CLEARANCE OF CHYLOMICRON-LIKE LIPID EMULSIONS IS INCREASED IN NORMAL RABBITS BUT NOT IN HETEROZYGOUS WATANABE HERITABLE HYPERLIPIDAEMIC RABBITS FOLLOWING TREATMENT WITH CHOLESTYRAMINE OR PRAVASTATIN

1. Cholestyramine and pravastatin are two potent hypocholesterolaemic drugs which lower plasma cholesterol by increasing the clearance of low density lipoproteins by high affinity uptake mechanisms. 2. We gave heterozygous Watanabe heritable hyperlipidaemic rabbits (hz-WHHL) cholestyramine and/or pravastatin for a two week period to try and ameliorate slow clearance of chylomicron remnants, which occurs because of reduced expression of the apolipoprotein B₁₀₀/E receptor. 3. In hz-WHHL rabbits the clearance of chylomicron-like lipid emulsions, traced by the decrease in plasma cholesteryl oleate radioactivity was not improved following treatment with either of the cholesterol lowering drugs. 4. In contrast, control rabbits had significantly less chylomicron-like emulsion cholesteryl-ester radioactivity remaining at each time of blood sampling. 5. Similarly, the clearance of chylomicron-like emulsion triolein was enhanced in normal rabbits receiving cholestyramine or pravastatin, whereas there was no detectable increase in clearance in hz-WHHL rabbits. 6. Combined treatment with cholestyramine and pravastatin increased the rate of receptor-mediated uptake in vivo in control rabbits but not in hz-WHHL rabbits. 7. The plasma lipid profiles of control and hz-WHHL rabbits parallelled the patterns of chylomicron-like emulsion clearance. Moderate hypertriglyceridaemia was identified in hz-WHHL rabbits compared to controls and there was no change in plasma triglyceride or cholesterol following drug therapy. In contrast, control rabbits had decreased plasma lipids following cholestyramine or pravastatin treatment. 8. It appears that therapy with lipid lowering drugs increased chylomicron remnant clearance in control rabbits by up-regulation of the apolipoprotein BIOO/E receptor. In contrast, in hz-WHHL rabbits receptor activity did not appear to be increased sufficiently to ameliorate defective remnant clearance. We have suggested that a critical receptor density is required for efficient remnant clearance.