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chapter20
Lipids III: Plasma Lipoproteins
disease,
which is rare, and the more common
fa m ilia l H D L
deficiency.
Polymorphisms in the ABC 1-transporter pro-
tein may lead to variations in HDL cholesterol levels in-
creasing the risk for premature coronary artery disease.
The rate of apo A-I catabolism is regulated by the size and
composition of the particle on which it resides. Smaller
lipid-depleted particles have a higher rate of catabolism.
In the absence of cholesterol efflux from cells, nascent
HDL is not formed and apo A-I is rapidly cleared from the
plasma. Modifications in HDL size are the result of the ac-
tion of enzymes which either esterify cholesterol (LCAT),
transfer cholesteryl esters (CETP), or hydrolyze HDL
lipids (hepatic lipase, lipoprotein lipase). Apo A-II, which
is present on larger HDL particles, inhibits hydrolysis of
HDL-triacylglycerol and phospholipids by hepatic lipase,
thereby retarding catabolism of larger HDL particles.
HDL binding sites have been reported in several tis-
sues. The interaction appears to be mediated by apo A-I.
However, a lipid-lipid interaction may mediate HDL-to-
cell binding in fibroblasts and smooth muscle cells. In
macrophages, binding occurs via apo A-I. HDL in the
macrophage then gains apo E and cholesterol from intra-
cellular lipid droplets. The apo E-enriched and cholesterol-
enriched HDL are then secreted (retroendocytosis) into the
plasma. An increase in the apo E concentration increases
HDL uptake by the liver. The liver and kidneys are believed
to be the principal organs for HDL catabolism.
20.3 Lipoprotein-Associated Disorders
TA BLE 20-4
Generalized Cutoff Values fo r Hyperlipidemia (95th
percentile)*
Age
(years)
Cholesterol
(mg/dL)
Triacylglycerol
(mg/dL)
1-9
200
120
10-19
205
140
20-29
210
140
30-39
240
150
40-49
265
160
>50
265
190
* Values were obtained from subjects who had fasted for 12-14 hours.
Hyperlipidemia occurs when levels are above these values.
H yperlipoprotein em ias
can be primary (genetic) or sec-
ondary. Some causes of secondary hyperlipoproteinemias
include diabetes mellitus, hypothyroidism, nephrotic syn-
drome, uremia, ethanol abuse, primary biliary cirrhosis,
and intake of oral contraceptives. Primary disorders can be
due to a single-gene defect or to a combination of genetic
defects. The latter type, known as multifactorial or poly-
genic hyperlipoproteinemias, are affected by secondary
disorders and environmental insults, such as a diet high in
saturated fat and cholesterol, obesity, and ethanol abuse.
In general, the polygenic hyperlipoproteinemias are more
common and exhibit lower plasma lipid levels than do the
single-gene defects.
Individuals in a given population who have plasma choles-
terol and triacylglycerol values that fall in the upper 5-1
0%
of the normal range are arbitrarily considered abnormal.
These values are age and sex-dependent. However, “nor-
mal” values for one population may be associated with a
high risk of heart disease, whereas for another population
they may be quite benign. This difference between the sta-
tistical “normal” for a population and the levels generally
associated with good health should be recognized. Values
in Table 20-4 represent the 95th percentile for the North
American population.
A practical classification of disorders of lipid trans-
port is based on concentrations of the major classes of
lipoproteins in plasma (Table 20-5). Lipoprotein pheno-
typing is carried out by measuring cholesterol and tri-
acylglycerol levels and by analyzing lipoprotein elec-
trophoretograms. However, the phenotypes so described
do not adequately represent current understanding of the
pathophysiology underlying these disorders. The disor-
ders can be characterized on the basis of the underlying
defects in apolipoproteins, enzymes, or cellular receptors.
Hyperlipidemias
Hypertriacylglycerolemias
Lipoprotein lipase (LPL) deficiency is inherited as an
autosomal recessive disorder.
H yperchylom icronem ia
is
present from birth. Upon fat ingestion, triacylglycerol lev-
els may rise to 5000-10,000 mg/dL. Chylomicron levels
are greatly elevated but not the VLDL levels
(type I h yper-
lipoproteinem ia).
Type I hyperlipoproteinemia can also be
TA BLE 20-5
Phenotyping Based on Hyperlipoproteinemia
Phenotype
Lipoprotein Present in Excess
I
Chylomicrons
lia
LDL
lib
LDL + VLDL
III
ß-VLDL
IV
VLDL
V
Chylomicrons + VLDL
