Familial hypercholesterolemia (FH) is a chronic illness often resulting in death from coronary heart disease before age 20 in the homozygous state. Skin fibroblasts from FH patients generally have very low binding activity for low density lipoprotein (LDL), but the cause of the reduced binding activity has not yet been established. To trace further the biochemical defects in this disorder we propose to study skin fibroblasts from both typical and atypical FH patients. The specific affinity and capacity for 125I-LDL binding will be determined and compared with a series of normal fibroblasts and with normal fibroblasrs in which LDL receptors have been downregulated by growth in cholesterol or LDL. The ability of compactin and mevinolin and other inhibitors of cholesterol biosynthesis to increase LDL receptor activity will be studied. The cholesterol metabolism of FH cells will be investigated after long-term culture in lipoprotein-free medium. Estimates of relative rates of cholesterol biosynthesis will be made using 3H-acetate and 3H-H20. Mass measurements of total cell, inner cell membrane, and culture medium cholesterol content will be done by gas chromatography. Finally, the abnormalities in LDL binding will be correlated with the abnormalities of cholesterol metabolism observed.