Low Density Lipoprotein Metabolism and Cholesterol Synthesis in Familial Homozygous Hypercholesterolemia: Influence of Portacaval Shunt Surgery

Abstract

Several recent studies of patients with the homozygous form of familial hypercholesterolemia (FH) have provided new insight into mechanisms underlying the elevation of plasma low density lipoprotein (LDL) in this disorder. Studies using cultured skin fibroblasts from FH homozygotes have suggested that the primary genetic defect in this disorder involves a deficiency in a cell surface receptor for LDL (1 – 4). In normal cells, LDL binding to the receptor is associated with cellular uptake and degradation of the lipoprotein (1, 2). The protein and cholesteryl ester components of LDL are subsequently hydrolyzed within the cell to liberate free cholesterol which, in turn, suppresses cellular cholesterol synthesis (5). Cells from FH homozygotes lack the LDL receptor and are therefore deficient in the ability to take up LDL (1 – 3). As a result, these cells overproduce cholesterol (6, 7) and show a diminished rate of degradation of LDL even when presented with high concentrations of this lipoprotein in the medium (1, 2).