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Conclusion:
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Ezetimibe and S6130, but not glucuronidated ezetimibe disturbed the co-localization of CD13 and its co-receptor CD64 (Fc receptor I) in membrane microdomains, and decreased the presence of both receptors in detergent-resistant membrane fractions. Biotinylated cholesterol absorption inhibitor C-5 (i.e. derivative of ezetimibe) was rapidly internalized to perinuclear tubular structures of cells, resembling endoplasmic reticulum (ER), but CD13 was detected on extracellular sites of the plasma membrane and endo-lysosomal vesicles. Administration of ezetimibe, but not of glucuronidated ezetimibe or S6130, was associated with decreased cellular cholesteryl ester content, indicating the sterol-O acyltransferase 1 (SOAT1)-inhibition by ezetimibe. Furthermore, ezetimibe decreased the expression of molecules involved in cholesterol uptake and synthesis, in parallel with increased apolipoprotein A-I-mediated cholesterol efflux and up-regulation of efflux-effectors. However, NPC1L1 the other claimed molecular target of ezetimibe, was not detected in macrophages, thereby excluding this protein as target for ezetimibe in macrophages.
Ezetimibe is very likely a CD13-linked microdomain-disruptor and SOAT1-inhibitor in macrophages leading to in vitro anti-atherosclerotic effects through a decrease of net cellular cholesterol content.
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