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BIOCHEMISTRY

LIPOPROTEINBY&
Dr.Liniyanti D.Oswari, MNS,
DYSLIPIDEMIA
MSc.

Learning Objectives

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

Lipoproteins

Clusters of lipids associated with


proteins that serve as transport vehicles
for lipids in the lymph and blood

Lipoproteins

Chylomicrons
VLDL Very low density lipoprotein
IDL Intermediate density
lipoprotein
LDL Low density lipoprotein
HDL High density lipoprotein

Lipoproteins

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

Lipoproteins

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

Lipids (%) in Plasma


Lipoproteins
Chylomicro
n

VLDL

IDL

Cholesterol

22

35

47

19

Triglyceride

82

52

20

Phospholipi
d

18

20

23

28

Lipid

LDL HDL

The Origins & Major


Functions of Lipoproteins

Functions of Chylomicrons

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

Further Delivery of Lipids in


Body

Liver

Synthesizes & metabolizes lipids


Central command center for
relation of lipid metabolism
Makes additional lipoproteins

Exogenous Pathway of Lipid


Metabolism

Cholest
AA
FA
P,
glycerol

Vessel
wall

Endogenous Pathway of Lipid


Metabolism

Endogenous & Exogenous Sources of


Cholesterol
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.

Endogenous & Exogenous


Cholesterol

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

Cholesterol Absorption in the Intestine

1000 mg

Inhibitors

Resins

Plant stanols

NPC1L1
(Ezetimibe)

There are several steps


involved in the absorption of
cholesterol from the intestinal
Cholesterol that is absorbed from the intestinal
lumen.

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.

Very-Low-Density
Lipoproteins (VLDL)

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

VLDL life cycle


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

3
1
2
4

Intermediate-Density
Lipoproteins (IDL)

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)

Low-Density Lipoproteins
(LDL)

Bad cholesterol; major lipid in LDL


Delivers cholesterol from liver to cells

Protein (21%)

Cell membranes
Hormone production
ApoB-100
Binds to specific LDL receptor

LDL receptors

Membrane-bound proteins that bind LDL,


causing them to be taken up & dismantled

Effect of Diet on LDL


Concentrations

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

LDL Oxidation and


Atherosclerosis

Mechanism of Atherogenic
Dyslipidemia
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

Increased Atherogenicity of Small


Dense LDL

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

High-Density Lipoproteins
(HDL)

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

HDL Metabolism

Key Enzymes and Cofactors in


Lipid Metabolism

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)

Effects of Diet on HDL


Concentration

What raises HDL?

Uncertain if low carbohydrate diets


offer protection
High MUFA intake
Lifestyle factors ( Exercise)

Genetic factors influence HDL

High Density Lipoprotein &


Atherosclerosis

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

Dyslipidemia Characteristics

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

Nature Medicine 2002

Mechanisms Relating
Insulin Resistance and
Dyslipidemia
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

Dyslipidemia in
Diabetes
Increased
Decreased
Apo B
HDL
Triglycerides
Apo A-I
VLDL
LDL and
Small Dense
LDL

Insulin Resistance:
Associated Conditions

Small dense LDL

VLDL1 gives rise to


small dense LDL
Increase TG/Chol
content through
CETP
Increase
delipidation by
hepatic lipase

Low HDL-cholesterol

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

Low HDL-cholesterol
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

Current Classifications

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)

Tangier Disease

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

Cardiovascular disease
(CVD)

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

Coronary Heart Disease


Athrogenesis
[CHD]

MVS 110: Lecture


#11

Lipoproteins and
cardiovascular disease (CVD)
LDL is positively associated with
risk
CVD

HDL is negatively associated with


CVD

A Plethora of Non-Lipid Markers of


Risk
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

Atherosclerosis Is an Inflammatory
Disease
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

Atherosclerosis Is an Inflammatory
Disease
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
endothelialleukocyte interaction: The selectins
tether and trap monocytes and other
leukocytes. Importantly, vascular cell adhesion
molecules (VCAMs) and intercellular adhesion

Atherosclerosis Is an Inflammatory
Disease

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

The Acute-Phase Response


Pathway
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.

LDL and atherosclerosis

Recommended blood lipids


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)

Desirable Levels LDL & HDL


Continued

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

Desirable Levels Triglyceride


Continued
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

Definition:(NCEP)
National Cholesterol Education Program (2001)
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)

Pathogenesis of the Metabolic


Syndrome

Central
obesity

Insulin
Resistan
ce

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

Treatment

NCEP ATP-III guidelines

Medications

Modification of lipids and major risk


factors
See Table 15.9
See Table 15.10

Procedures

Angioplasty
CABG

Drugs

Nicotinic Acid (Niaspan)


Bile Acid Sequestrants (cholestyramine
and colestipol)
HMG CoA Reductase Inhibitors
(lovastatin, pravastatin, simvastatin)
Fibric Acid Derivatives (Clofibrate,
gemfibrozil)
Probucol

Treatment

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 Table 15.11 for summary, complete
guidelines in Appendix E9

Nutrient Recommendations of TLC


Diet
Nutrient
(TLC=
Therapeutic
lifestyle
Recommended Intake
Changes)
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.
* Increase Intake of Omega -3 essential Fatty Acids

Nutrition Therapy - Other

Increase sources of soluble fiber


Increase intake of plant sterols
Weight loss BMI 18.5-24.9
Regular physical activity

Medical Treatments

Coronary
Angioplasty

Coronary Bypass
Surgery (CABG)

Diet Supplements

Fish Oil (source of omega-3 polyunsaturated fatty acids)

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

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)

Cholesterol Control With


Foods and Herbs

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.