Low Density Lipoprotein Oxidation and Its Pathobiological Significance*

Background The fact that low density lipoprotein (LDL) 1 is extremely sus- ceptible to oxidative damage has been known for some time (1, 2), but until quite recently this was primarily a nuisance for the student of lipoprotein metabolism. It now appears that oxidation of LDL plays a significant role in atherogenesis. Beginning in the 1980s evidence began to accumulate that cholesterol accumulation in the developing atherosclerotic lesion was probably not due to the uptake of native LDL by way of the Brown/Goldstein LDL receptor but instead due to the uptake of some modified form of LDL (then still unidentified) by way of one or more alternative receptors (also then unidentified). This conclusion grew from two well accepted observations. First, patients and animals totally lacking the LDL receptor nevertheless accumulate cholesterol in foam cells much the same way as do patients and animals with normal LDL receptors; second, the two cell types in lesions that give rise to cholesterol-laden foam cells (the monocyte/ macrophage and the smooth muscle cell) do not accumulate choles- terol in vitro even in the presence of very high concentrations of native LDL (3, 4). This paradox could be resolved if circulating LDL underwent some form of modification and if the modified form, rather than native LDL itself, then served as the ligand for delivery of cholesterol to developing foam cells. Acetylation of LDL in vitro generated a modified LDL that could induce cholesterol accumula- tion in macrophages (3). The uptake of this acetylated LDL was by way of a new receptor designated the acetyl LDL receptor (later cloned and renamed scavenger receptor A (SRA) (5). SRA, unlike the LDL receptor, is not down-regulated when the cholesterol con- tent of the cell increases. Thus, acetyl LDL could, in principle, account for foam cell formation. However, there was (and still is) no evidence that acetylation