Role of Low Density Lipoprotein Oxidation in Foam Cell Formation

  • Urs P. Steinbrecher
Part of the NATO ASI Series book series (NSSA, volume 189)


The pathophysiology of atherosclerosis is complex, and probably involves multiple interacting mechanisms. The two hypotheses that have been invoked most often to explain atherogenesis are the “response to endothelial injury” hypothesis, and the “lipid infiltration” hypothesis.1,2 It has become clear that these two seemingly distinct hypotheses are in fact so closely linked that they cannot be considered in isolation.2 Pathologically, one of the hallmarks of the atherosclerotic lesion is the presence of lipid-laden foam cells in the arterial intima. Several lines of evidence indicate that in early lesions foam cells are derived from macrophages, although in more advanced lesions, smooth muscle cells apparently can also undergo foam cell transformation.3–8 The mechanism by which these cells accumulate excess lipid in the artery wall in vivo has not been deteimsined. However, studies using cultured macrophages have suggested potential mechanisms by which foam cell formation might occur. When macrophages are exposed to “physiologic” or even to high concentrations or normal lipoproteins in vitro the rate at which they accumulate cholesterol is usually insufficient to cause foam cell formation.9 An exception to this is the observation that J774 cells, a mouse macrophage-like cell line that exhibits unusually high acyl-CoA:cholesterol acyltransferase (ACAT) activity, can accumulate cholesterol ester when incubated with normal LDL.10 This phenomenon apparently does not occur with primary cultured macrophages, and hence its applicability to foam cell formation in vivo remains speculative. Cultured macrophages can also accumulate lipid when exposed to βVLDL, but the reason for this is not entirely clear, as the receptor responsible for the internalization of βVLDL appears to be identical to the classical LDL receptor11–13 and its expression would therefore be expected to be regulated by cellular cholesterol content. In any case, uptake of βVLDL and related triglyceride-rich lipoproteins remains a potentially important mechanism for lipid accumulation. Macrophages have also been found to possess a high affinity uptake mechanism for certain types of modified lipoproteins.9,14 This has been termed the scavenger or “acetyl-LDL” receptor. The expression of this receptor is not subject to regulation by cellular cholesterol content, and therefore can lead to massive cholesterol accumulation. Several different chemical modifications of LDL can lead to uptake via this receptor, including acetylation, acetoacetylation, carbamylation, and modification by malondialdehyde.14–19 These modifications share as a common feature the ability to derivatize lysine residues and result in a neutralization of the positive charge of the lysine epsilon amino group, resulting in a net increase in electrophoretic mobility. In addition to these chemical modifications of LDL, a “biological” modification of LDL has also been described that leads to uptake by the scavenger receptor. This modification is the result of peroxidation of LDL, either initiated by incubation of LDL with cultured cells or by exposure of LDL to redox-active metal ions in the absence of cells.20–26 Although many changes to LDL structure and composition result from oxidation, the recognition of oxidized LDL by the scavenger receptor can be explained by the modification of lysine residues.


Foam Cell Scavenger Receptor Foam Cell Formation Bovine Aortic Endothelial Cell Cholesterol Ester Hydrolase 


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Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Urs P. Steinbrecher
    • 1
  1. 1.Department of MedicineUniversity of British ColumbiaVancouverCanada

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