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:
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.
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