section 20.2
Due to the structural similarity between apo(a) and plas-
minogen, it is thought that Lp(a) interferes with fibrinol-
ysis and thus promotes thrombosis. Normally, formation
of a blood clot (thrombus) and its dissolution by fibrinol-
ysis is carefully regulated and the two processes are in
a delicate balance (Chapter 36). The clot is cleaved and
solubilized by the serine protease plasmin which is derived
from its precursor plasminogen by proteolysis. Lp(a) ex-
erts its antifibrinolytic activity by competitively inhibiting
the binding of plasminogen to endothelial cells and mono-
cytes, and to fibrin which is required for formation of plas-
min (Chapter 36). Elevated homocysteine levels (homo-
cysteinemia) promote fibrin binding of Lp(a), thus further
preventing the formation of plasmin and subsequent im-
paired thrombolysis.
Several prospective studies have shown that an excess
plasma level of Lp(a) is a risk factor and an independent
predictor of coronary heart disease. Survivors of myocar-
dial infarcts have higher Lp(a) levels than do controls.
In individuals with Lp(a) levels greater than 30 mg/dL
(0.78 mM/L), the relative risk for coronary heart disease
is 2- to 3.5-fold higher than that of controls. Population
studies have shown that plasma Lp(a) levels in Africans are
several-fold higher compared with Asian and Caucasian
populations. Lp(a) levels are elevated in end-stage renal
disease. In postmenopausal women, Lp(a) is increased but
estrogen replacement therapy can lower the Lp(a) levels.
Most lipid-lowering drugs (except nicotinic acid) do not
affect plasma Lp(a) concentration.
Lipoprotein-X (Lp-X), an abnormal lipoprotein, occurs
in patients with obstructive liver disease or LCAT defi-
ciency. Lp-X floats in the density range of LDL and has the
same electrophoretic mobility as LDL. It can be separated
from LDL, however, by hydroxyapatite chromatography
or by zonal centrifugation. The composition of Lp-X dif-
fers from that of LDL, and it does not react with antisera
to LDL. The major apoproteins of Lp-X isolated from pa-
tients with LCAT deficiency are albumin, apo C, and apo
A. Lp-X also contains small amounts of apo D and apo E.
Lp-X from patients with obstructive liver disease has been
reported to lack apo A-I, a powerful activator of LCAT. The
lipid constituents of Lp-X are cholesterol (almost entirely
unesterified) and phospholipids. In electron microscopy,
negatively stained Lp-X preparations appear as stacks of
disk-like structures
20.2 Metabolism
Plasma lipoproteins are in a dynamic state. Their con-
tinuous synthesis and degradation are accompanied by
rapid exchanges of lipid and protein components between
the different lipoprotein classes. Major sites of plasma
lipoprotein synthesis are the intestine and liver. Synthesis
takes place in rough and smooth endoplasmic reticulum.
The necessary components are triacylglycerols, choles-
terol (and cholesteryl esters), phospholipids, and apopro-
teins. At various points in the metabolic cycle four en-
zymes play an important role in the delivery, storage, and
mobilization of lipoprotein lipids.
Lipoprotein lipase
(LPL) is a glycoprotein that
belongs to a family of serine esterases that include
hepatic lipase and pancreatic lipase. LPL is
synthesized by many types of parenchymal cells in
the body but is concentrated mainly in muscle and
adipose tissue. After its synthesis in the parenchymal
cells, LPL undergoes secretion and translocation to
the lumenal surface of endothelial cells lining the
vascular beds where it is bound to heparan sulfate.
Purified LPL is a dimer in the active state and loses
activity when it dissociates into monomers. Each
subunit of LPL contains binding sites for
glycosaminoglycans and apo C-II, both of which
promote dimerization of LPL. Apo C-II is required
for the activation of LPL
in vivo.
Liver is the site of
apo C-II synthesis and, in the plasma, it recycles
between HDL, triacylglycerol-rich lipoproteins,
chylomicrons, and VLDLs.
LPL is the major enzyme involved in the
processing of chylomicrons and VLDL by hydrolysis
of fatty acids from triglycerides. Phospholipids may
also serve as substrates for LPL. Apo C-III inhibits
the activation of LPL by apo C-II
in vitro,
albeit at
high levels, but the physiological importance of
inhibition is not understood.
In the postprandial state, elevated serum insulin
increases LPL activity in adipose tissue (but not in
muscle) and promotes fuel storage as triacylglycerols.
In the postabsorptive state, serum insulin levels
decrease causing a decrease in LPL activity in
adipose tissue; however, LPL activity in muscle
remains high or increases releasing fatty acids from
VLDL particles for use as fuel. In general, LPL has
different functions in different tissues. In cardiac and
skeletal muscle it provides energy; in white adipose
tissue it stimulates triacylglycerol storage; in brown
adipose tissue it is thermogenesis; and in lactating
breast it is triacylglycerol synthesis for milk
production. LPL also is involved in surfactant
synthesis in the lungs and in phospholipid and
glycosphingolipid synthesis in the brain.
Hepatic lipase,
like LPL, is synthesized in the
parenchymal cells of liver and is localized on the
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