Page 83 - Academic Press Encyclopedia of Physical Science and Technology 3rd BioChemistry

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

650 Lipoprotein/Cholesterol Metabolism

lipolysis, the apoC-III protein falls off the particle, thereby
exposing apo-E and permitting it to mediate particle
clearance.

Some Key Points
In terms of mass movement, export of triglyceride

(TG) from the liver and intestine is where the action
is. This means net movement to extrahepatic cells.
Most of the plasma TG (in the fasting state, when no

chylomicrons are present) is carried in VLDL. Thus,
if fasting plasma TG is high, VLDL is high.
Dietary fat is packaged into chylomicrons in the

intestine. Excess endogenous substrate is converted
into TG for export by the liver.
Chylomicrons and VLDL are depleted of TG in the

circulation, thus accomplishing their mission of
delivering TG to peripheral cells.
Chylomicron remnants are not converted to LDL; they

FIGURE 8 The LDL receptor pathway. LDL is internalized via
are cleared by the liver.
receptor-mediated endocytosis. The endosomes are a sorting
Only VLDL can be converted to LDL.

compartment; the receptor recycles to the plasma membrane,
In humans, most of the plasma cholesterol is carried in while the LDL is delivered to the lysosomes, where the cholesterol

LDL. If plasma cholesterol is elevated without esters are hydrolyzed by lysosomal lipases. The free cholesterol
elevation of plasma TG, then LDL is high. then exits the lysosome and is able to inhibit de novo choles-
terol synthesis by reducing the abundance of several cholesterol
biosynthetic enzymes (e.g., HMG-CoA reductase) and the LDL
receptor. Cells protect themselves from cholesterol toxicity by
VII. THE LDL RECEPTOR re-esterifying cholesterol to form a cytoplasmic cholesterol ester
droplet. [From Brown, M. S., and Goldstein, J. L. (1986). Science
The discovery of the LDL receptor pathway by Michael S. 232, 34–47.]
Brown and Joseph L. Goldstein represents the most signif-
icant triumph in the field of atherosclerosis research. In an
extraordinary collaboration begun in 1972, they discov- 3. It inhibits production of new LDL receptor, thus
ered that cells possess a high-affinity receptor that binds diminishing the further supply of cholesterol to the
to the apo-B100 moiety of LDL. (They were awarded the cell.
Nobel Prize in 1985.)
Binding of LDL to its receptor results in rapid endocyh- The LDL receptor pathway assures a constant steady-
tosis and the formation of an endocytic vesicle (Fig. 8). state level of cellular cholesterol. This is accomplished
The LDL and the receptor separate while in this vesi- both by adjusting cellular cholesterol synthesis according
cle and part ways; the receptor recycles and returns to to ambient LDL levels and by altering LDL receptor num-
the cell surface, while the LDL particle is delivered to ber to limit the amount of LDL getting into cells. Like free
the lysosome, where the protein and lipid moieties are fatty acids, unesterified cholesterol can be toxic to cells.
degraded. The formation of cholesterol esters protects cells from
Hydrolysis of LDL cholesterol esters in the lysosome cholesterol toxicity.
results in the release of free cholesterol, which exits the About two-thirds of LDL is catabolized by the liver.
lysosome and exerts three important regulatory functions: The rest is cleared by just about all other tissues. Steroid-
producing tissues are especially active in LDL uptake.
1. It suppresses cellular cholesterol synthesis by Adrenal cells (and presumably ovarian and testicular cells)
reducing the levels of the rate-limiting enzymes in the do not synthesize cholesterol at rates sufficient to sup-
cholesterol biosynthetic pathway, principally port high rates of steroidogenesis. They supplement their
3-hydroxy-3-methyl-glutaryl-coenzyme A reductase cholesterol supply by consuming cholesterol carried on
(HMG-CoA reductase). LDL and HDL.
2. It enhances the re-esterification of cholesterol for The level of LDL receptor activity is affected by the
storage in a cytoplasmic lipid droplet. steady-state level of cholesterol in a cell. Thus, any factors