DEVELOPMENT OF UNESTERIFIED CHOLESTEROL-RICH LIPID PARTICLES IN ATHEROSCLEROTIC LESIONS OF WHHL AND CHOLESTEROL-FED NZW RABBITS

Previously, we isolated and characterized unesterified cholesterol-ric h lipid particles (UCLP) that accumulate in extracellular spaces of at herosclerotic lesions of humans and cholesterol-fed rabbits. In the pr esent study, we examined early developing atherosclerotic lesions to d etermine 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. UCL P of peak density 1.04 g/ml appear as early as 4 weeks after the onset of cholesterol feeding and progressively accumulate during atheroscle rotic lesion development. Beginning with their appearance and afterwar ds, UCLP contain a saturating level (2:1 molar ratio) of cholesterol r elative to phospholipid. Whereas, early UCLP are enriched in phosphati dylcholine, with time UCLP become enriched with sphingoymelin. Another UCLP population having a peak density of 1.09 g/ml was present in con trol aortas and increased in amount more slowly than the d 1.04 g/ml U CLP during cholesterol feeding. The d 1.09 g/ml particles were predomi nantly unilamellar vesicles, the majority between 100 and 200 nm in di ameter. They contained > 90% of their cholesterol in unesterified form and their ratio of unesterified cholesterol to phospholipid progressi vely increased from 0.6 to 1.7 during cholesterol feeding. Liposome re sistance to solubilization by high density lipoproteins is known to be increased by enrichment with unesterified cholesterol and sphingomyel in. Sphingomyelin enrichment of unesterified cholesterol-rich lipid pa rticles (UCLP) could stabilize cholesterol in a form that does not rea dily 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.