Familial hypercholesterolemia: dissection of a receptor disease

In 1973, studies with cultured human fibroblasts by Brown, Goldstein, and colleagues showed that receptor-mediated endocytosis of low-density lipoprotein (LDL) is the regulatory principle in cellular cholesterol homeostasis. The complete sequence of metabolic events associated with the binding, uptake, and degradation of these cholesterol-rich lipoprotein particles by mammalian cells has been termed the LDL receptor pathway. This important process has two main tasks. First, it supplies cells with cholesterol, thereby mediating the removal of cholesterol-rich lipoproteins from the circulation. Second, it protects cells from over-accumulation of cholesterol, because the cholesterol derived from lysosomal hydrolysis of LDL cholesterylesters exerts a series of feedback control mechanisms designed to maintain a constant level of cholesterol within the cell. Thus, high extracellular concentrations of LDL reduce cellular synthesis of cholesterol (by suppression of the activities of 3 hydroxy-, 3-methyl-glutaryl-CoA synthase and reductase, rate-limiting enzymes in cholesterol synthesis), stimulate its re-esterification, and decrease the number of LDL receptors, preventing further cellular entry of cholesterol. The suppression of LDL receptor activity by high plasma levels of LDL is beneficial for most cells, but the consequences caused by reduction of LDL receptor activity in the liver can be devastating. This is best documented in familial hypercholesterolemia (FH), in which defects in the LDL receptor gene disrupt the normal functions of the LDL receptor pathway. The clinical manifestation of the failure to remove LDL from the bloodstream at normal rates includes severe hypercholesterolemia and premature atherosclerosis. Some of the important findings that emerged from studies on structure/function relationships of the key player in the process, the LDL receptor itself, are described.