Evolution of the LDL receptor concept-from cultured cells to intact animals

The initial observations in cultured fibroblasts made six years ago allowed the formulation of a series of hypotheses concerning LDL metabolism in tissues of animals and man. The most important of these hypotheses was that a large fraction of LDL was removed from plasma by a specific receptor-mediated uptake mechanism whose function was to supply cholesterol to extrahepatic cells. This hypothesis is strongly supported by genetic observations in patients with familial hypercholesterolemia and by studies of the four model systems discussed above. These studies by no means solve all of the important questions about LDL metabolism. We still need to know which tissues take up the most LDL; we need to know how much LDL is cleared by the liver and whether this clearance involves the same LDL receptor that operates in extra-hepatic cells; we need to know the mechanism for the clearance of the one-half to two-thirds of LDL that leaves the plasma by receptor-independent pathways; and finally we need to know how an abnormal accumulation of LDL in the plasma leads to the deposition of cholesterol in scavenger cells and produces atherosclerosis.