The development of atherosclerotic lesions in the artery wall is a complex process involving the endothelium,
lipid engorged macrophages (foam cells) and smooth muscle cells. In recent years it has become clear that
chylomicron remnants, the
lipoproteins which carry
lipids of dietary origin in the blood, are strongly atherogenic, and there is increasing evidence to indicate that this is due to direct interaction of the remnant particles with cells of the artery wall.
Chylomicron remnants have been demonstrated to inhibit endothelium dependent vasorelaxation and to activate signal transduction pathways associated with
inflammation in cultured endothelial cells. They have also been shown to be taken up by smooth muscle cells and macrophages, and to cause the extensive
lipid accumulation associated with foam cell formation, as well as influencing the expression of key genes regulating macrophage
lipid uptake and metabolism. Furthermore, oxidative modification of the remnant particles is not required for many of these effects.
Chylomicron remnants, therefore, have multiple direct effects on three major cell types of the arterial wall which are likely to promote the development of atherosclerotic lesions. These effects may be modulated by various
lipids carried by the particles, including the type of fat (saturated or unsaturated or oxidised fat),
micronutrients such as
vitamins and
carotenoids which have
antioxidant properties, and orally administered lipophilic drugs. Delayed clearance of
chylomicron remnants from the blood occurs in a number of
dyslipidemias associated with premature
atherosclerosis development, and the potentially atherogenic effects of the particles would clearly be enhanced in these circumstances. Thus, elucidation of the mechanisms involved will aid in the identification of new
drug targets which may be particularly useful for these conditions.