceptible to oxidation
due to decreased remnant
antioxidants in the core accumulation
Enter and attach more easily Insulin
to arterial wall resistance
Endothelial cell dysfunction
Good cholesterol; major lipid is phospholipid
Lipoprotein made by liver & intestine that circulates
in the blood to collect excess cholesterol from cells
Lowest lipid-to-protein ratio

Composition
30% PHOSPHOLIPIDS
20% CHOLESTEROL

Protein (50%)
ApoA, ApoC, ApoE

Reverse cholesterol transport


Salvage excess cholesterol from cells
Transported back to liver
LDLR

50%ofHDLCmay
Returntotheliver
OnLDLviaCETP
42
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
Anti- against oxidation
inflammatory

Anti-thrombotic Modulation of
HDL-C endothelial function

Cholesterol Cholesterylester Reverse


acceptor donor Cholesterol
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
Triglyceride Apo A-I
s
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
Niacin
(type B) Statin
Low HDL

cholesterol
CETP

ABCA-1
Total Cholesterol : HDL + LDL + Triglycerides/5

LDL : Total Cholesterol (HDL + Triglycerides/5)

HDL : Total Cholesterol (LDL +Triglycerides/5)

VLDL : Triglycerides/ 5
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, 7th59
Edition: http://www.accesspharmacy.com
Lipid Phenotype Plasma Lipid Phenoty Clinical Signs
Levels [mmol/L Lipoprotein pe
(mg/dL)] Elevated
Isolated hypercholesterolemia
Familial Heterozygotes TC = LDL IIa Usually develop
hypercholesterolem 713 (275500) xanthomas in adulthood
ia and vascular disease at
3050 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-100 713 (275500)
Polygenic TC = 6.59 (250 LDL IIa Usually asymptomatic
hypercholesterolem 350) until vascular disease
ia develops; no xanthomas
Isolated hypertriglyceridemia
Familial TG= 2.88.5 (250 VLDL IV Asymptomatic; may be
hypertriglyceridemi 750) associated with
a 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,
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th60
hepatosplenomegaly
Edition: http://www.accesspharmacy.com
Lipid Plasma Lipid Levels Lipoprotein Phenotyp Clinical Signs
Phenotype [mmol/L (mg/dL)] Elevated e

Hypertriglyceridemia and hypercholesterolemia


Combined TG= 2.88.5 (250 VLDL, LDL IIb Usually
hyperlipidemia 750); TC = 6.513 asymptomatic until
(250500) vascular disease
develops; familial
form may present as
isolated high TG or
isolated high LDL
cholesterol
Dysbetalipo- TG= 2.88.5 (250 VLDL, IDL; III Usually
proteinemia 750); TC = 6.513 LDL normal asymptomatic until
(250500) vascular disease
develops; may have
palmar or
tuboeruptive
xanthomas

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th61
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

62 62
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
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

a
Diabetes regarded as coronary heart disease (CHD) risk equivalent.
b
HDL cholesterol>60 mg/dL counts as "negative"risk factor; its presence removes on
factor from the total count.

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th67
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, Monocyt
Integrins e
VCAM-
LDLE-Selectin, 1,
P-Selectin ICAM-1

MCP-1
Intima
OxLDL
M-CSF

Other Macrophage
inflammato Activation &
ry triggers Division

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 (NFB) 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
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
Proinflammatory
Risk Factors

Primary Pro-inflamatory Cytokines


(eg, IL-1, TNF-)
IL-6
Messenger
Cytokine
ICAM-1
Selectins, HSPs, CRP
etc. 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 inactivity food intake
intervention Stress
Smoking

Obesity
Hypertension
Risk factor Diabetes
modificatio Dyslipidaemia
n

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 factor
Genetic variation

Abdominal
Adipokines obesity Cytokines

Adipocyte Inflammatory markers Monocyte/


Insulin resistance macrophag
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)
Bile Acid Sequestrants (cholestyramine and

colestipol)
HMG CoA Reductase Inhibitors (lovastatin,

pravastatin, simvastatin)
Fibric Acid Derivatives (Clofibrate, gemfibrozil)
Probucol
Statin drugs inhibit the
enzyme HMG-CoA reductase
This is an enzyme in the
synthesis pathway of
cholesterol
Statins also increase
cholesterol uptake from the
bloodstream by resulting in
more LDL receptor expression
Vytorin is actually a
combination drug made of
simvastatin and ezetimibe,
(Zetia) which prevents
cholesterol absorption from
the digestive tract.
89
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 Intake Recommended
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 calories Approx. 15% of total
Limit Cholesterol intake <200 mg/day
Total calories Balance energy intake and
expenditure to maintain
desirable body weight/ prevent weight gain

*Avoid Trans Fats.


*Increase Intake of Omega -3 essential Fatty Acids
*From Journal Of the American Medical Association 285 :2486-
97(2001)
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.