Turnover and Aortic Uptake of Very Low Density Lipoproteins (VLDL) from Hypercholesteremic Rabbits as a Model for Testing Antiatherosclerotic Compounds

Abstract

VLDL from hypercholesteremic (HC) rabbits display features which are suggestive of inherent atherogenicity. The lipid composition, compared to that of control VLDL, shows an enrichment of cholesterol esters, which have a very high 18:1/18:2 ratio in their fatty acids, and an increased sphingomyelin content, with decreased PC/Sph ratio. This lipid composition is very similar to that of the atherosclerotic plaque. Apoprotein peptides of HC VLDL show a predominance of arg-rich proteins, similar to human conditions (Type III hyperlipoproteinemia and hypothyroidism) characterized by early and severe atherosclerosis. Turnover of ¹²⁵I-labelled HC VLDL is significantly slower than that of control VLDL, both when the lipoprotein is injected into the donor animals and into controls. Conversion of HC VLDL into lipoproteins of higher density is also very small, as compared to control VLDL. Uptake of radioactivity into the aortic wall after injection is about doubled, as compared to control VLDL, when HC rabbits receive their own lipoprotein, and almost tripled when control rabbits receive HC VLDL. This experimental model suggests that structural modifications of HC VLDL make them poorly metabolizable, and possibly more akin to the recently described arterial lipoprotein complexing factor (ALCF). Metformin was selected as the test compound, because it has been shown to decrease aortic and liver lipid accumulation in cholesterol fed rabbits, while only slightly affecting plasma cholesterol levels. VLDL from rabbits fed cholesterol and metformin (HC+Met), while still enriched in cholesterol esters, have a higher protein content, less sphingomyelin and more phosphatidylethanolamine and phosphatidylinositol than HC VLDL, while fatty acid composition of cholesterol esters does not differ. Turnover of HC+Met VLDL is extremely rapid, with a t½ even shorter than that of control VLDL. Apoprotein composition shows a decrease of both arg-rich and C peptides. Affinity for the ALCF of this lipoprotein is very low, as shown by the very small percentage of aortic uptake of radioactivity after injection, and by in vitro studies with isolated ALCF.