Reduced apoprotein B and increased lipoprotein turnover in cholesterol-fed rabbits after partial ileal bypass.

Plasma lipid and lipoprotein levels and composition of the very low-, low-, and high-density lipoproteins (VLDL, LDL, HDL) were studied in white New Zealand rabbits in the control state, 8 weeks after initiation of a 2% cholesterol-enriched diet, and sequentially for 16 weeks following a partial ileal bypass (PIB) procedure. Turnover and aortic uptake of 125I-labeled VLDL, obtained from the rabbits before and 16 weeks after PIB, were also analyzed. A significant reduction of plasma cholesterol from the postdiet levels to well below the prediet mean, despite continuation of the high cholesterol diet, followed PIB. A very early reduction of the apoprotein B percentage content in both VLDL and LDL was observed after the procedure, even when a relative cholesterol ester enrichment of these lipoproteins was still present. HDL cholesterol levels were somewhat lowered by the experimental diet and further reduced after PIB. 125I-labeled VLDL after PIB showed a reduced arterial uptake, as compared to the same lipoproteins from animals before PIB. These findings may provide an interpretation for the decreased atherogenesis after PIB.

Metaformin: an antiatherosclerotic agent modifying very low density lipoproteins in rabbits.

The composition of very low density lipoproteins (VLDL: d less than 1.019) of New Zealand male rabbits reciving cholesterol (2 g/day) and metformin (135 mg/kg/day) is investigated. These rabbits, while showing only a slight reduction of plasma cholesterol levels, as compared to cholesterol-fed (h.c.) animals, show a marked decrease of the aortic cholesterol esters and atheromatous process. VLDL from the cholesterol + metformin group (h.c. + met), as compared to the h.c. animals, are homogenous in size and not separable into VLDL-1 and VLDL-2 subfractions by Sepharose 4B chromatography. These findings are confirmed by electron microscopy, which shows homogeneity of particle size, as well a decreased tendency of h.c. + met VLDL to aggregate. Chemical composition of h.c. + met VLDL is characterized by increased triglycerides and phospholipids, while the percentage of cholesterol esters is not significantly decreased. Phospholipid distribution of h.c. + met VLDL shows a significant decrease of sphingomyelin and increased phosphatidylinositol, the latter both as compared to h.c. and control VLDL. Apoprotein pattern of h.c. + met VLDL in polyacrylamide gels shows a relative increase of peptides with C mobility and a decrease of proteins corresponding to the arg-rich peptides. These findings exemplify a case of altered lipoprotein composition and decreased atheromatosis, in the presence of marked hypercholesteremia.

Turnover and aortic uptake of very low density lipoproteins (VLDL) from hypercholesteremic rabbits as a model for testing antiatherosclerotic compounds.

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 plaqua. 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 HC VLDL. This experimental model suggests that structural modifications of the HC VLDL make them poorly metabolizable, and possible 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 t1/2 even shorter than that of control VLDL.

Very low density lipoproteins in normal and cholesterol-fed rabbits: lipid and protein composition and metabolism. Part 1. Chemical composition of very low density lipoproteins in rabbits.

The lipid and apoprotein composition of very low density lipoproteins (VLDL) (d less than 1.019 g/ml) from normal and hypercholesteremic (h.c.) rabbits are compared. Significant changes are observed in the apoproteins, as well as in the fatty acid composition of cholesterol esters, and in the relative distribution of phospholipids. Apoproteins show a marked increase of peptides with slow mobility (R2 and R3), corresponding to arginine-rich proteins, both in the rabbit and in some types of human hyperlipoproteinemias (hypothyroidism and Fredrickson Type III). VLDL were separated into the two fractions, VLDL-1 and VLDL-2. Peptides of slow mobility were shown to be present in a higher concentration in VLDL-1. Cholesterol esters of h.c. VLDL have a very high content of oleic acid, the 18:1/18:2 ratio being about three times higher than in normal VLDL. Phospholipid distribution in h.c. VLDL is characterized by an increase of sphingomyelin and decrease of phosphatidylethanolamine. The PC/Sph ratio is about one fifth that of normal. These changes in VLDL lipids are very similar to those occurring in the lipid composition of the atherosclerotic plaques in mammals.

Very low density lipoproteins in normal and cholesterol-fed rabbits: lipid and protein composition and metabolism. Part 2. Metabolism of very low density lipoproteins in rabbits.

The metabolic fate of very low density lipoproteins (VLDL) in normal and hypercholesteremic (h.c.) rabbits has been investigated. VLDL were labelled with 125I in the protein moieties and injected into normal and h.c. animals. The turnover of h.c. VLDL is markedly delayed as compared to that of normal VLDL, and conversion into lipoprotein classes of higher density is considerably decreased. This is observed when h.c. VLDL are injected either into h.c., or into normal rabbits. Arterial uptake of radioactivity is much higher with h.c. VLDL than with the normal lipoproteins, and it is highest when h.c. VLDL are injected into normal recipients. These data, together with those reported in the previous study, support the hypothesis that h.c. VLDL have an inherent atherogenicity. Injection of h.c. VLDL into normal animals also offers an experimental model for testing drugs or diets against atherosclerosis, using untreated animals.