A receptor-mediated pathway for cholesterol homeostasis.

In 1901 a physician, Archibald Garrod, observed a patient with black urine. He used this simple observation to demonstrate that a single mutant gene can produce a discrete block in a biochemical pathway, which he called an “inborn error of metabolism”. Garrod’s brilliant insight anticipated by 40 years the one gene-one enzyme concept of Beadle and Tatum. In similar fashion the chemist Linus Pauling and the biochemist Vernon Ingram, through study of patients with sickle cell anemia, showed that mutant genes alter the amino acid sequences of proteins. Clearly, many fundamental advances in biology were spawned by perceptive studies of human genetic diseases (1). We began our work in 1972 in an attempt to understand a human genetic disease, familial hypercholesterolemia or FH. In these patients the concentration of cholesterol in blood is elevated many fold above normal and heart attacks occur early in life. We postulated that this dominantly inherited disease results from a failure of end-product repression of cholesterol synthesis. The possibility fascinated us because genetic defects in feedback regulation had not been observed previously in humans or animals, and we hoped that study of this disease might throw light on fundamental regulatory mechanisms. Our approach was to apply the techniques of cell culture to unravel the postulated regulatory defect in FH. These studies led to the discovery of a cell surface receptor for a plasma cholesterol transport protein called low density lipoprotein (LDL) and to the elucidation of the mechanism by which this receptor mediates feedback control of cholesterol synthesis (2,3). FH was shown to be caused by inherited defects in the gene encoding the LDL receptor, which disrupt the normal control of cholesterol metabolism. Study of the LDL receptor in turn led to the understanding of receptor-mediated endocytosis, a genera! process by which cells communicate with each other through internalization of regulatory and nutritional molecules (4). Receptor-mediated endocytosis differs from previously described biochemical pathways because it depends upon the continuous and highly controlled movement of membraneembedded proteins from one cell organelle to another in a process termed