ANALYSIS OF PARTICLE-SIZE AND LIPID-COMPOSITION AS DETERMINANTS OF THE METABOLIC-CLEARANCE OF HUMAN HIGH-DENSITY-LIPOPROTEINS IN A RABBIT MODEL

Hypertriglyceridemia is commonly associated with triglyceride (TG) enr ichment of high density lipoprotein (HDL) and reduction in HDL cholest erol and apolipoprotein A-I levels. We have recently reported that lip olytic modification of TG-dch HDL, which reduces particle size, enhanc es its clearance from the circulation, In the present study, we examin ed the role of particle size and lipid composition in determining the metabolic clearance of human HDL, in the absence of substantial in viv o modification of the particle by hepatic lipase. The rabbit, which ha s a very low hepatic lipase activity, was used for this purpose, Plasm a fractions d < 1.21 g/ml were first isolated by ultracentrifugation f rom fasting humans with normal (NTG, n = 6, mean plasma TG concentrati on = 1.26 +/- 0.21 (SEM) mmol/l) or elevated plasma TG levels (HTG, n = 5, TG = 4.49 +/- 0.65 mmol/l), Small and large HDL particles were se parated by gel filtration chromatography and were labeled with either I-125 or I-131. Large HDL were cleared more rapidly than small HDL in 10 out of 11 studies (P = 0.006), There was, however, no difference in the fractional catabolic rate (FCR) of large HDL isolated from NTG ve rsus from HTG subjects or in the FCR of small HDL from NTG versus HTG individuals, There was also no correlation between the TG content of H DL and its FCR, In summary, large, lipid-rich human high density lipop roteins (HDL) are cleared more rapidly than small human HDL in rabbits . These results, combined with our previous observation, also support the hypothesis that triglyceride enrichment of HDL, in the absence of substantial lipolytic modification, is not sufficient to enhance its c learance from the circulation.