Molecular signaling operated by a diet-compatible mixture of oxysterols in up-regulating CD36 receptor in CD68 positive cells

Oxidation of dietary cholesterol during food storage and processing, and/or that of endogenous cholesterol in the presence of increased steady-state levels of reactive oxygen species, leads to the production of derivatives, termed oxysterols. Among the biochemical effects exerted by an oxysterol mixture, it has recently been observed that marked up-regulation of CD36 scavenger receptor on macrophage cells plays a primary role in foam cell formation. This article reports evidence of a significant co-localization of CD36 receptor with cells of the macrophage lineage, i.e. CD68 positive cells, LDL apoprotein B100 and lipids in human advanced atherosclerotic lesions. In addition, it provides a comprehensive analysis of the molecular signaling operated by a nutritionally relevant mixture of oxysterols in overexpressing CD36 receptor in cells of the macrophage lineage. The involvement of a G protein, Src, phospholipase C cascade and peroxisome proliferator-activated receptor γ in oxysterol-mediated signaling was demonstrated by using selective inhibitors, while the central role of the downstream protein kinase Cδ and extracellular signal-regulated kinase pathways in oxysterol-induced enhancement of CD36 was conclusively proved by means of small interfering RNA (siRNA) technology.