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chapter20
Lipids III: Plasma Lipoproteins
Recombinant DNA technology has begun to link
specific mutations to altered biochemical expression.
For example, the failure to cluster in coated pits, the
internalization-defective phenotype, arises from a mu-
tation that results in a loss of the membrane-spanning
and cytoplasmic domains of the LDL-receptor protein
(Figure 20-5). The abnormal protein is secreted from the
cell with about 30% remaining on the cell surface; having
no transmembrane portion, it is unable to migrate to coated
pits. The autosomal dominant gene of FH is expressed in
heterozygous form in approximately 1 in 500 individu-
als. Thus, 1 in 250,000 marriages will pair FH heterozy-
gotes; and one fourth of their offspring, or
1
of
1
,
0 0 0 , 0 0 0
individuals, will be homozygous for FH. FH heterozy-
gotes have normal triacylglycerol and HDL levels, but
their LDL cholesterol levels are typically between 320 and
500 mg/dL. LDL residence time in plasma is increased
to about 2.5 times normal. About half of affected indi-
viduals have palpable tendon xanthomas and experience
onset of coronary artery disease in their third or fourth
decade of life. In homozygous subjects, cholesterol levels
between 600 and 1200 mg/dL are common, tendon xan-
thomas and corneal opacification are usually present, and
onset of coronary disease before
1 0
years of age is typical.
Since the appearance of accelerated atherogenesis is often
accompanied by no other risk factors, it contributes impor-
tant evidence linking elevated plasma cholesterol levels
with atherosclerosis.
Defects in the LDL receptor result in decreased uptake
of LDL and also in increased production caused by an
increase in the fraction of IDL that is converted to LDL
(Figure 20-9). Members of kindreds with FH may show
primary elevation of only LDL (type Ila) or combined el-
evations of LDL and VLDL (type lib hyperlipoproteine-
mia). These patterns may also be seen in familial combined
hyperlipidemia, for which the molecular defects remain
unknown, although the basic abnormality appears to be
overproduction of lipoproteins containing apo B. In many
individuals with this disorder, the secretion rates of VLDL
are elevated and result in
hypertriacylglycerolemia
(type
IV hyperlipoproteinemia),
whereas other members of the
same kindred may show hypercholesterolemia, presum-
ably due to excessive conversion of VLDL to LDL or
to defective LDL clearance. Some individuals may show
elevations of VLDL and LDL levels, so that diagnosis
of familial combined hyperlipidemia can be made only
by family screening. As opposed to FH patients, indi-
viduals with familial combined hyperlipidemia rarely ex-
hibit hyperlipidemia before adulthood. Hypertriacylglyc-
erolemia in these patients may be exacerbated by obesity
or diabetes. In many patients with primary hypercholes-
terolemia in which LDL is grossly elevated, a monogenetic
FIG U R E 20-9
LDL-receptor deficiency. In the normal condition (a), VLDL produced by
the liver loses triacylglycerol as free fatty acids (FFA) via lipoprotein
lipase to peripheral tissues and then proceeds down the metabolic cascade
to IDL and LDL. A major portion of these two lipoprotein species is taken
up by the liver or peripheral tissues via the LDL (apo B, E) receptor. In
individuals with down-regulated or genetically defective LDL receptors
(b), the residence time in the plasma of IDL is increased, a greater
proportion being converted to LDL. LDL production and turnover time are
increased, and total plasma cholesterol levels become grossly abnormal.
inheritance cannot be demonstrated. In this case, alteration
of multiple gene products may be responsible for the ele-
vation of LDL, and the defect is classified as polygenic hy-
percholesterolemia. Secondary hypercholesterolemia may
occur in hypothyroidism from delayed clearance of LDL,
the result of down-regulation of LDL receptors. In the
nephrotic syndrome, overproduction of VLDL results ei-
ther in elevated VLDL itself or in elevated LDL due to an
increase in conversion. Elevated LDL cholesterol has also
been reported in porphyria, anorexia nervosa, and Cush-
ing’s syndrome.
Hypolipidemias
In
abetalipoproteinemia
(acanthocytosis;
Bassen-Kornz-
weig syndrome),
lipoproteins containing apo B (LDL,
VLDL, and chylomicrons) are absent. This experiment of
nature indicates that apo B is absolutely essential for the
formation of chylomicrons and VLDL (and hence LDL).
Clinical findings include retinitis pigmentosa, malabsorp-
tion of fat, and ataxic neuropathic disease. Erythrocytes
are distorted and have a “thorny” appearance due to pro-
toplasmic projections of varying sizes and shapes (hence
the term
acanthocytosis,
from Greek
akantha
“thorn”).
Serum triacylglycerol levels are low. The genetic defect
