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chapter20
Lipids ill: Plasma Lipoproteins
membrane surfaces of the hepatic endothelial cells of
blood vessels bound to heparan sulfate. It also occurs
on the endothelial cells of blood vessels of adrenals
and gonads. The role of hepatic lipase is not
completely understood, however, it continues the
lipolysis of VLDL and IDL in their stepwise
conversion to LDL. Hepatic lipase also hydrolyzes
phospholipids and HDL-triacylglycerol. It performs
these functions both on the endothelial cell surface
and within endosomes as lipoproteins are endocytosed
into cells via receptor-mediated endocytosis. Hepatic
lipase activity responds positively to androgens and
negatively to increasing levels of estrogen.
3.
Lecithin-cholesterol acyltransferase
(LCAT) is a
glycoprotein synthesized in the liver. LCAT circulates
in the plasma with HDL, LDL, apo D, and cholesteryl
ester transfer protein (CETP). It is activated by apo
A-I. LCAT catalyzes the transfer of long-chain fatty
acids from phospholipids to cholesterol, forming
cholesteryl esters and permitting the storage and
transport of cholesteryl esters in the lipoprotein core.
Cholesteryl esters are exchanged between
lipoproteins, a process mediated by CETP. Apo D
bound to HDL may also play a role in the formation
of cholesteryl esters by providing a binding site for
the cholesterol. There is a net transfer of cholesteryl
esters from HDL to LDL and VLDL with an
exchange of triacylglycerol. The VLDL is
transformed into LDL in the circulation (discussed
later). The cholesterol content of LDL is increased
thus promoting its atherogenicity.
HDL is antiatherogenic and removes cholesterol
from peripheral cells and tissues for eventual
transport to hepatocytes and excretion in the bile
directly or after conversion into bile acids. The efflux
of cholesterol from peripheral cells is mediated by the
ATP-binding cassette (ABC) transporter protein
(discussed later). The flux of cholesterol transport
from extrahepatic tissues (e.g., blood vessel wall)
toward liver for excretion is known as the reverse
cholesterol transport pathway. In contrast, the forward
cholesterol pathway involves the transport of
cholesterol from liver to the peripheral cells and
tissues via the VLDL —»■
IDL —» LDL pathway. It
should be noted, however, that the liver plays a major
role in the removal of these lipoproteins. Thus, the
system of reverse cholesterol transport consisting of
LCAT, CETP, apo D, and their carrier lipoproteins is
critical for maintaining cellular cholesterol
homeostasis. The role of CETP is exemplified in
clinical studies involving patients with polymorphic
forms of CETP that promote cholesteryl ester transfer
from HDL to LDL or that increase plasma CETP
levels. These patients exhibit an increased risk of
coronary heart disease. Homozygous CETP
deficiency found in some Japanese people results in
increased HDL cholesterol levels; there is anecdotal
evidence of longevity in this group of individuals.
4.
Acyl-CoA:cholesterol acyltransferase
(ACAT)
esterifies free cholesterol by linking it to a fatty acid.
ACAT is an intracellular enzyme that prepares
cholesterol for storage as in liver parenchymal cells.
The roles of these enzymes in lipoprotein metabolism
will become more apparent in the discussion of the
origin and fate of each class of lipoprotein.
Chylomicrons
After partial hydrolysis in the gut, dietary fatty acids,
monoacylglycerols, phospholipids, and cholesterol are ab-
sorbed into the mucosal enterocytes lining the small in-
testine (Chapter 12). Once within the cell, the lipids are
reesterified and form a lipid droplet within the lumen of
the smooth endoplasmic reticulum. These droplets con-
sists of triacylglycerol and small amounts of cholesteryl
esters and are stabilized by a surface film of phospho-
lipid. At the junction of the smooth and the rough endo-
plasmic reticulum, the droplet acquires apoproteins B-48,
A-I, A-II, and A-IV, which are produced in the lumen
of the rough endoplasmic reticulum in the same way as
other proteins bound for export. The lipoprotein particle
is then transported to the Golgi stacks where further pro-
cessing yields chylomicrons, which are secreted into the
lymph and then enter the blood circulation at the thoracic
duct.
Synthesis and secretion of chylomicrons are directly
linked to the rate of dietary fat absorption. When fat is
absent from the diet, small chylomicrons with a diameter
of about 50 nm are secreted at a rate of approximately 4 g
of triacylglycerol per day. On a high-fat diet, the mass of
lymphatic triacylglycerol transport may increase 75-fold,
owing partly to greater production of chylomicrons but
primarily to a dramatic increase in size of the particles,
which may have diameters of
1 2 0 0
nm, and a 16-fold
increase in the amount of triacylglycerol within their
core.
In the circulation, chylomicrons undergo a number of
changes (Figure 20-3). First, they acquire apo C and apo
E from plasma HDL in exchange for phospholipids. Next,
hydrolysis of triacylglycerols by endothelial LPL (e.g., in
adipose tissue and skeletal muscle) begins. Progressive
hydrolysis of triacylglycerol through diacylglycerol and
