Development of unesterified cholesterol-rich lipid particles in atherosclerotic lesions of WHHL and cholesterol-fed NZW rabbits.

Abstract

Previously, we isolated and characterized unesterified cholesterol-rich lipid particles (UCLP) that accumulate in extracellular spaces of atherosclerotic lesions of humans and cholesterol-fed rabbits. In the present study, we examined early developing atherosclerotic lesions to determine when UCLP appear and when they become enriched in cholesterol and sphingomyelin. Cholesterol-fed NZW rabbits, which rapidly develop atherosclerotic lesions, and genetically hyperlipidemic WHHL rabbits, which develop lesions over a longer period of time, were studied. UCLP of peak density 1.04 g/ml appear as early as 4 weeks after the onset of cholesterol feeding and progressively accumulate during atherosclerotic lesion development. Beginning with their appearance and afterwards, UCLP contain a saturating level (2:1 molar ratio) of cholesterol relative to phospholipid. Whereas, early UCLP are enriched in phosphatidylcholine, with time UCLP become enriched with sphingomyelin. Another UCLP population having a peak density of 1.09 g/ml was present in control aortas and increased in amount more slowly than the d 1.04 g/ml UCLP during cholesterol feeding. The d 1.09 g/ml particles were predominantly unilamellar vesicles, the majority between 100 and 200 nm in diameter. They contained > 90% of their cholesterol in unesterified form and their ratio of unesterified cholesterol to phospholipid progressively increased from 0.6 to 1.7 during cholesterol feeding. Liposome resistance to solubilization by high density lipoproteins is known to be increased by enrichment with unesterified cholesterol and sphingomyelin. Sphingomyelin enrichment of unesterified cholesterol-rich lipid particles (UCLP) could stabilize cholesterol in a form that does not readily crystallize. However, at the same time, the early and progressive accumulation of UCLP in developing atherosclerotic lesions may limit reverse cholesterol transport and accelerate disease progression.