Characterization of Hepatic Low Density Lipoprotein Binding and Cholesterol Metabolism in Normal and Homozygous Familial Hypercholesterolemic Subjects

A bstract. Patients with familial hypercholes-terolemia have elevated levels of plasma low density li-poproteins (LDL), increased hepatic synthesis of apoli-poprotein B-containing lipoproteins, defective binding of low density lipoproteins to fibroblasts, and premature atherosclerosis. The role of a hepatic low density lipo-protein receptor in normal man and its importance in the pathogenesis of familial hypercholesterolemia have not been previously determined. In the present study, direct comparison was made of the binding of LDL to hepatic membranes from normal and receptor-negative homozygous familial hypercholesterolemic subjects. The effects ofcalcium, EDTA, and temperature on the binding of lipoproteins to the hepatic membranes were also eval-uated. At 4VC, no significant difference in specific binding ofLDL to hepatic membranes from normal and familial hypercholesterolemic subjects was observed. At 370C, both total and specific binding ofLDL were significantly reduced in patients with familial hypercholesterolemia. Hepatic membrane binding ofLDL from the two patients homozygous for receptor-negative familial hypercholes-terolemia was 53 and 59 % of normal. The activity of the rate-limiting enzyme in cholesterol biosynthesis, 3-hy-droxy-3-methylglutaryl coenzyme A reductase was nor-mal; however, the total hepatic cholesterol and cholesteryl ester content was significantly increased from 53 to 129%. A preliminary account of this work was presented at the America