A critical step in the uptake of dietary cholesterol by the liver is the binding of remnant lipoprotein particles to receptors in the space of Disse. We have found that increases in the cholesterol content of hepactocyte membranes reduces the binding of beta-very low density lipoproteins (beta-VLDL) and decreases internalization. This increase in membrane cholesterol of human hepatoma cells (HepG2) produces a similar effect on binding to primary human fibroblasts. However, receptor-negative familial hypercholesterolemic (FH) fibroblasts lack the ability to respond to membrane cholesterol modification. A polyclonal antibody directed against the C-terminus region of the apo-B,E-(LDL) receptor importantly affects the internalization process, suggesting that protein-protein interactions consolidate the pattern formation of receptors, a process that triggers lipoprotein internalization. We propose that cholesterol interferes with this pattern formation by affecting the lateral movement and organization of the receptors.