Structure of Lipoproteins

Free cholesterol

Phospholipid Triglyceride

Apolipoprotein 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
Cancer
worldwide (1996)6.3
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 Leukocyte
endothelial adhesion
adhesion molecules

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

Formation of
necrotic core
Accumulation of
macrophages

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
Growth of thrombus
Intraluminal 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
Remnant
Remnant
Chylomicron
Chylomicron receptor
receptor
FFA remnant
remnant
to
to atheroma
atheroma

Adipose
Adipose
tissue
tissue
 Endogenous Pathway of Lipid
Metabolism

LPL
LPL Lipoprotein
Lipoprotein lipase
lipase

HL
HL Hepatic
Hepatic lipase
lipase
LPL
LDL
LDL
IDL
IDL
LDL HL LPL
LDL
receptor
receptor
HL Small
Small
VLDL
VLDL LPL

HL Large
Large
VLDL
VLDL
Liver
Liver
 Reverse Cholesterol Transport
cholesterol transport

Cell
membrane Liver
SRB1

LDL
CE CE receptor
FC
ABCA1 VLDL, IDL, LDL
LCAT CETP
HDL HDL3
TG

Peripheral
tissues

FC Free cholesterol
TG Triglycerides
CE Cholesterol esters
LCAT Lecithin cholesterol acyl transferase
CETP 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
Metabolisme
Synthesis Pathway
acetyl CoA
lemak
HMG-CoA synthase
HMG-CoA
HMG-CoA reductase 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