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Encyclopedia of Physical Science and Technology EN008C-380 June 29, 2001 16:42

Lipoprotein/Cholesterol Metabolism 657

tures are domains termed “kringle domains.” The kringle
domain that is repeated in the apo(a) gene is homologous
to a kringle domain of plasminogen, an enzyme involved
in the dissolution of fibrin clots.
Why is Lp(a) so strongly correlated with risk of CHD?
Because of its homology with plasminogen, it has been
suggested that Lp(a) competes with plasmin for bind-
ing to fibrin clots and therefore would tend to be an-
tithrombolytic. Another hypothesis is that Lp(a) might be
atherogenic because it has been shown in vitro to stim-
ulate smooth muscle cell proliferation, a hallmark of the
atherosclerotic process.

FIGURE 13 Inverse relationship between plasma triglyceride XIV. COMMON ISOFORMS OF
and HDL cholesterol levels. A higher level of VLDL correlates with APOLIPOPROTEIN E (apoE)
lower HDL levels. Two processes simultaneously remove triglyc-
erides from VLDL particles. First, lipoprotein lipase hydrolyzes the
Apo-E occurs in three common isoforms, apo-E2, apo-
triglycerides to free fatty acids and glycerol. Second, cholesterol
ester transfer protein (CETP) in the bloodstream catalyzes the ex- E3, and apo-E4. They differ at amino acids 112 and 158
change of triglyceride and cholesterol ester between VLDL and (Table VII). In apo-E4, both of these amino acids are argi-
HDL, respectively. As HDL accumulates triglyceride, it is a sub- nine. In apo-E2, both amino acids are cysteine, and apo-
strate for lipoprotein lipase and hepatic lipase. This shrinks the E3 has Cys-112 and Arg-158. The presence of cysteine
HDL particles, causing them to be cleared by the kidneys.
at amino acid 158 virtually abolishes the LDL receptor-
binding activity of apo-E. Consequently, VLDL remnants
The abundance of VLDL relative to HDL significantly in- with apo-E2 accumulate in the circulation.From 0.2–1.6%
fluences HDL metabolism, probably due to enhanced ex- of individuals in different populations are E2/E2 homozy-
change of triglyceride into the HDL particles. Individuals gotes. A subgroup of E2/E2 individuals have an unusually
withgeneticallyreducedlevelsofcholesterolestertransfer severeformofhypercholesterolemiaduetoexcessiverem-
protein have extremely high HDL levels. Heavy exercise nant lipoproteins rather than high LDL. This disorder is
is also associated with increased HDL levels. Exercise in- called Type III hyperlipidemia.
creases the expression of muscle lipoprotein lipase. The Individuals with apo-E2 exhibit delayed clearance of
resulting increase in VLDL lipolysis decreases the amount chylomicronremnants.Thedelayedclearanceofremnants
of triglyceride that can participate in the CETP lipid ex- means cholesterol delivery to the liver is reduced. This
change process. This results in an elevation in HDL. causes an upregulation of the LDL receptor, resulting in
lower plasma LDL levels. Thus, the total cholesterol in
E2/E2 individuals (except those with Type III disease)
XIII. Lp(a) AND apo(a) mightbenormal,eventhoughtheyhaveaproblemclearing
chylomicron remnants.
Apo(a) is a protein found covalently linked to apo-B100 in Apo-E4 is associated with higher total cholesterol lev-
some LDL particles. Those LDL particles to which apo(a) els than apo-E2 or apo-E3. This has been attributed to
isattachedarecalledlipoprotein(a)orLp(a).Plasmalevels the relatively high affinity of apo-E4 for VLDL particles.
of Lp(a) correlate with increased cardiovascular disease Enrichment of VLDL with apo-E results in enhanced
risk in most populations, but not in African-Americans. clearance by the liver (through the LDL receptor) and
The level of Lp(a) appears to be entirely genetically deter- greater downregulation of the LDL receptor, thus in-
mined. The Lp(a) concentration is almost entirely related creased LDL levels.
to the particular alleles of the Lp(a) gene expressed by an
TABLE VII Apo-E Isoforms
individual.
The Lp(a) gene is highly polymorphic (variable in struc- Apo-E2 Apo-E3 Apo-E4
ture). Thus, it appears that most individuals have different
Amino acid 112 Cys Cys Arg
forms of the gene. The reason for this unusually high de-
Amino acid 158 Cys Arg Arg
gree of genetic variability is that the gene comprises mul-
LDL receptor binding <0.1% Normal Normal
tiple repeat structures. Repeat structures lead to unequal
LDL cholesterol Low Normal High
crossing over during meiosis, causing the production of
VLDL cholesterol High Normal Normal
new variants of the gene in the offspring. The repeat struc-