Analysis of particle size and lipid composition as determinants of the metabolic clearance of human high density lipoproteins in a rabbit model

Benoît Lamarche,Kristine D Uffelman,George Steiner,P Hugh R Barrett,Gary F Lewis

doi:10.1016/s0022-2275(20)32540-2

Benoît Lamarche, Kristine D Uffelman + Show 3 more

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https://doi.org/10.1016/s0022-2275(20)32540-2

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Abstract

Hypertriglyceridemia is commonly associated with triglyceride (TG) enrichment of high density lipoprotein (HDL) and reduction in HDL cholesterol and apolipoprotein 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 composition 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 = 6, mean plasma TG concentration = 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 separated by gel filtration chromatography and were labeled with either 125I or 131I. 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 versus 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 HDL and its FCR. In summary, 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 circulation.—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.

Highlights

Hypertriglyceridemia is commonly associated with triglyceride (TG) enrichment of high density lipoprotein (HDL) and reduction in HDL cholesterol and apolipoprotein A-I levels
We have recently investigated the potential contribution of in vivo lipolytic modification in determining the rate at which human HDL are cleared in rabbits by comparing the fractional catabolic rate (FCR) of large, postprandial, triglyceride-rich HDL isolated after a high fat meal to the FCR of small, lipolytically modified HDL, isolated after intravenous heparin in humans [17]
Results from the present study first suggest that lipidrich human HDL is catabolized more rapidly than small HDL in rabbits

Summary

Introduction

Hypertriglyceridemia is commonly associated with triglyceride (TG) enrichment of high density lipoprotein (HDL) and reduction in HDL cholesterol and apolipoprotein A-I levels. 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, support the hypothesis that triglyceride enrichment of HDL, in the absence of substantial lipolytic modification, is not sufficient to enhance its clearance from the circulation.—Lamarche, B., K. Analysis of particle size and lipid composition as determinants of the metabolic clearance of human high density lipoproteins in a rabbit model. Brinton and coworkers [8, 11] reported that the HDL cholesterol/A-I ϩ A-II ratio, a crude but not direct measure of particle size, may represent one of the primary determinants of apoA-I FCR, implying that small HDL particles may be cleared more rapidly than large ones.

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