Direct Interaction of Dietary Lipids Carried in Chylomicron Remnants with Cells of the Artery Wall: Implications for Atherosclerosis Development

Abstract

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.

Role of Smooth Muscle Cells in the Initiation and Early Progression of Atherosclerosis

“…43 Cholesterol uptake studies have confirmed that these receptors are indeed functional and in the presence of various forms of cholesterol, SMCs can become "lipid laden." 32 In vitro, the LDL receptor on SMCs can mediate the uptake of unmodified LDL, 36 acetylated LDL, 44 enzymatically modified LDL, 35 as well as chylomicron remnants [45][46][47] in the same manner demonstrated in macrophages. The scavenger receptor CXCL16/SR-PSOX, which is found in atherosclerotic but not healthy vessels, is also associated with the uptake of oxidized LDL into human SMCs.…”

Disturbed Chylomicron Metabolism in Type 2 Diabetes - A Preventable Cause of Atherosclerosis?

“…The inflammatory process is at the centre of the atherosclerotic lesion. Chylomicron remnants induce macrophage foam cell formation [93,94]. The fatty acid composition of chylomicron remnants markedly influences the formation of macrophage foam cells.…”

Postprandial Lipid Metabolism: The Missing Link Between Life-Style Habits and the Increasing Incidence of Metabolic Diseases in Western Countries?~!2009-09-30~!2010-01-26~!2010-03-30~!

“…CMR have been shown to penetrate the artery wall and to be retained within the intima [28][29][30], and remnant-like lipoproteins have been found in human atherosclerotic plaque [31][32][33]. CMR and TRLs have also been demonstrated to cause endothelial dysfunction [34][35][36][37][38], macrophage foam cell formation [34,39] and the proliferation of VSMCs [34]. Other pro-inflammatory and potentially atherogenic effects of postprandial lipoproteins include activation of leukocytes, promoting adhesion to the endothelium and invasion of the artery wall [12,40].…”

“…Postprandial hyperlipidemia is a feature of common, often inter-related, metabolic diseases, including obesity, insulin resistance, the metabolic syndrome (a combination of obesity, hypertension, insulin resistance/diabetes), non alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus [12,34,81] (Fig. 1).…”

“…Remnant lipoproteins have been shown to penetrate the vessel wall as efficiently as LDL and to cause foam cell formation [34]. In addition, however, evidence suggests that they may upregulate the expression of adhesion molecules on endothelial cells and activate leukocytes, thus facilitating their entry into the artery wall, where they differentiate into macrophages eventually become foam cells [12,40].…”