Three-fold effect of lovastatin treatment on low density lipoprotein metabolism in subjects with hyperlipidemia: increase in receptor activity, decrease in apoB production, and decrease in particle affinity for the receptor. Results from a novel triple-tracer approach - PubMed (original) (raw)

Three-fold effect of lovastatin treatment on low density lipoprotein metabolism in subjects with hyperlipidemia: increase in receptor activity, decrease in apoB production, and decrease in particle affinity for the receptor. Results from a novel triple-tracer approach

L Berglund et al. J Lipid Res. 1998 Apr.

Abstract

To differentiate effects of lovastatin on low density lipoprotein (LDL) receptor activity from effects on LDL metabolic properties, LDL apolipoprotein B (apoB) turnover was studied in eight hyperlipidemic subjects during baseline and lovastatin treatment, in the latter case with LDL tracers isolated during both baseline (CLDL) and drug treatment (Rx-LDL) conditions. Lovastatin (40 mg/day) significantly lowered total plasma and LDL cholesterol levels (27% and 25%, respectively) as well 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 tracer FCR was higher when C-LDL tracer isolated during the untreated period was injected during lovastatin treatment (0.496+/-0.177 vs. 0.339+/-0.108 pools/day, P < 0.02). These in vivo studies in humans were confirmed by injecting LDL tracers from two patients into five guinea pigs. The C-LDL tracer was cleared consistently faster than the Rx-LDL 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). The decrease in LDL particle affinity partially negated the expected effect of increased LDL receptors on LDL clearance. The present study provides an explanation for earlier observations by several investigators using contemporaneous tracers that treatment with HMG-CoA reductase inhibitors resulted in only modest increases in low density lipoprotein functional catabolic rate.

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Figures

Fig. 1

Schematic model of the study design. In the illustrated case, Rx-LDL was labeled with 131I and C2-LDL with 125I. This was done for four of the subjects, and in the other four subjects Rx-LDL was labeled with 125I and C2-LDL with 131I.

Fig. 2

Kinetic model for LDL apoB metabolism. The model used had two compartments, one circulating and the other non-circulating. L21 and L22 represent the kinetics of exchange between the two pools, and L01 the catabolism from the circulating pool. One two-pool model was used for each tracer study, and the three studies were combined in an integrated model for each subject. The figure illustrates the integrated model with ten parameters, as L21 and L22 were the same in the Rx and C2 tracer models. The ten-parameter integrated model was the one used in most of the subjects.

Fig. 3

Displacement of a standard 125I-labeled LDL by C-LDL (엯) or Rx-LDL (▴). Human fibroblasts were incubated as described in the text for 2.5 h with varying concentrations of C-LDL or Rx-LDL in medium containing 5 μg/ml of 125I-labeled LDL. Results from one patient are shown and displayed as percent displacement of 125I-labeled LDL in the absence of competitor.

Fig. 4

Plasma decay data and fitted curves of LDL apoB with two different tracers (C-LDL and Rx-LDL) injected in the same individual during baseline and lovastatin therapy, resulting in three different LDL apoB decay curves (C1-LDL during baseline, crosses; C2-LDL during treatment, closed circles; Rx-LDL during treatment, open circles). The solid lines are best fit curves with the integrated model. Data are shown for subjects #2 and #7.

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Three-fold effect of lovastatin treatment on low density lipoprotein metabolism in subjects with hyperlipidemia: increase in receptor activity, decrease in apoB production, and decrease in particle affinity for the receptor. Results from a novel triple-tracer approach - PubMed (original) (raw)