Structure of Lipoproteins

Free cholesterol
Phospholipid

Apolipoprotein

Triglyceride

Cholesteryl ester

LDL-Cholesterol
Strongly associated with atherosclerosis
and CHD events
10% increase results in a 20% increase
in CHD risk
Risk associated with LDL-C is increased by other
risk factors:
low HDL-cholesterol
smoking
hypertension
diabetes

LDL-Cholesterol
Strongly associated with atherosclerosis
and CHD events
10% increase results in a 20% increase
in CHD risk
Risk associated with LDL-C is increased by other
risk factors:
low HDL-cholesterol
smoking
hypertension
diabetes

HDL-Cholesterol
HDL-cholesterol has a protective effect for risk
of atherosclerosis and CHD
The lower the HDL-cholesterol level, the
higher the risk for atherosclerosis and CHD
low level (<40 mg/dL) increases risk

HDL-cholesterol tends to be low when

triglycerides are high
HDL-cholesterol is lowered by smoking,
obesity and physical inactivity

Triglycerides

Associated with increased risk of CHD events

Link with increased CHD risk is complex
may be related to:

low HDL levels

highly atherogenic forms of LDL-cholesterol
hyperinsulinaemia/insulin resistance
procoagulation state
hypertension
abdominal obesity

May have accompanying dyslipidaemias

Normal triglyceride levels <150 mg/dL
Very high triglycerides (>1000 mg/dL,
11.3 mmol/L) increase pancreatitis risk

Cardiovascular disease is the

leading cause
of death among adults
Coronary disease
7.2 million
worldwide (1996)6.3
Cancer
Cerebrovascular disease

4.6

Acute lower respiratory tract infections

3.9

Tuberculosis

3.0

COPD (chronic obstructive pulmonary disease)

2.9

Diarrhea (including dysentery)

2.5

Malaria

2.1

AIDS

1.5

Hepatitis B

1.2

Endothelial Dysfunction in
Atherosclerosis
Upregulation of
endothelial
adhesion molecules

Leukocyte
adhesion

Increased
endothelial
permeability
Migration of
leukocytes
into the
artery wall

Adapted from Ross R. N Engl J Med 1999;362:115126

Fatty Streak Formation in

Atherosclerosis
Adherence and
entry of
leukocytes

Migration of
smooth
muscle cells

Formation
of foam cells

Activation of T cells
Adherence and aggregation of
platelets
Adapted from Ross R. N Engl J Med 1999;362:115126

Formation of the Complicated

Atherosclerotic Plaque
Formation of
the fibrous cap

Accumulation of
macrophages

Formation of
necrotic core

Adapted from Ross R. N Engl J Med 1999;362:115126

The Unstable Atherosclerotic

Plaque

Thinning of the
fibrous cap

Haemorrhage from
plaque
microvessels
Rupture of the
fibrous cap

Adapted from Ross R. N Engl J Med 1999;362:115126

Atherosclerotic Plaque
Rupture and Thrombus
Formation
Intraluminal thrombus

Growth of thrombus

Blood Flow

Intraplaque thrombus

Lipid pool

Adapted from Weissberg PL. Eur Heart J Supplements 1999:1:T1318

The Vulnerable Atherosclerotic

Plaque

Adapted from Libby P. Circulation 1995;91:28442850

Exogenous Pathway of Lipid

Metabolism
Intestine
Intestine

Dietary
Dietary
triglycerides
triglycerides
and
and cholesterol
cholesterol

Chylomicron
Chylomicron
LP
LP lipase
lipase
Liver
Liver

Skeletal
Skeletal muscle
muscle
FFA

Chylomicron
Chylomicron
remnant
remnant

Remnant
Remnant
receptor
receptor
to
to atheroma
atheroma

Adipose
Adipose
tissue
tissue

Endogenous Pathway of Lipid

Metabolism

LPL
LPL Lipoprotein
Lipoprotein lipase
lipase
HL
HL
LDL
LDL
LDL
LDL
receptor
receptor

LPL
HL

IDL
IDL
HL

LPL

Small
Small
VLDL
VLDL LPL
HL

Liver
Liver

Large
Large
VLDL
VLDL

Hepatic
Hepatic lipase
lipase

Reverse Cholesterol
Transport
cholesterol transport
Cell
membrane

CE

CE
ABCA1

Liver

SRB1

FC
LCAT
HDL

CETP
HDL3

LDL
receptor
VLDL, IDL, LDL

TG
Peripheral
tissues

FC
TG
CE
LCAT
CETP

Free cholesterol
Triglycerides
Cholesterol esters
Lecithin cholesterol acyl transferase
Cholesteryl ester transfer protein

The Synthesis and

Breakdown of Atheromatous
Plaques

Adapted from Libby P. Circulation 1995;91:28442850

Statins and Lipid-modifying

Therapies

Mechanism of Action of Statins:

Cholesterol
Synthesis
Pathway
Metabolisme
acetyl CoA

lemak

HMG-CoA
HMG-CoA reductase

HMG-CoA synthase

X Statins

squalene
cholesterol

ATHEROSCLEROSIS
The global epidemic of
modern living

Coronary mortality:
alarming worldwide forecasts

Atherosclerosis:
a multifactorial disease

Main risk factors for coronary

heart disease

Atherosclerosis

Arterial wall:
structure and function

~10% Weight loss = ~30%

Visceral
adipose tissue loss

Classification of lipids and

lipoproteins

Characteristics of lipoproteins

Triglyceride-rich lipoproteins:
size, structure and composition

Digestion and metabolism of

dietary fat

How to reduce plaque formation

Intervention on risk factors