BIOCHEMISTRY

LIPOPROTEIN &
DYSLIPIDEMIA
For
Medical Student Block 7
Sriwijaya University
BY
Dr.Liniyanti D.Oswari, MNS, MSc.
2019
 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

DIPA Fakultas Kedokteran

Universitas Sriwijaya

Clusters of lipids associated with proteins

that serve as transport vehicles for lipids
in the lymph and blood
Cholesterol Ester
Synthesis
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
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 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
APOPROTEINS
The protein part of lipoproteins are
known as apolipoproteins, or simply,
apoproteins.
Functions of major
apoproteins
 Type Association Function

B48 Chylomicron Carry cholesterol

esters
Lacks LDL recpt
binding domain

B100 VLDL,IDL,LDL Binds LDL recpt.

C-II Chyl. VLDL, IDL, HDL Activates LPL

C-III Chyl. VLDL, IDL, HDL Inhibits LPL

E Chyl. Remnant, VLDL, IDL Binds LRP

HDL
A-1 HDL/Chylomicron LCAT activator
(lecithin:cholesterol
acyltransferase)
 Lipids (%) in Plasma
Lipoproteins
Lipid Chylomicron VLDL IDL LDL HDL
Cholesterol 9 22 35 47 19

Triglyceride 82 52 20 9 3

Phospholipid 7 18 20 23 28
The Origins&Major Functions of
Lipoproteins
 Regulation of Lipoprotein
Lipase
Fed state - LPL synthesis and activity
(adipocytes)
LPL synthesis and activity (skeletal
and heart muscle)

Fasted/ LPL synthesis and activity

- (adipocytes)
LPL synthesis and
exercise
activity (muscle)
state

Lactating
- LPL
activity
Mammary
gland
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
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
21
22
Exogenous Pathway of Lipid
Metabolism

Cholest
AA Vessel wall
FA
P,
glycerol
Endogenous Pathway of Lipid
Metabolism
Endogenous & Exogenous Sources of
Cholesterol

Exogenou
Dietary
cholesterol
s Fecal bile acids
(~300–700 Intest and neutral
mg/day) ine sterols
Biliary
cholesterol ~700
(~1000
mg/day) mg/day
Liv
Synthesis
er
(~800
mg/day)
Extrahepati
c
tissues
Endogenou
s
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.
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 lumen.
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
31
Very-Low-Density Lipoproteins
(VLDL)
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)
 VLDL life cycle

1- Assembly and
secretion
3
2- Hydrolysis by LPL
3- Direct uptake by 1
hepatocyte
4- Flux of pathway 2
into LDL
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)
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
Effect of Diet on LDL
Concentrations
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
LDL Oxidation &
Atherosclerosis
Mechanism of Atherogenic
Dyslipidemia

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
Increased Atherogenicity of Small
Dense LDL
Direct Association
◦ Longer residence time in Indirect
plasma than normal sized LDL
due to decreased recognition
Association
by receptors in liver ◦ Inverse
◦ Enhanced interaction with relationship with
scavenger receptor promoting HDL
foam cell formation
◦ More susceptible to oxidation
◦ Marker for
due to decreased antioxidants atherogenic TG
in the core remnant
◦ Enter and attach more easily to accumulation
arterial wall ◦ Insulin
◦ Endothelial cell dysfunction
resistance
High-Density Lipoproteins
(HDL)
“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
HDL and Reverse Cholesterol
Transport

LDL-R

50% of HDL C may

Return to the liver
On LDL via CETP
HDL Metabolism
49
 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
Anti-inflammatory oxidation

Anti-thrombotic Modulation of
HDL-C endothelial function

Cholesterol Cholesterylester Reverse Cholesterol

acceptor donor Transport (RCT)

Protection of the vessel wall

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

Nature Medicine
Mechanisms Relating Insulin
Resistance and Dyslipidemia
Fat Live
Cells r
↑FFA
CE
↑TG ↑VL (CETP)
IR HD
DL
↑Apo B TG L (hepatic lipase)
↑VLDL
CE (CETP) TG Apo A-1

S
Insulin D Kidne
LD
LD y
L
L
(lipoprotein
or
hepatic lipase)
Dyslipidemia in Diabetes

Increased Decreased
Apo B HDL
Triglyceride Apo A-I
s
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
inhibit
ors
High triglycerides
Post-prandial
lipemia Fibrat
Small dense LDL e
Niaci
(type B) Stati
n
n
Low HDL
cholesterol
CETP

ABCA-1
How to count Total Cholesterol
& LDL & HDL
Total Cholesterol : HDL + LDL + Triglycerides/5

LDL : Total Cholesterol – (HDL + Triglycerides/5)

HDL : Total Cholesterol – (LDL +Triglycerides/5)

VLDL : Triglycerides/ 5
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)
 Hyperlipoproteinemia
Classification
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
66
Edition: http://www.accesspharmacy.com
 Lipid Phenotype Plasma Lipid Lipoprotein Phenoty Clinical Signs
Levels [mmol/L Elevated  pe 
(mg/dL)]
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 LDL IIa Usually asymptomatic
hypercholesterolemi (250–350) until vascular disease
a develops; no xanthomas
Isolated hypertriglyceridemia 
Familial TG = 2.8–8.5 VLDL IV Asymptomatic; may be
hypertriglyceridemia (250–750) 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,
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th
hepatosplenomegaly 67
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 = 2.8–8.5 VLDL, LDL IIb Usually asymptomatic

hyperlipidemia (250–750); TC = 6.5–13 until vascular disease
(250–500) develops; familial
form may present as
isolated high TG or
isolated high LDL
cholesterol
Dysbetalipo-prot TG = 2.8–8.5 VLDL, IDL; III Usually asymptomatic
einemia (250–750); 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
68
Edition: http://www.accesspharmacy.com
Etiology
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

69 69
 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

Lipoproteins and cardiovascular disease

(CVD) risk
- LDL is positively associated with CVD

- HDL is negatively associated with CVD

 a
Risk Factors
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 one risk
factor from the total count.

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th
74
Edition: http://www.accesspharmacy.com
 Coronary Heart Disease
[CHD]
Athrogenesis

MVS 110: Lecture #11

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
5. Other: Homocysteine
Atherosclerosis Is an Inflammatory
Disease
L-Selectin, Monocyte
Integrins
VCAM-1
LDL E-Selectin, ,
P-Selectin ICAM-1

MCP-
1 Inti
OxLDL
ma
M-CS
F
Other Macrophage
inflammator Activation & Division
y triggers

Medi
a
Smooth Muscle
Libby et al. Circulation Cell
2002;105:1135-1143. 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 κB (NFκB) 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.
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 a sequence that leads to formation of
a fibrous atheroma.
 The Acute-Phase Response Pathway

Proinflammatory Risk
Factors

Primary Pro-inflamatory Cytokines

(eg, IL-1, TNF-α)
IL-6
“Messenger”
Cytokine
ICAM-1
Selectins, HSPs, etc. CR
P
SA
Live
Endothelium
and other cells A r

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
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
Effect of Exercise

Increases LPL activity in muscle.

Reduces TGL from the particle.
Reduction in weight
Increases HDL
Effect of diet
Vegetarian diet – Cholesterol intake less
Reduced Carbohydrate – VLDL TG Reduced
Reduced Fat – Reduces CM TG
Unsaturated fats ( Mono and Poly)- Reduction
in Plasma cholesterol
Fiber – decreases cholesterol absorption
 Postprandial Changes in
Plasma Lipid Metabolism
Fat storage via LPL

Exchange of cholesterol for VLDL TG in HDL (CETP)

LCAT activity = esterification of free cholesterol (HDL)

These postprandial changes are beneficial in

maintaining whole body homeostasis of glycerides
and cholesterol
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

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

Treatment
◦ NCEP ATP-III guidelines
● Modification of lipids and major risk factors
● See Table 15.9
◦ Medications
● See Table 15.10
◦ Procedures
● Angioplasty
● CABG
Medicines

Nicotinic Acid (Niaspan)

Bile Acid Sequestrants (cholestyramine and
colestipol)
HMG CoA Reductase Inhibitors (lovastatin,
pravastatin, simvastatin)
Fibric Acid Derivatives (Clofibrate, gemfibrozil)
Probucol
Statin Drugs (optional slide)
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.
99
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 the next Table for summary
Nutrient Recommendations of TLC Diet
(TLC= Therapeutic lifestyle Changes)
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)
Type of Lipids
Saturated fat
◦Animal oil like meat, milk, butter
◦Vegetable oil like coconut and
palm kernel oil
Polyunsaturated fat
◦Plan source like safflower, corn,
cottonseed, sunflower oil and
soybean oil
Monounsaturated fat
◦Plant and animal product like olive
oil, canola oil, avocado and peanut
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)
◦ 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
Cholesterol Control With Foods &
Herbs
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.
Prevention of Lipid Disorder
Reduce fat
◦Cut down on high fat foods
◦E.g. butter, margarine, oil,
mayonnaise
Consume small amounts of
unsaturated fats
◦Do not eliminate fat
completely since it is high in
calories
Prevention of Lipid
Disorder
Limit added sugar and alcohol
◦Added sugar and alcohol are
‘empty calories’
Watch portions of all food
◦‘fat free’ ≠ ‘calorie-free’
Drink at least 8 glasses of
water everyday
◦Water is calorie-free, refreshing,
and filling
Prevention of Lipid Disorder
Increase intake of
vegetables, fruits, and
whole grains
◦Loaded with fiber
◦Contain high amounts of
vitamins, minerals, and
phytonutrients
Include low-fat protein-rich
food with every meal
◦E.g. tofu, beans, eggs, and fish
Prevention of Lipid Disorder

Slow down when eating

◦Too fast eating will exceed
calorie needs before realizing
we are full