Background: The liver is a key organ in lipid and lipoprotein metabolism. It has been postulated that a small diameter of sinusoidal fenestrae retards clearance of chylomicron remnants, resulting in hypercholesterolemia and atherosclerosis. However, this hypothesis has not been rigorously tested hitherto.
Methods: In the current study, we compared plasma levels of proatherogenic lipoproteins and assessed the development of atherosclerosis at distinct locations throughout the arterial tree in heterozygous New Zealand White and Dutch Belt rabbits that are deficient in low-density lipoprotein receptor and with an average fenestrae size of 103 and 124 nm, respectively.
Results: Feeding of a 0.15% cholesterol diet for 4 months resulted in similar total plasma cholesterol levels in New Zealand White (420±20 mg/dl) and Dutch Belt (380±30 mg/dl) rabbits. Following isolation of lipoproteins by ultracentrifugation, no biologically significant differences in very-low-density lipoprotein, intermediate-density lipoprotein, and low-density lipoprotein cholesterol levels were observed between cholesterol-fed New Zealand White and Dutch Belt rabbits. Furthermore, the relative amount of intestinally derived apolipoprotein-B48-containing lipoproteins did not differ significantly between both strains (7.3±0.42% vs. 8.0±0.54%). Atherosclerosis was more pronounced in the thoracic aorta in New Zealand White rabbits than in Dutch Belt rabbits, but the reverse was observed with the abdominal aorta. These topographic differences cannot be explained by circulating lipoprotein levels.
Conclusions: The data presented in this study do not support the hypothesis that the diameter of fenestrae is an important determinant of chylomicron remnant levels, diet-induced hypercholesterolemia, and atherosclerosis in cholesterol-fed rabbits.
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