Apo-E occurs in three common isoforms, apo-E2, apo-
E3, and apo-E4. They differ at amino acids 112 and 158
(Table VII). In apo-E4, both of these amino acids are arginine.
In apo-E2, both amino acids are cysteine, and apo-
E3 has Cys-112 and Arg-158. The presence of cysteine
at amino acid 158 virtually abolishes the LDL receptorbinding
activity of apo-E. Consequently, VLDL remnants
with apo-E2 accumulate in the circulation. From 0.2–1.6%
of individuals in different populations are E2/E2 homozygotes.
A subgroup of E2/E2 individuals have an unusually
severe form of hypercholesterolemia due to excessive remnant
lipoproteins rather than high LDL. This disorder is
called
Type III hyperlipidemia.
Individuals with apo-E2 exhibit delayed clearance of
chylomicron remnants. The delayed clearance of remnants
means cholesterol delivery to the liver is reduced. This
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)
might be normal, even though they have a problem clearing
chylomicron remnants.
Apo-E4 is associated with higher total cholesterol levels
than apo-E2 or apo-E3. This has been attributed to
the relatively high affinity of apo-E4 for VLDL particles.
Enrichment of VLDL with apo-E results in enhanced
clearance by the liver (through the LDL receptor) and
greater downregulation of the LDL receptor, thus increased
LDL levels.
TABLE VII Apo-E Isoforms
|
Apo-E2 |
Apo-E3 |
Apo-E4 |
Amino acid 112 |
Cys |
Cys |
Arg |
Amino acid 158 |
Cys |
Arg |
Arg |
LDL receptor binding |
<0.1% |
Normal |
Normal |
LDL cholesterol |
Low |
Normal |
High |
VLDL cholesterol |
High |
Normal |
Normal |