Abstract
This study investigates the effect of altered lipoprotein free cholesterol (FC) content on the transfer of cholesteryl ester (CE) and triglyceride (TG) from very low- (VLDL), low- (LDL), and high-(HDL) density lipoproteins by the plasma-derived lipid transfer protein (LTP). The FC content of VLDL and HDL was selectively altered by incubating these lipoproteins with FC/phospholipid dispersions of varying composition. FC-modified lipoproteins were then equilibrated with [3H] TG, [14C]CE-labeled lipoproteins of another class to facilitate the subsequent modification of the radiolabeled donor lipoproteins. LTP was added and the extent of radiolabeled TG and CE transfer determined after 1 h. With either LDL or VLDL as lipid donor, an increase in the FC content of these lipoproteins caused a concentration-dependent inhibition (up to 50%) of CE transfer from these particles, without any significant effect on TG transfer. In contrast, with HDL as donor, increasing the HDL FC content had little effect on CE transfer from HDL, but markedly stimulated (up to 2.5-fold) the transfer of TG. This differential effect of FC on the unidirectional transfer of radiolabeled lipids from VLDL and HDL led to marked effects on LTP-facilitated net mass transfer of lipids. During long-term incubation of a constant amount of LTP with FC-modified VLDL and HDL, the extent of net mass transfer was linearly related to lipoprotein FC content; a 4-fold increase in FC content resulted in a 3-fold stimulation of the CE mass transferred to VLDL, which was coupled to an equimolar, reciprocal transfer of TG mass to HDL. Since lipid transfer between lipoproteins is integral to the process of reverse cholesterol transport, we conclude that lipoprotein FC levels are a potent, positive regulator of the pathways involved in sterol clearance. FC may modulate lipid transfer by altering the availability of CE and TG to LTP at the lipoprotein surface.
Highlights
From The Department of Brain and Vascular Research, Research Instituteof the Cleveland Clinic Foundation, Cleveland, Ohio 44195
We report that theFC content of lipoproteins has profound affects on the transfer of radiolabeled triglyceride and cholesteryl ester
The in vitro modification of lipoprotein free cholesterol (FC) content was accomplished by exposure of lipoproteins to FC-PC dispersions [31]
Summary
With low- (VLDL),low- (LDL), and high-(HDL) density li- lipoprotein substrates, thesereactions are predominately chopoproteinsby the plasma-derived lipid transfer protein lesteryl ester-for-cholesteryl ester or triglyceride-for-triglyc-. The FC content of VLDL and HDL was selec- eride transfers which facilitate the equilibration of the molectively alteredby incubating these lipoproteins withFC/ ular species of lipids, and cholesteryl ester-for-triglyceride phospholipid dispersions of varying composition. Long-term feeding of diets enriched in saturated fatty acids, which decreases lipoprotein lipid fluidity [17], results in a loss of the normal equilibration of LDL and HDL core lipids [18], suggesting that LTP is inhibited by increased lipoprotein lipid microviscosity. The abbreviations used are: LTP, lipid transfer protein; VLDL, very low density lipoprotein(s); LDL, low density lipoprotein(s); HDL, high density lipoprotein(s); IDL, intermediate density lipoprotein(s); PC, phosphatidylcholine; FC, free cholesterol; PL, phospho-.
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