Lipoprotein receptors, macrophages, and sphingomyelinase.

Cholesteryl ester–filled macrophages are the hallmark of atherosclerotic lesions. Unraveling the pathways responsible for lipid accumulation in macrophages has been viewed as an important aspect for understanding a piece of the atherosclerotic process.1 Investigations into the mechanisms through which macrophages accumulate cholesteryl esters from lipoproteins have delineated the involvement of several different receptorand non–receptormediated pathways. For instance, macrophages express LDL receptors as well as several other members of the LDL receptor family, such as the LDL receptor–related protein (LRP) and the VLDL receptor.2 The LDL receptor family recognizes apolipoprotein (apo) B-100– and particularly apoE-containing lipoproteins. The uptake of lipoproteins via LDL receptor family members is facilitated by additional apoE, as well as by the presence of lipoprotein lipase. Each member of the LDL receptor family appears to be capable of contributing to a portion of the uptake of lipoproteins by macrophages; however, the contribution of each particular member will vary depending on the underlying pathophysiological condition. For instance, the LDL receptor is not functional in LDL receptor deficiency, and the contribution of either the LRP or the VLDL receptor would be expected to be low in apoE deficiency.3 In addition, macrophages express an apoE-independent pathway for the uptake of triglyceride-rich lipoproteins that recognizes apoB-48 or the similar domain on apoB-100 and has been termed the apoB-48 receptor.4 Finally, macrophages express several different scavenger receptors that recognize modified lipoproteins, particularly lipoproteins that have been modified by oxidation.5 Other lipoprotein modifications, such as aggregation, proteoglycan complex formation, and glycation, can lead to lipid accumulation in macrophages via these as well as other receptor and nonreceptor pathways.