3-FOLD EFFECT OF LOVASTATIN TREATMENT ON LOW-DENSITY-LIPOPROTEIN METABOLISM IN SUBJECTS WITH HYPERLIPIDEMIA - INCREASE IN RECEPTOR ACTIVITY, DECREASE IN APO-B PRODUCTION, AND DECREASE IN PARTICLE AFFINITY FOR THE RECEPTOR - RESULTS FROM A NOVEL TRIPLE-TRACER APPROACH

To differentiate effects of lovastatin on low density lipoprotein (LDL ) receptor activity from effects on LDL metabolic properties, LDL apol ipoprotein B (apoB) turnover tvas studied in eight hyperlipidemic subj ects during baseline and lovastatin treatment, in the latter case with LDL tracers isolated during both baseline (C-LDL) and drug treatment (Rx-LDL) conditions. Lovastatin (40 mg/day) significantly lowered tota l plasma and LDL cholesterol levels (27% and 25%, respectively) as wel l as plasma triglyceride levels (30%). Using contemporaneous tracers ( C-LDL before and Rx-LDL during treatment), lovastatin caused a modest increase in LDL fractional catabolic rate (FCR) (0.410 +/- 0.113 vs. 0 .339 +/- 0.108 pools/day, P < 0.04 by paired t). The increase in LDL t racer FCR was higher when CLDL tracer isolated during the untreated pe riod was injected during lovastatin treatment (0.496 +/- 0.177 vs. 0.3 39 +/- 0.108 pools/day, P < 0.02). These in vivo studies in humans wer e confirmed by injecting LDL tracers from two patients into five guine a pigs. The CLDL tracer was cleared consistently faster than the Rx-LD L tracer (0.082 +/- 0.018 vs. 0.057 +/- 0.015 pools/h, P < 0.001). The results demonstrate three important outcomes of lovastatin treatment in these subjects: LDL receptor activity increased by 49% (P < 0.02); LDL apoB production rate decreased by 17% (P < 0.03), and LDL particle in vivo affinity for the LDL receptor decreased by 15% (P < 0.01). Th e decrease in LDL particle affinity partially negated the expected eff ect of increased LDL receptors on LDL clearance. The present study pro vides an explanation for earlier observations by several, investigator s using contemporaneous tracers that treatment with HMG-CoA reductase inhibitors resulted in only modest increases in low density lipoprotei n functional catabolic rate.