Although apolipoprotein (apo)A-I and apoB are measured by many laboratories as an adjunct to HDL and LDL concentrations, respectively, lipoproteins contain numerous other proteins, some of which have a profound effect on lipoprotein metabolism. ApoE, for example, resides on both antiatherogenic HDL particles and on proatherogenic apoB-containing lipoproteins, thus confounding the usefulness of apoE as a cardiovascular risk marker in unfractionated samples. Nevertheless, apoE has many different roles in lipoprotein metabolism, some of which may account for the macrophage lipid accumulation observed in this interesting case. The best understood function of apoE is that it can serve as a ligand for the cellular uptake of apoB-containing proteins, as well as perhaps HDL, by various receptors. In the absence of a normal form of apoE, there is decreased hepatic clearance of lipoproteins, which leads to their increased oxidation and uptake by macrophage scavenger receptors. ApoE can also help prevent lipid accumulation in cells, particularly in macrophages, which synthesize apoE, by promoting the efflux of excess intracellular cholesterol by the ABCA1 transporter and by other cholesterol efflux mechanisms.
Recently, a new role for apoE has been described, which may also be relevant to the macrophage lipid accumulation observed in this case. The presence of apoE on lipoproteins also facilitates the lysosomal processing of endocytosed lipoproteins (1). In the absence of apoE or possibly, as in this case, in the presence of an abnormal form of apoE, the endocytosed lipoproteins interfere with the delivery of the various hydrolytic enzymes to the lysosome, by perhaps altering the production and/or trafficking of the mannose-6-phosphate receptor, which normally shepherds these enzymes to the lysosome. This interference results in a defect in the intracellular lipolysis of lipoproteins and the accumulation of cholesteryl esters in lysososomes. In addition, cathepsin B, normally a lysosomal proteolytic enzyme, is instead secreted into the extracellular space, where it may contribute to the formation of unstable plaques. Currently, the only apoE-based test routinely performed in clinical laboratories is a genotype type test for apoE isoforms, for assessing the risk of Alzheimer disease. Given the multifaceted role of apoE in lipoprotein metabolism, the measurement of apoE on specific lipoprotein fractions may be a fruitful area for future research on cardiovascular risk markers.
Grant/funding Support: None declared.
Financial Disclosures: None declared.
- © 2008 The American Association for Clinical Chemistry