Page 81 - Academic Press Encyclopedia of Physical Science and Technology 3rd BioChemistry

P1: GNH Final Pages
Encyclopedia of Physical Science and Technology EN008C-380 June 29, 2001 16:42

648 Lipoprotein/Cholesterol Metabolism

remnants are cleared from the circulation, primarily by the
liver.

IV. VLDL METABOLISM (ENDOGENOUS
TRIGLYCERIDE METABOLISM)

VLDL assembly and secretion is similar to the corre-
sponding pathway for chylomicrons. Triglycerides and
cholesterol esters are packaged into the core of the lipopro-
tein particle. However, in contrast to intestinal chylomi-
cron secretion, hepatocytes secrete VLDL directly into
the bloodstream. In the bloodstream, VLDL is acted
upon by lipoprotein lipase, delivering its triglyceride
cargo to muscle and adipose tissue. The resulting VLDL
remnant particle, also termed IDL (intermediate den-
sity lipoprotein), is further metabolized as discussed
below. FIGURE 5 Sources of fatty acid for hepatic triglyceride synthe-
In both the liver and the intestine, triglyceride incor- sis. (1) Adipose tissue lipolysis, catalyzed by hormone-sensitive
lipase, provides fatty acids that travel through the bloodstream to
poration into lipoprotein particles requires the action of
the liver. (2) Chylomicron remnants still carry some triglyceride
microsomal triglyceride transfer protein (MTP). MTP re-
and are cleared from the circulation by the liver. (3) Carbohydrate
sides in the lumen of the endoplasmic reticulum (ER) and is converted to fatty acids when glycogen stores are maintained.
facilitates the transfer of triglycerides and cholesterol es-
ter from the cytoplasmic side of the ER to the interior of
the lipoprotein particle. Mutations in MTP cause abetal-
LDL is cholesterol rich. The production of a cholesterol-
ipoproteinemia, an inability to secrete chylomicrons and
rich lipoprotein from a triglyceride-rich lipoprotein occurs
VLDL.
by selective removal of triglyceride from VLDL.
In humans, the liver is a major lipogenic tissue. The liver
In summary, dietary fat is packaged into chylomicrons
is able to transform excess carbohydrate or protein into fat
in the intestine. Dietary cholesterol is also packaged into
(remember, when we eat too much of anything we get fat!).
chylomicrons, but a substantial fraction is delivered to the
Fatty acid substrates for hepatic triglyceride production
liver via chylomicron remnants. This cholesterol can then
are derived from three sources (Fig. 5): (1) a continuous
compete for the core of VLDL and appear in the blood-
supply of albumin-bound fatty acid to the liver, primarily
stream as cholesterol ester-enriched VLDL particles. Ex-
from adipose tissue triglyceride stores (after a meal this
cess substrate in any form is converted into TG for export
source drops, due to the antilipolytic action of insulin), (2)
by the liver. For example, in some people, diets high in
dietary fat already transported in chylomicrons delivered
simple carbohydrates (e.g., fructose and sucrose) can lead
to the liver, and (3) carbohydrate in excess of the liver’s
to hypertriglyceridemia.
capacity for storage as glycogen.
V. IDL AND LDL METABOLISM VI. APOLIPOPROTEINS MEDIATE
LIPOPROTEIN METABOLISM
Unlike chylomicron remnants, IDL has two competing
metabolic fates: (1) uptake by the liver and (2) further Chylomicrons and VLDL carry many apolipoproteins,
processing to become LDL (Fig. 6). among them apo-B and apo-E. Apo-B is a large
SinceIDLcanbeclearedbytheliverorcanbeprocessed (MW = 516 kDa) protein stably associated with the
to become LDL, this branch point represents an important lipoprotein particle. The intestine produces a truncated
stage where LDL concentrations can be regulated. Inef- form of the apoB, termed apo-B48, which is missing the
ficient clearance of IDL tends to lead to increased LDL carboxy-terminal half of apoB. The mechanism for the
production. truncation involves a unique RNA editing event in the in-
LDL is formed in the bloodstream through the testine that changes a Gln codon (CAA) to a STOP codon
catabolism of VLDL at the surface of blood vessels. In (UAA). Since only VLDL is converted to LDL, this means
addition, VLDL is a triglyceride-rich lipoprotein, while all apo-B in LDL is apo-B100 (Fig. 7).