CLEARANCE OF CHYLOMICRON-LIKE LIPID EMULSIONS IS INCREASED IN NORMAL RABBITS BUT NOT IN HETEROZYGOUS WATANABE HERITABLE HYPERLIPIDEMIC 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 lo w density lipoproteins by high affinity uptake mechanisms. 2. We gave heterozygous Watanabe heritable hyperlipidaemic rabbits (hz-WHHL) chol estyramine and/or pravastatin for a two week period to try and amelior ate slow clearance of chylomicron remnants, which occurs because of re duced expression of the apolipoprotein B-100/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 improv ed following treatment with either of the cholesterol lowering drugs. 4. In contrast, control rabbits had significantly less chylomicron-lik e emulsion cholesteryl-ester radioactivity remaining at each time of b lood sampling. 5. Similarly, the clearance of chylomicron-like emulsio n 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 pravast atin increased the rate of receptor-mediated uptake in vivo in control rabbits but not in hz-WHHL rabbits. 7. The plasma lipid profiles of c ontrol and hz-WHHL rabbits parallelled the patterns of chylomicron-lik e emulsion clearance. Moderate hypertriglyceridaemia was identified in hz-WHHL rabbits compared to controls and there was no change in plasm a triglyceride or cholesterol following drug therapy. In contrast, con trol rabbits had decreased plasma lipids following cholestyramine or p ravastatin treatment. 8. It appears that therapy with lipid lowering d rugs increased chylomicron remnant clearance in control rabbits by up- regulation of the apolipoprotein B-100/E receptor. In contrast, in hz- WHHL rabbits receptor activity did not appear to be increased sufficie ntly to ameliorate defective remnant clearance. We have suggested that a critical-receptor density is required for efficient remnant clearan ce.