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) enrichment of high density lipopro- tein (HDL) and reduction in HDL cholesterol and apolipo- protein A-I levels. We have recently reported that lipolytic modification of TG-rich HDL, which reduces particle size, enhances its clearance from the circulation. In the present study, we examined the role of particle size and lipid com- position in determining the metabolic clearance of human HDL, in the absence of substantial in vivo modification of the particle by hepatic lipase. The rabbit, which has a very low hepatic lipase activity, was used for this purpose. Plasma fractions d , 1.21 g/ml were first isolated by ultra- centrifugation from fasting humans with normal (NTG, n 5 6, mean plasma TG concentration 5 1.26 6 0.21 (SEM) mmol/l) or elevated plasma TG levels (HTG, n 5 5, TG 5 4.49 6 0.65 mmol/l). Small and large HDL particles were separated by gel filtration chromatography and were la- beled with either 125 I or 131 I. Large HDL were cleared more rapidly than small HDL in 10 out of 11 studies ( P 5 0.006). There was, however, no difference in the fractional cata- bolic rate (FCR) of large HDL isolated from NTG versus from HTG subjects or in the FCR of small HDL from NTG versus HTG individuals. There was also no correlation be- tween the TG content of HDL and its FCR. In summar y, large, lipid-rich human high density lipoproteins (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 clearance from the circula- tion.— Lamarche, B., K. D. Uffelmann, G. Steiner, P. H. R. Barrett, and G. F. Lewis. Analysis of particle size and lipid composition as determinants of the metabolic clearance of human high density lipoproteins in a rabbit model. J. Lipid Res. 1998. 39: 1162-1172.