The metabolic basis of familial hypercholesterolemia.

Familial hypercholesterolaemia (FH) is a dominantly inherited error of metabolism characterised by a raised plasma low-density lipoprotein (LDL) concentration, xanthomas of skin and tendons, and a tendency to premature heart disease due to atherosclerosis of the coronary arteries. The clinical and biochemical abnormalities are more marked in homozygotes than in heterozygotes. Other biochemical changes include an increased concentration of very-low-density lipoprotein (VLDL) remnants and of a minor subfraction of high-density lipoproteins. Measurement of plasma lipoprotein turnover shows reduced fractional rates of catabolism of LDL and VLDL remnants, and increased production of LDL. Similar abnormalities are found in Watanabe rabbits, an inbred strain carrying a mutation similar to that responsible for FH. Cultured cells from human and animal tissues express surface receptors with high binding affinity for LDL. Binding of LDL to LDL receptors is followed by endocytosis and lysosomal digestion of the lipoprotein. Cultured cells from FH heterozygotes express only half the normal number of LDL receptors; those from homozygotes have little or no receptor activity and are therefore unable to degrade significant amounts of LDL by the LDL-receptor pathway. The LDL receptor has been isolated from cell membranes; it has a molecular weight of about 160 kd. Several different mutant forms of the receptor have been identified in the cells of FH homozygotes. The LDL-receptor pathway for the catabolism of LDL accounts for at least 1/3 of the total LDL catabolised by normal human subjects in vivo and almost none of that catabolised by FH homozygotes. Deficiency of LDL receptors accounts for the increased plasma concentrations of LDL and VLDL remnants in FH. The increased plasma concentration in these lipoproteins is the cause of deposition of lipid in xanthomas and arterial wall, but the mechanism by which lipoprotein enters the cells in which lipid accumulates is not yet understood.