The low density lipoprotein and low density lipoprotein receptors and their possible importance in the pathogenesis of atherosclerosis

Abstract

In man and in experimental animals, elevations in plasma cholesterol lead to premature atherosclerosis. It is likely that the cholesterol-rich low density lipoprotein (LDL) plays a keyrole in atherogenesis. LDL accumulates in patients with familial hypercholesterolemia (FH), a genetic syndrome associated with a defective LDL receptor in parenchymal cells and premature atherosclerosis. Monocytic/macrophage-like cells invading the vessel wall are becoming enriched with cholesteryl ester and concentrating in the early atherosclerotic lesion. Modification of LDL stimulates the uptake of cholesterol by macrophages in vitro leading to the conversion of the cells to lipid laden foam cells. Because of this phenomenon recent investigations were focussing on the lipid metabolism of macrophages. In vitro studies have demonstrated that macrophages have specific cell surface receptors for modified forms of LDL. It was suggested that these scavenger receptors could mediate foam cell formation in vivo, too. In vivo analysis by sequential scintiscans revealed that the liver is accumulating most actively modified LDL, possibly acting as a sieve for atherogenic lipoproteins. The putative liver receptor for modified (= atherogenic) LDL was characterized as a membrane protein of 220 000 to 250 000 D by ligand blotting.