The discovery of the LDL receptor pathway by Michael S.
Brown and Joseph L. Goldstein represents the most significant
triumph in the field of atherosclerosis research. In an
extraordinary collaboration begun in 1972, they discovered
that cells possess a high-affinity receptor that binds
to the apo-B100 moiety of LDL. (They were awarded the
Nobel Prize in 1985.)
Binding of LDL to its receptor results in rapid endocyhtosis
and the formation of an endocytic vesicle (Fig. 8).
The LDL and the receptor separate while in this vesicle
and part ways; the receptor recycles and returns to
the cell surface, while the LDL particle is delivered to
the lysosome, where the protein and lipid moieties are
Hydrolysis of LDL cholesterol esters in the lysosome
results in the release of free cholesterol, which exits the
lysosome and exerts three important regulatory functions:
- It suppresses cellular cholesterol synthesis by
reducing the levels of the rate-limiting enzymes in the
cholesterol biosynthetic pathway, principally
3-hydroxy-3-methyl-glutaryl-coenzyme A reductase
- It enhances the re-esterification of cholesterol for
storage in a cytoplasmic lipid droplet.
- It inhibits production of new LDL receptor, thus
diminishing the further supply of cholesterol to the
|Figure 8 The LDL receptor pathway.
LDL is internalized via
endocytosis. The endosomes are a sorting
compartment; the receptor recycles to the
while the LDL is
delivered to the lysosomes, where the
esters are hydrolyzed by
lysosomal lipases. The free cholesterol
then exits the lysosome and is able to
inhibit de novo cholesterol
reducing the abundance of several
biosynthetic enzymes (e.g.,
HMG-CoA reductase) and the LDL
receptor. Cells protect themselves from
cholesterol toxicity by
cholesterol to form a cytoplasmic
droplet. [From Brown,
M. S., and Goldstein, J. L. (1986).
The LDL receptor pathway assures a constant steadystate
level of cellular cholesterol. This is accomplished
both by adjusting cellular cholesterol synthesis according
to ambient LDL levels and by altering LDL receptor number
to limit the amount of LDL getting into cells. Like free
fatty acids, unesterified cholesterol can be toxic to cells.
The formation of cholesterol esters protects cells from
About two-thirds of LDL is catabolized by the liver.
The rest is cleared by just about all other tissues. Steroidproducing
tissues are especially active in LDL uptake.
Adrenal cells (and presumably ovarian and testicular cells)
do not synthesize cholesterol at rates sufficient to support
high rates of steroidogenesis. They supplement their
cholesterol supply by consuming cholesterol carried on
LDL and HDL.
The level of LDL receptor activity is affected by the
steady-state level of cholesterol in a cell. Thus, any factors
that increase or decrease the cholesterol level of a cell
will affect the rate of LDL clearance from the circulation.
This means that nutritional factors (proportion and
type of dietary fat), hormonal status, pharmacological factors
(drugs that inhibit cholesterol synthesis), and agents
that affect bile acid metabolism all affect plasma cholesterol
by influencing the level of expression of the LDL