Abstract
We investigated the metabolism of very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) apolipoprotein B (apoB) in seven patients with combined hyperlipidemia (CHL), using 125I-labeled VLDL and 131I-labeled LDL and compartmental modeling, before and during lovastatin treatment. Lovastatin therapy significantly reduced plasma levels of LDL cholesterol (142 vs 93 mg/dl, P less than 0.0005) and apoB (1328 vs 797 micrograms/ml, P less than 0.001). Before treatment, CHL patients had high production rates (PR) of LDL apoB. Three-fourths of this LDL apoB flux was derived from sources other than circulating VLDL and was, therefore, defined as "cold" LDL apoB flux. Compared to baseline, treatment with lovastatin was associated with a significant reduction in the total rate of entry of apoB-containing lipoproteins into plasma in all seven CHL subjects (40.7 vs. 25.7 mg/kg.day, P less than 0.003). This reduction was associated with a fall in total LDL apoB PR and in "cold" LDL apoB PR in six out of seven CHL subjects. VLDL apoB PR fell in five out of seven CHL subjects. Treatment with lovastatin did not significantly alter VLDL apoB conversion to LDL apoB or LDL apoB fractional catabolic rate (FCR) in CHL patients. In three patients with familial hypercholesterolemia who were studied for comparison, lovastatin treatment increased LDL apoB FCR but did not consistently alter LDL apoB PR. We conclude that lovastatin lowers LDL cholesterol and apoB concentrations in CHL patients by reducing the rate of entry of apoB-containing lipoproteins into plasma, either as VLDL or as directly secreted LDL.
Highlights
We investigated the metabolism of very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) apolipoprotein B in seven patients with combined hyperlipidemia (CHL), using lZ5Ilabeled VLDL and ‘311-labeledLDL and compartmental modeling, before and during lovastatin treatment
Because overproduction of apolipoprotein B (apoB)-containing lipoproteins appears to be a common characteristic of subjects with C H L [5,6,7], we hypothesized that lovastatin might reduce LDL and/or VLDL apoB production in C H L subjects
Since LDL apoB metabolism is closely linked to apoB metabolism in VLDL and IDL, we undertook a study of apoB metabolism in all three lipoprotein classes in subjects classified phenotypically as having CHL, before and during treatment with lovastatin
Summary
The third patient had previously suffered two myocardial infarctions and had markedly elevated LDL cholesterol levels, normal plasma triglyceride concentrations, and large tendon xanthomas. She had not had LDL receptor studies, but had a clinical and family history compatible with heterozygous FH. Eight hours before the start of the VLDL turnover study (which began at 8 AM), a liquid formula diet consisting of 75% carbohydrates and 25% protein and providing 60% of the subject's caloric requirements was started This liquid diet, consumed every 3 h throughout the 48 h of the VLDL turnover study, results in stable plasma cholesterol and triglyceride levels [21]. All subjects continued taking lovastatin during the second turnover study
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