The effects of 3-hydroxy-3-methylglutaryl
coenzyme A (
HMG-CoA) reductase inhibitors on the metabolism of
apolipoprotein (
apo) B-containing
lipoproteins appear to differ according to the predominant
lipoprotein profiles present and the condition being treated. In
familial hypercholesterolemia, with isolated
low density lipoprotein (
LDL) elevations, the
LDL-
apoB elimination rate is increased by up-regulated
LDL-receptors. In
familial combined hyperlipidemia where
very low density lipoprotein (VLDL) and
LDL both may be increased and enhanced production of
LDL-
apoB may be present,
HMG-CoA reductase inhibitors seem to diminish increased
LDL-
apoB production. The
drug-induced decreases in
LDL-
apoB production could be due to decreased production of precursor VLDL-
apoB or due to decreased conversion of VLDL-
apoB to
LDL-
apoB after enhanced removal of VLDL by up-regulated
LDL-receptors. To distinguish between these possibilities, we assessed the effects of
HMG-CoA reductase inhibitors in another condition in which there is both
apoB overproduction and accumulation of VLDL and
LDL in plasma, the
nephrotic syndrome. We used endogenous labeling of
apoB with [13C]
leucine and a multicompartmental model to calculate the metabolic parameters of
apoB-containing
lipoproteins. Only subjects with focal segmental glomerular
sclerosis (FSGS) were included, as FSGS is a chronic, very slowly progressive form of
nephrotic syndrome. A double-blind, randomized, placebo-controlled, crossover design was used. Treatment periods of 6 weeks were separated by a 2-week washout period. Of the four men studied, three had high
triglyceride levels and four had
high cholesterol levels.
Lovastatin (20 mg/day) significantly decreased
cholesterol (27.6 +/- 6%),
LDL-cholesterol (27.6 +/- 9%) and plasma
apoB (17.9 +/- 2.9%) (P < 0.01 for all). During the placebo period, calculation of kinetic parameters revealed VLDL-,
intermediate density lipoprotein (IDL)-, and
LDL-
apoB overproduction and decreased VLDL-
apoB fractional catabolic rate.
Lovastatin significantly decreased
LDL-
apoB production rate in all cases (34.1 +/- 14%, P = 0.03). The decreased
LDL-
apoB was mainly due to a channelling of
LDL precursors away from conversion to
LDL (conversion of VLDL to
LDL decreased from 80.6 +/- 8.3% to 55.9 +/- 17.2%, P = 0.05). Thus,
lovastatin decreased
LDL-cholesterol in nephrotic subjects mainly by inhibiting
LDL-
apoB production from VLDL.