Cholesterol metabolism in hypercholesterolemia-resistant rabbits.

Area of Science:

• Biochemistry
• Molecular Biology
• Cardiovascular Research

Background:

• Normal rabbits show increased plasma cholesterol on high-cholesterol diets.
• A variant rabbit resistant to diet-induced hypercholesterolemia was previously identified.

Purpose of the Study:

• To characterize cholesterol homeostasis components in hypercholesterolemia-resistant rabbits.
• To investigate the roles of B/E receptor, HMG-CoA reductase, and ACAT in cholesterol resistance.

Main Methods:

• Liver membrane preparation from normal and resistant rabbits fed varying cholesterol diets.
• Ligand binding assays using [125I]beta-VLDL to determine B/E receptor capacity and affinity.
• Enzyme activity assays for hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) and acyl-coenzyme A: cholesterol acyltransferase (ACAT).
• Direct measurement of cellular cholesterol and cholesteryl ester concentrations.

Main Results:

• Resistant rabbits displayed significantly higher B/E receptor binding capacity (70-240%) compared to normal rabbits.
• Hepatic HMG-CoA reductase activity was approximately 2-fold higher in resistant rabbits, increasing further on a cholesterol-enriched diet.
• Basal ACAT activity was lower in resistant rabbits, with a blunted induction response to cholesterol feeding compared to normal rabbits.
• Resistant rabbits maintained lower intracellular cholesterol and cholesteryl ester concentrations.

Conclusions:

• Resistant rabbits exhibit distinct quantitative differences in cholesterol metabolism and its regulation.
• Elevated B/E receptor capacity and HMG-CoA reductase activity, coupled with reduced ACAT activity, contribute to cholesterol resistance.
• The precise underlying cause of this resistance remains to be elucidated.