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
TG

B-100,C-II,E

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

Chylomicro
n

VLDL

IDL

Cholesterol

22

35

47

19

Triglyceride

82

52

20

Phospholipi
d

18

20

23

28

Lipid

LDL HDL

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

12

13

Cholest
AA
FA
P,
glycerol

Vessel
wall

Dietary
cholesterol

Exogenous
Intestine

(~300700 mg/day)

Biliary
cholesterol

Fecal bile
acids
and neutral
sterols

~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
20

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

1- Assembly and
secretion
2- Hydrolysis by LPL
3- Direct uptake by
hepatocyte
4- Flux of pathway
into LDL

3
1
2
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

SFAs
Trans fatty acids
High cholesterol
intake
Lifestyle factors
Genetics

Decrease

LDL
High PUFA diet
-3 fatty acids
Dietary fiber
Lifestyle
factors
Genetics

Insulin resistance
increased NEFA
and glucose flux to
liver

Increased
VLDL

IR impairs
LDLR
Insulin
resistance and
decreased apoB degradation

Insulin
resistance
and
decreased
LPL

FCHL
DM II
Metabolic
syndrome

Direct Association

Longer residence time in

plasma than normal sized LDL
due to decreased recognition
by receptors in liver
Enhanced interaction with
scavenger receptor
promoting foam cell
formation
More susceptible to oxidation
due to decreased
antioxidants in the core
Enter and attach more easily
to arterial wall
Endothelial cell dysfunction

Indirect

Association
Inverse
relationship
with HDL
Marker for
atherogenic TG
remnant
accumulation
Insulin
resistance

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

33

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 oxidation

Antiinflammatory
Anti-thrombotic

Modulation of
endothelial function

HDL-C

Cholesterol
acceptor

Cholesterylester
donor

Protection of the vessel wall

Reverse
Cholesterol
Transport (RCT)

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 calciuminduced 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

IR

Insulin

CE
TG
VLDL (CETP) HDL
(hepatic lipase)
Apo B
TG
VLDL
Apo A-1
CE (CETP) TG
LDL

SD
LDL

(lipoprotein
or
hepatic lipase)

Kidney

Increased
Apo B
Triglyceride
s
VLDL
LDL and
Small Dense
LDL

Decreased
HDL
Apo A-I

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
Small dense LDL
(type B)
Low HDL
cholesterol

Fibrate
Niacin
Statin

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 LDLC and/or high TG levels
Familial Dyslipidemias High TG and low HDL
Familial Dysbetalipoproteinemia (Type III)

Fredrickson-Levy-Lees Classification
Type

Lipoprotein Elevation

Chylomicrons

IIa

LDL

IIb

LDL + VLDL

III

IDL (LDL1)

IV

VLDL

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, 7th50
Edition: http://www.accesspharmacy.com

Lipid Phenotype

Plasma Lipid
Phenoty
Levels [mmol/L
Lipoprotein pe
(mg/dL)]
Elevated
Isolated hypercholesterolemia
Familial
Heterozygotes TC = LDL
IIa
hypercholesterolem 713 (275500)
ia

Clinical Signs

Homozygotes TC
>13 (>500)

LDL

IIa

Usually develop
xanthomas in adulthood
and vascular disease in
childhood

Familial defective
Apo B-100

Heterozygotes TC = LDL
713 (275500)

IIa

IIa

Usually asymptomatic
until vascular disease
develops; no xanthomas

IV

Asymptomatic; may be
associated with
increased risk of
vascular disease

Polygenic
TC = 6.59 (250
hypercholesterolem 350)
ia

LDL

Isolated hypertriglyceridemia
Familial
TG= 2.88.5 (250 VLDL
hypertriglyceridemi 750)
a
Familial LPL
deficiency

TG>8.5 (750)

May be asymptomatic;
may be associated with
pancreatitis, abdominal
pain,
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic
Approach, 7th51
hepatosplenomegaly
Edition: http://www.accesspharmacy.com

Chylomicron I, V
s, VLDL

Usually develop
xanthomas in adulthood
and vascular disease at
3050 years

Lipid
Phenotype

Plasma Lipid Levels Lipoprotein Phenotyp Clinical Signs

[mmol/L (mg/dL)]
Elevated
e

Hypertriglyceridemia and hypercholesterolemia

Combined
TG= 2.88.5 (250
VLDL, LDL
IIb
hyperlipidemia 750); TC = 6.513
(250500)

Dysbetalipoproteinemia

TG= 2.88.5 (250

750); TC = 6.513
(250500)

VLDL, IDL;
LDL normal

III

Usually
asymptomatic until
vascular disease
develops; familial
form may present as
isolated high TG or
isolated high LDL
cholesterol
Usually
asymptomatic until
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, 7th52
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

53 53

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

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

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.
a

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th58
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,
Integrins
VCAMLDLE-Selectin,
1,
P-Selectin
ICAM-1

Monocyt
e

MCP-1
OxLDL

Intima

M-CSF
Other
inflammato
ry triggers

Macrophage
Activation &
Division

Media
Libby et al. Circulation 2002;105:1135-1143.

Smooth Muscle Cell

Migration

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-)

ICAM-1
Selectins, HSPs,
etc.
Endothelium
and other
cells

IL-6
Messenger
Cytokine

CRP
SAA

Liver

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 (5.26mmol/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

Life style
intervention

Physical
inactivity

Excessive
food intake
Stress

Smoking
Obesity

Hypertension

Risk factor
modificatio
n

Diabetes
Dyslipidaemia

Atherosclerosis

Chronic
heart failure

Atherosclerosis

Arterial & venous

thrombosis/
cardiac & cerebral events

Arrhythmia

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)

Central
obesity

Insulin
Resistanc
e

Type 2
Diabetes
Dyslipidemi
a
Hypertensio
n

Pathophysiology of the metabolic syndrome

leading to atherosclerotic CV disease

Environmental factor

Genetic variation

Abdominal
Adipokines obesity
Adipocyte

Cytokines

Monocyte/
macrophag

Inflammatory markers
Insulin resistance
Tg

Metabolic syndrome

HDL

BP

Atherosclerosis

Reilly & Rader

2003;
Eckel et al 2005

Plaque rupture/thrombosis

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.
80

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 :248697(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 VLDLTG 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 cholesterollowering 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 HMGCoA reductase. Same ingredient in Lovastatin.