PATHOGENESIS

Lipoprotein Classification and

Composition
The plasma lipoproteins are divided into five
major classes based on their relative density

chylomicrons
very low density lipoproteins
(VLDLs)
intermediate-density lipoproteins
(IDLs)
low-density lipoproteins (LDLs)
high-density lipoproteins (HDLs)
 The density of a lipoprotein is determined by the
amount of lipid per particle.
HDL is the smallest and most dense lipoprotein,
whereas chylomicrons and VLDLs are the largest
and least dense lipoprotein particles.
Most plasma triglyceride is transported in
chylomicrons or VLDLs, and most plasma
cholesterol is carried as cholesteryl esters in LDLs
and HDLs.
The density and size-distribution of the major classes of lipoprotein particles.
Lipoprotein Classification and
Composition
Lipoproteins are large macromolecular complexes that transport hydrophobic lipids
(primarily triglycerides, cholesterol, and fat-soluble vitamins) through body fluids
(plasma, interstitial fluid, and lymph) to and from tissues.

Lipoproteins play an essential role in the

1. absorption of dietary cholesterol, long-chain fatty acids, and fat-soluble vitamins
2. transport of triglycerides, cholesterol, and fat-soluble vitamins from the liver to
peripheral tissues
3. transport of cholesterol from peripheral tissues to the liver.
The exogenous and endogenous lipoprotein metabolic pathways. The exogenous pathway transports dietary
lipids to the periphery and the liver. The endogenous pathway transports hepatic lipids to the periphery. LPL,
lipoprotein lipase;
Various classes of blood lipids are transported as
lipoproteins complexed to specific apoproteins.

Dyslipoproteinemias result from either mutations that yield

defective apolipoproteins or some other underlying disorder,
such as the nephrotic syndrome, alcoholism, hypothyroidism,
or diabetes mellitus.

Examples of lipoprotein abnormalities frequently found in the

population (and, indeed, present in many myocardial
infarction survivors) are:

(1) increased LDL cholesterol levels,

(2) decreased HDL cholesterol levels, and
(3) increased levels of the abnormal lipoprotein Lp(a)
 hypercholesterolemia

1. The major lipids in atheromatous plaques are plasma-derived

cholesterol and cholesterol esters.

2. Oxidized LDL is observed in macrophages in arteries at sites of fatty

streaks. Antioxidant treatment protects against the development of
atherosclerosis in hypercholesterolemic experimental animals.
3. Genetic defects in lipoprotein metabolism causing
hyperlipoproteinemia are associated with accelerated
atherosclerosis.
For example, homozygous familial hypercholesterolemia, which often
results in myocardial infarction before age 20 years, is caused by
defects in the LDL receptor, leading to inadequate hepatic uptake of
LDL and markedly increased circulating LDL.
This is also seen experimentally when atherosclerosis is induced in
animals genetically modified to have abnormal lipid metabolism (such
as apolipoprotein-deficient and LDL receptor-deficient mice).
4. Other genetic or acquired disorders (e.g., diabetes
mellitus, hypothyroidism) that cause hypercholesterolemia
lead to premature and severe atherosclerosis.

5. Experimental animals fed high-cholesterol diets develop

atherosclerosis-like vascular lesions.

6. Epidemiologic analyses demonstrate a significant

correlation between the severity of atherosclerosis and
the levels of total plasma cholesterol or LDL cholesterol.
7. Lowering levels of serum cholesterol by diet or drugs slows
the rate of progression of atherosclerosis, causes
regression of some plaques, and reduces the risk of
cardiovascular events.
Indeed, lowering cholesterol increases overall survival and reduces
risk of atherosclerosis-related events in patients with established
coronary heart disease who have elevated or average cholesterol
levels, as well as in patients with hypercholesterolemia, but without
overt atherosclerosis-related disease.
Hypercholesterolemia, may
directly impair EC function Chemical change of lipid
through increased induced by free radicals
production of oxygen free generated in
radicals that deactivate NO, macrophages or ECs in
the major endothelial- the arterial wall yields
relaxing factor. oxidized (modified) LDL.

With chronic
hyperlipidemia,
lipoproteins accumulate
within the intima at sites
of increased endothelial
permeability.
 ingested by
macrophages through
the scavenger
receptor, distinct from
the LDL receptor, thus
forming foam cells;

increases
cytotoxic to Oxidized monocyte
ECs and SMCs.
LDL accumulation
in lesions

stimulates
release of
growth factors
and cytokines