Low density lipoprotein receptor-independent hepatic uptake of a synthetic, cholesterol-scavenging lipoprotein: implications for the treatment of receptor-deficient atherosclerosis.

Abstract

The metabolism of infused "'In-labeled phospholipid liposomes was examined in Watanabe heritable hyperlipidemic (WHHL) rabbits, which lack low density lipoprotein (LDL) receptors, and in normal control rabbits. The half-times (t/,2) for clearance of "'In and excess phospholipid from plasma were 20.8 ± 0.9 hr and 20.3 ± 4.6 hr in WHHL and 20.0 ± 0.8 hr and 19.6 ± 2.2 hr in the normal rabbits (means ± SEM; n = 4). By 6 hr postinfusion, the plasma concentration of unesterified cholesterol increased by 2.2 --_ 0.23 mmol/liter in WIHHL and 2.1 ± 0.04 mmol/liter in normal rabbits, presumably reflecting mobilization of tissue stores. Disappearance of excess plasma cholesterol was >90% complete in both groups of rabbits by 70 hr postinfusion. By quantitative y camera imaging, hepatic trapping of "'Inlabeled liposomes over time was indistinguishable between the two groups. At autopsy, the liver was the major organ of clearance, acquiring 22.0% ± 1.7% (WHHL) and 16.8% + 1.0% (normal) of total "'In. Aortic uptake of "'In was <0.02%. Thus, mobilization of cholesterol and hepatic uptake of phospholipid liposomes do not require LDL receptors. Because phospholipid infusions produce rapid substantial regression of atherosclerosis in genetically normal animals, our results suggest that phospholipid liposomes or triglyceride phospholipid emulsions (e.g., Intralipid) might reduce atherosclerosis in WHHL rabbits and in humans with familial hypercholesterolemia.

Rapid Restoration of Normal Endothelial Functions in Genetically Hyperlipidemic Mice by a Synthetic Mediator of Reverse Lipid Transport

“…The rise in the plasma concentration of unesterified cholesterol, which reflects the mobilization of tissue cholesterol by liposomes, 27-30 tended to be slightly higher in the apoE knockout mice than in the wild-type mice (75Ϯ17 versus 50Ϯ7.0 mg/dL, respectively, at 8 hours after the injection; meanϮSEM, nϭ4; PϭNS), similar to previous findings in other hyperlipidemic animals. 29,39 The overall rate of LEV clearance was similar between apoE knockout and wild-type mice (24 hours after the injection, 22.6Ϯ2.9% and 23.3Ϯ2.4% of the injected dose remained in serum in the 2 respective groups of mice; PϭNS), with no difference in hepatic accumulation of LEV label. Thus, LEVs mobilize tissue cholesterol and then are cleared by the liver in both apoE knockout and wild-type mice, demonstrating that these particles mediate reverse lipid transport in vivo even in the absence of apoE.…”

“…24,25,[27][28][29]32 These sequelae include endothelial dysfunction, platelet hyperreactivity, and atherosclerosis, including the development of lipid-rich rupture-prone plaques. Our data indicate that treatment with LEVs, which accelerate reverse lipid transport in vivo without reducing long-standing elevations in plasma concentrations of cholesterol-rich atherogenic lipoproteins, is sufficient to rapidly restore important indices of macrovascular and microvascular endothelial function to normal.…”

Fluorescent Probe-Labeled Lipid Microsphere Uptake by Human Endothelial Cells: A Flow Cytometric Study

“…When the tri glyceride in the cores of some microspheres is hydro lyzed, surface phospholipids are left behind as vesicles (24). These vesicles then scavenge tissue cholesterol and thereby become transporters of cholesterol to the liver (25). Phospholipid vesicles or infused phospholipid liposomes have also been shown to acquire apolipopro teins in the circulation, including apo E, apo A-I, and possibly apo A-IV (26).…”

Meyer Friedman

“…[1][2][3] He published over 70 papers on various aspects of cholesterol metabolism, not least of which was the introduction of a method for removing atheromatous deposits from the aortas of hypercholesterolemic rabbits, 4 a finding confirmed by more refined methods some 30 years later. 5 Early on he demonstrated by meticulous pathologic techniques that acute myocardial infarction was not a question of either atheroma or thrombosis, but actually a combination of these two processes, 6 essentially the current concept regarding the pathogenesis of this disease. Over 20 years later, Forrester et al credited Friedman with this in their own paper on the subject.…”