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chapter 20
Lipids III: Plasma Lipoproteins
F IG U R E 2 0 -6
Cellular uptake and metabolism of LDL. ( 1
) LDL in extracellular fluid.
(2) LDL is bound to receptors that cluster in clathrin-coated pits. (3) The
pits are endocytosed to form coated vesicles. (4) Clathrin is recycled to the
surface, leaving uncoated endosomes. (5) ATP-dependent proton pumps in
the endosomal membrane lower the intravesicular pH, resulting in the
separation of ligand and receptor. (6) Multivesicular bodies form, as
receptors are segregated into finger-like projections. (7) Most receptors are
recycled to the cell surface. (8) Multivesicular bodies fuse with primary
lysosomes to form secondary lysosomes, which digest LDL to free
cholesterol and amino acids. • = LDL; Y = LDL receptor;
T = clathrin coat.
plasma LDL saturates the high-affinity, receptor-mediated
LDL uptake process. Linder these conditions, LDL enters
cells by a nonspecific endocytic process known as “bulk-
phase pinocytosis.” This mechanism seems to play no role
in regulation of
d e novo
synthesis of cholesterol and leads
to its excessive accumulation, with pathological conse-
quences (e.g., atherosclerosis). Abnormally high plasma
LDL levels cause scavenger cells (e.g., macrophages) to
take up lipids, which results in xanthoma in tendons and
skin.
High-Density Lipoproteins
HDLs are secreted in nascent form by hepatocytes and en-
terocytes (Figure 20-7). Loss of surface components, in-
cluding phospholipids, free cholesterol, and protein from
chylomicrons and VLDL as they are acted on by lipopro-
tein lipase, may also contribute to formation of HDL in
plasma. Discoidal, nascent HDL is converted to spheri-
cal, mature HDL by acquiring free cholesterol from cell
membranes or other lipoproteins. This function of HDL
in peripheral cholesterol removal may underlie the strong
inverse relationship between plasma HDL levels and in-
cidence of coronary heart disease. After esterification of
HDL surface cholesterol by LCAT, which is activated by
apo A-I, HDL sequesters the cholesteryl ester in its hy-
drophobic core. This action increases the gradient of free
cholesterol between the cellular plasma membrane and
HDL particles. Cholesteryl esters are also transferred from
HDL to VLDL and LDL via apo D, the cholesteryl ester
transfer protein (Figure 20-8).
Removal of cholesterol from cells requires an ac-
tive transport system involving an ATP-binding cassette
(ABC1) transporter. ABC 1-transporter is a member of
a superfamily of proteins involved in energy-dependent
transport of several substances across cell membranes.
It is activated by protein kinases via phosphorylation.
The role of ABC 1-transporter in cholesterol efflux is ex-
emplified by an autosomal recessive disease known as
Tangier d isea se
in which disorder mutations in the gene
encoding the ABC 1-transporter lead to accumulation of
cholesterol esters in the tissues with almost complete
absence of HDL cholesterol (discussed later). Other in-
herited diseases caused by mutations in ABC-proteins
are
cystic fib ro sis
(Chapter 12),
ea rly o n set m acular
degeneration
(Chapter 38),
sitosterolem ia
(Chapter 19),
adrenoleukodystrophy, Z ellw eg er syndrom e,
and
progres-
sive fa m ilia l in trah epatic ch olestasis.
Under normal physiological conditions, HDL exists in
two forms: HDL
2
(d =
1.063-1.125 g/mL) and HDL
3
(d
=
1.125-1.210 g/mL). Fluctuations in plasma HDL
levels have been principally associated with changes
in HDL
2
. This fraction is often found in much higher
concentration in females and may be associated with
their reduced risk for atherosclerotic disease. Clinically,
the cholesterol fraction of total HDL
(d
=
1.063-1.210)
is commonly measured, and low values are frequently
associated
with
increased
risk
of
coronary
heart
disease.
The primary determinant of HDL cholesterol levels in
human plasma appears to be the cholesterol efflux medi-
ated by ABC 1-transporter (also called cholesterol efflux
regulatory protein). A defect in this protein causes
Tangier
