The LDL Receptor

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 degraded.

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:

1. 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 (HMG-CoA reductase).
2. It enhances the re-esterification of cholesterol for storage in a cytoplasmic lipid droplet.
3. It inhibits production of new LDL receptor, thus diminishing the further supply of cholesterol to the cell.

Figure 8 The LDL receptor pathway. LDL is internalized via receptor-mediated endocytosis. The endosomes are a sorting compartment; the receptor recycles to the plasma membrane, while the LDL is delivered to the lysosomes, where the cholesterol esters are hydrolyzed by lysosomal lipases. The free cholesterol then exits the lysosome and is able to inhibit de novo cholesterol 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 re-esterifying cholesterol to form a cytoplasmic cholesterol ester droplet. [From Brown, M. S., and Goldstein, J. L. (1986). Science 232, 34–47.]

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 cholesterol toxicity.

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 receptor.