Role of apolipoproteins in cholesterol efflux from macrophages to lipid microemulsion: proposal of a putative model for the pre-.beta.-high-density lipoprotein pathway

Abstract

Lipid microemulsion of phospholipid and triglyceride with the size of low-density lipoprotein was capable of removing cholesterol from cholesterol-loaded mouse peritoneal macrophages, resulting in reduction of intracellularly accumulated cholesteryl ester. Apolipoproteins (apo) A-I, A-II, C-III, and E bound to the surface of the microemulsion did not modulate the interaction of the microemulsion with the cells in terms of the cholesterol efflux. The cholesterol removal by the microemulsion was enhanced by some 30% only when apoA-I, -A-II, and -E were present in excess to provide their free forms in the medium, but apoC-III did not show such an effect even by its excess amount. The kinetics including the results with apoC-III were consistent with a model that the apparent enhancement was due to generation of pre-beta high-density lipoprotein (HDL)-like particles upon the interaction of free apolipoproteins with macrophages [Hara, H., & Yokoyama, S. (1991) J. Biol. Chem. 266, 3080-3086]. However, pre beta-HDL-like particle was not detected after 6- and 24-h incubation in the medium where cholesterol efflux to the emulsion was maximally enhanced by the apolipoproteins, and cholesterol and phospholipids removed from the cells were all found with the microemulsions. It was also shown separately that the lipids in pre beta-HDL-like particles generated by apoA-I and macrophages were rapidly, within the order of minutes, transferred to the apo-lipoprotein-covered microemulsions when they were incubated together. Thus, the data were consistent with a model that the free form of certain apolipoproteins, such as apoA-I, -A-II, and -E but not apoC-III, generates pre beta-HDL-like particles with cellular lipids in situ and these particles act as mediators for cholesterol transfer from the cells to other lipoproteins.

Apolipoprotein A-I, Phospholipid Vesicles, and Cyclodextrins as Potential Anti-Atherosclerotic Drugs: Delivery, Pharmacokinetics, and Efficacy

“…Apolipoproteins facilitate the removal of cell cholesterol by PLs Hara and Yokoyama 1992). By promoting the removal of cholesterol from intimal macrophages, HDL permits the transfer of this cell cholesterol to the liver and facilitates its excretion in bile (Goldberg et al 1991;Johnson et al 1991;Oram and Yokoyama 1996).…”

“…First, apoA-I may be excreted via the kidneys (Horowitz et al 1992). Alternatively, it may enter the interstitial space where it has the capacity to recruit PLs and cholesterol from PMs thus forming nascent HDL particles (Bielecki et al 1992;Hara and Yokoyama 1992;Forte et al 1995;Li et al 1995). Third, lipid-free apoA-I can reincorporate into preexisting HDL particles that are increasing in size from an accumulation of core CEs generated by LCAT (Liang et al 1995).…”

“…This small particle may possibly be ltered through the capillaries more than pre-b 1 particles that are at least twice as large. This free apoA-I also contributes to the formation of pre-b 1 by interacting with PMs of the peripheral cells and accepting cholesterol and PL (Hara and Yokoyama 1992).…”

“…Using MPMs. Hara and Yokoyama (1992) demonstrated that pre-b -HDL-like particles transferred their cholesterol and PL loads to microemulsions made from PC and triolein. The half-life of the particle was estimated to be less than 10 min.…”

“…These studies suggest an apoLP-independent pathway of cholesterol ef ux. Furthermore, emulsions of PLs and triglycerides have been shown to deplete intracellular cholesterol (as esters) from macrophages during long incubations (Hara and Yokoyama 1992).…”