The direct way from gut to vessel wall: atheroinitiation

It has always been enigmatic that regional nutritional differences that are not directly reflected in fasting plasma cholesterol concentrations greatly influence the risk for atherosclerotic vascular disease [1]. In addition, the vast majority of cardiovascular incidents occur in subjects with ‘normal’ cholesterol levels in populations which as a whole have relatively high cholesterol concentrations. This may be due to a direct atherogenic effect of chylomicrons and their remnants, which transport nutritional fat and cholesterol to adipose tissue and liver. In particular, chylomicron remnants are not easily detected in plasma by routine lipid measurements. Hypotheses on the atherogenicity of chylomicrons and their remnants have thus far always involved indirect pathways. Chylomicron remnants are supposed to deliver cholesterol acquired from high-density lipoprotein (HDL) to the hepatocyte, thereby down-regulating the low-density lipoprotein (LDL) receptor [2]. In this issue of the European Journal of Clinical Investigation, intriguing and elegant evidence has been provided by Proctor & Mamo [3] that chylomicron remnants directly transgress the endothelial cell layer, are trapped in the subendothelial space and lead to retention of atherogenic fatty material. This may very well be the initial event in fatty streak formation with classic atherosclerotic plaque formation as a consequence. It may, in addition, explain the direct atherogenicity of fat food, independent of fasting cholesterol. Previously, it had been shown that chylomicron remnants are avidly taken up by macrophages and smooth muscle cells and lead to foam cell formation [2,4]. Thus, chylomicron remnants may promote atherosclerosis by retention in the subendothelial space, uptake by macrophages and accumulation in smooth muscle cells. This pathophysiological background strengthens the concept of atherogenesis as a post-prandial phenomenon [5], for which ample clinical evidence is available [6–9]. However, the controversy is far from settled and many questions remain open. The clearance of chylomicron remnants from the circulation in humans is a complex mechanism that has not been fully elucidated. Hepatic chylomicron remnant clearance is mediated by the action of lipoprotein lipase (LPL), hepatic lipase (HL), the interaction of apolipoprotein (apo) E and apoCs with specific receptors, and nonreceptor binding to cellular surfaces. Several hepatic receptors may be involved in the clearance of chylomicron remnants: the LDL receptor-related protein–a2-macroglobulin receptor, a parenchymal liver cell remnant receptor, the asialoglycoprotein receptor, the lipolysis-stimulated receptor and the LDL receptor. Recently, the very lowdensity lipoprotein (VLDL) receptor, a new member of the LDL receptor supergene family, has been described as a physiological receptor for chylomicron remnants in nonhepatic tissues [10]. Although the present paper does not show uptake by the different cell types in the vessel wall or binding to specific cellular receptors and transformation into foam cells, the elegant methodology described will provide the opportunity to study these processes in more detail. Moreover, the study of specific interventions in vivo on this early stage of atherosclerosis seems possible. At present, improvement of chylomicron remnant clearance by HMGCoA reductase inhibitors [11] and fibrates has been demonstrated [12,13]. Other factors, such as physical activity, dietary changes and stopping smoking, have been shown to improve chylomicron remnant clearance. Most of these interventions result in small changes in the clearance of chylomicron remnants, and the clinical importance remains to be established. Until now there have been no clinical studies available demonstrating on a large scale that improved chylomicron remnant clearance results in lower morbidity and mortality. Moreover, rapid disappearance of chylomicron remnants from the plasma does not necessarily imply reduction in risk for atherosclerosis because the cellular mechanisms involved are not yet well understood. Although the liver is the major organ for chylomicron remnant uptake, a large number of these particles are taken up by other tissues. Most investigations of post-prandial lipoprotein metabolism have been hindered by the lack of methods to determine the metabolic changes in vivo of these lipoproteins. Different procedures have been used to determine the rate of clearance of chylomicrons and their remnants. In most studies, post-prandial lipoprotein metabolism has been assessed by oral [11–14] or intravenous [15] fat tolerance tests. Some investigators have used either retinyl