© 1997 American Heart Association, Inc.
Articles |
Lovastatin Decreases De Novo Cholesterol Synthesis and LDL Apo B-100 Production Rates in Combined-Hyperlipidemic Males
From the Lipid Research Laboratory, Division of Endocrinology, Metabolism and Molecular Medicine, New England Medical Center, Boston (M.C., J.S.M., E.J.S., G.G.D., A.H.L.); the School of Dietetics and Human Nutrition, McGill University, Ste-Anne-de-Bellevue, Quebec, Canada (P.J.H.J.); and the Cattedra di Gerontologia e Geriatria, Istituto di Medicina Interna, Universitá degli Studi, Milan, Italy (C.V.).
Correspondence to Dr. Alice H. Lichtenstein, New England Medical Center, NEMC Box 216, Boston, MA 02111. E-mail lichtenst_li{at}hnrc.tufts.edu
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Abstract |
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Abstract The effect of lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, on the kinetics of de novo cholesterol synthesis and apolipoprotein (apo) B in very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) was investigated in five male patients with combined hyperlipidemia. Subjects were counseled to follow a Step 2 diet and were treated with lovastatin and placebo in randomly assigned order for 6-week periods. At the end of each experimental period, subjects were given deuterium oxide orally and de novo cholesterol synthesis was assessed from deuterium incorporation into cholesterol and expressed as fractional synthesis rate (C-FSR) and production rate (C-PR). Simultaneously, the kinetics of VLDL, IDL, and LDL apo B-100 were studied in the fed state using a primed-constant infusion of deuterated leucine to measure fractional catabolic rates (FCR) and production rates (PR). Drug treatment resulted in significant decreases in total cholesterol (-29%), VLDL cholesterol (-40%), LDL cholesterol (-27%), and apo B (-16%) levels and increases in HDL cholesterol (+13%) and apolipoprotein (apo) A-I (+11%) levels. Associated with these plasma lipoprotein responses was a significant reduction in both de novo C-FSR (-40%; P=.04) and C-PR (-42%; P=.03). Treatment with lovastatin in these patients had no significant effect on the FCR of apoB-100 in VLDL, IDL, or LDL, but resulted in a significant decrease in the PR of apoB-100 in IDL and LDL. Comparing the kinetic data of these patients with those of 10 normolipidemic control subjects indicates that lovastatin treatment normalized apoB-100 IDL and LDL PR. The results of these studies suggest that the declines in plasma lipid levels observed after treatment of combined hyperlipidemic patients with lovastatin are attributable to reductions in the C-FSR and C-PR of de novo cholesterol synthesis and the PR of apoB-100 containing lipoproteins. The decline in de novo cholesterol synthesis, rather than an increase in direct uptake of VLDL and IDL, may have contributed to the decline in the PR observed.
Key Words: lovastatin • cholesterol • kinetics • lipoproteins • hyperlipidemia • fractional catabolic rate • production rate • apo B-100
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Introduction |
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An elevated LDL cholesterol concentration is considered to be one of the major risk factors for the development of coronary heart disease (CHD).1 The efficacy of LDL reduction in the prevention of CHD has been clearly demonstrated.2 3 4 5 6 The most powerful classes of cholesterol-lowering drugs are the inhibitors of the activity of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis. Treatment with HMG CoA reductase inhibitors has been reported to reduce plasma total and LDL cholesterol, and LDL apolipoprotein (apo) B levels in hypercholesterolemic subjects independent of the underlying metabolic disorder.7 8 9 10 11 12 13
Changes in cholesterol synthesis rates during HMG CoA reductase inhibitor treatment have been studied in patients with heterozygous familial hypercholesterolemia using several in vivo methodologies. Studies conducted using the cholesterol balance technique,14 urinary mevalonate excretion,15 16 and changes in serum lathosterol concentration17 have suggested that HMG CoA reductase inhibitors decrease the rate of de novo cholesterol synthesis.
Despite the postulated mechanism of action of HMG CoA reductase inhibitors, the effects of this class of drugs on the metabolism of apoB-containing lipoproteins has yet to be fully elucidated. Early studies on the action of HMG CoA reductase inhibitors in subjects with hypercholesterolemia have attributed the reduction in plasma cholesterol levels to increased LDL receptor activity secondary to a fall in the intracellular free cholesterol pools.18 An increase in LDL receptor-mediated catabolism of apo B-containing lipoproteins has also been postulated in studies conducted in normolipidemic subjects19 and in patients with mixed hyperlipoproteinemia.20 In contrast, studies in subjects with a variety of primary hyperlipidemic disorders10 11 13 21 22 23 24 and secondary hyperlipidemic disorders25 26 suggest that the plasma LDL cholesterol reduction may be due to decreased production of LDL apo B-100, possibly due to decreased hepatic secretion of apo B-containing lipoproteins or increased uptake of VLDL remnants.
The objective of this study was to further investigate mechanisms by which lovastatin decreases plasma cholesterol and apo B-100 levels in patients with combined hyperlipidemia. We used stable isotope tracers to simultaneously assess the effect of lovastatin on de novo cholesterol synthesis and apo B-100 metabolism in five patients with elevated plasma total cholesterol, LDL cholesterol, and triglyceride levels, and decreased HDL cholesterol levels.
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Methods |
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Subjects
Five male patients with combined hyperlipidemia were recruited from the Lipid Clinic at the New England Medical Center Hospital in Boston. All patients had total cholesterol, LDL cholesterol, and triglyceride levels above the 90th percentile for appropriate age and sex norms, and HDL cholesterol levels below the 10th percentile (Table 1
). Patients were evaluated for cardiac,
hepatic, renal, endocrine, and metabolic diseases by
routine clinical and laboratory analysis. The clinical
characteristics and selected risk factor status of study patients are
shown in Table 1. The mean age of the subjects was 51 years (range
33-66 years). The two subjects with the highest total and LDL
cholesterol levels had established disease. Patient 2
developed angina at age 35 years, and at age 39 years had
coronary artery bypass grafting for significant three-vessel
disease. Cardiac medications were a long-acting nitrate and sublingual
nitroglycerine as necessary, which continued throughout
the course of the study. Additionally, thyroid hormone replacement
therapy was maintained in order to normalize thyroid status (a normal
TSH concentration). Patient 4 developed evidence of left carotid artery
stenosis at age 52 years. He underwent left carotid artery
surgery at the age of 58 and subsequently had a complete occlusion of
that vessel. He was instructed to take 3 g of niacin per day,
which was later decreased to 1-2 g/d because of difficulty
with compliance. This therapy was terminated before the start of
the study.
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All patients had been instructed by a registered dietitian to consume a Step 2 diet for at least 3 months prior to the start of the study and were seen on a regular basis to reinforce these guidelines.1 Lovastatin was well tolerated by all the study patients. The experimental protocol was approved by the Human Investigation Review Committee of the New England Medical Center and Tufts University and each subject gave written informed consent.
Ten control subjects for comparison purposes were selected on the basis of age from a group of healthy male volunteers with total cholesterol and triglyceride levels below the 90th percentile for age and sex norms. These subjects were part of a larger population that has previously been reported.27
Experimental Protocol
Each patient was studied on two occasions, at the end of a
6-week placebo treatment period and at the end of a 6-week
lovastatin treatment period (40 mg/d twice a day).
The order of placebo and drug treatment was randomized and administered
in a double-blind fashion. A 6-week washout period separated the two
phases.
At the end of each treatment period the patients were admitted to the Clinical Research Center at New England Medical Center for a 2-day period. All kinetic studies were carried out with patients in the continuously fed state as previously described.27 28 Briefly, patients were provided with small hourly meals containing 1/20 of their daily caloric intake for a total of 20 hours. The diet was composed of solid foods and the nutrient content was consistent with Step 2 guidelines. Five hours after the first meal each subject received an oral bolus of 1.2 g/kg of estimated body water (60% of body weight) of deuterium oxide to study de novo cholesterol synthesis rates. Simultaneously, a 15-hour primed-constant infusion of deuterated [2H3]-leucine was started to assess apolipoprotein (apo) B-100 kinetics (bolus injection of 10 µmol/kg of body weight, immediately followed by a constant infusion of 10 µmol/kg of body weight per hour). Blood samples were taken for deuterium enrichment determinations at 0 and 15 hours for cholesterol and at 0, 1, 2, 3, 4, 6, 8, 10, 12, and 15 hours for apo B-100 leucine.
Analytical Procedures
Plasma lipids, lipoproteins, and apoproteins. Blood
samples were collected in tubes containing EDTA (0.1% final
concentration). Plasma was separated by centrifugation
at 3000 rpm at 4°C and assayed for total cholesterol and
triglyceride levels using enzymatic
reagents.29 HDL cholesterol was measured after
precipitation of apo B-containing lipoproteins with dextran
sulfate-MgCl from plasma.30
Lipoprotein fractions representing triglyceride-rich lipoprotein (d<1.006 g/mL), which contains chylomicrons and VLDL in the fed state, intermediate density lipoprotein (IDL, d=1.006-1.019 g/mL), and LDL (d=1.019-1.063 g/mL) were isolated from plasma by sequential ultracentrifugation.31 As it is assumed that essentially all the apo B-100 in the triglyceride-rich lipoprotein fraction was contained in VLDL, this fraction will henceforth be referred to as VLDL.
Apo B concentrations were quantified in plasma, VLDL, and IDL with a noncompetitive ELISA using immunopurified polyclonal antibodies.32 LDL apo B concentration was calculated by difference [LDL apo B = plasma apo B-(VLDL apo B+IDL apo B)]. Apo B-100 was isolated from VLDL, IDL, and LDL fractions by preparative SDS polyacrylamide gradient (4-22.5%) gel electrophoresis.33
Cholesterol deuterium enrichment. Deuterium enrichment in plasma cholesterol was determined as described previously.34 35 36 37 Briefly, after lipid extraction and saponification, cholesterol was separated by thin-layer chromatography, eluted from the silica gel, and combusted in the presence of cupric oxide and sterling silver. Both water derived from the combustion of cholesterol and plasma water were reduced to hydrogen gas in the presence of zinc. Hydrogen gas deuterium enrichment was measured by differential isotope ratio mass spectrometry (VG Isomass, 903D, Cheshire, England). The instrument was calibrated daily using water standards of known isotopic composition. Samples of each subject were analyzed using a single set of standards.
Apo B-100 deuterium enrichment. Polyacrylamide gel bands containing apo B-100 were excised from the gel and acid hydrolyzed. The amino acids from apo B-100 were then isolated using Dowex AG-50W-X8 100-200 mesh cation exchange resin (Bio-Rad Labs, Richmond, Calif) and converted to the n-propyl ester N-heptafluorobutyramide derivatives.38 The dried derivatives were extracted into ethyl acetate prior to analysis by GC/MS.38
Kinetic Analysis
Cholesterol kinetic
analysis. Cholesterol fractional synthetic
rate (C-FSR; pools per day) was determined from the incorporation rate
of the precursor deuterium into plasma total cholesterol
relative to the maximum theoretical enrichment using the linear
regression model.36 The assumptions underlying the use of
labeled water as tracer for measurements of C-FSR and model
consideration have been extensively described elsewhere.36
The cholesterol production rate (C-PR; in grams per
day) was derived by multiplying C-FSR by the cholesterol
central pool size. The central pool size of cholesterol was
estimated from body weight and plasma concentration of both
cholesterol and triglyceride as described by
Goodman et al.39 The C-PR provides a measure of the daily
production of newly synthesized cholesterol.
Apo B-100 kinetic analysis. Fractional catabolic rate (FCR; pools per day) of apo B-100-containing particles was calculated with CONSAM with a multicompartmental model as previously described.27 Briefly, the model features secretion of newly synthesized apo B-100 into VLDL. The model structure includes a VLDL delipidation chain, a slow VLDL compartment, a fast and slow IDL compartment, and a single LDL compartment. Production rates (PR; mg/kg/d) of the apo B-100-containing particles were calculated by multiplying the apo B-100 FCR by the estimated apo B pool size: [apo B concentration (mg/dL) x body weight (kg) x0.045]. All kinetic rates are expressed per 24 hours.
Statistics
Comparison between drug and placebo phases was determined using
a Student's paired t-test. Comparisons between patients and
normal control subjects were determined using an unpaired
Student's t-test.
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Results |
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Six weeks of drug treatment resulted in a significant decrease in total cholesterol (-29%), VLDL cholesterol (-40%), LDL cholesterol (-27%), and apo B (-16%) levels (Table 2
). Also observed was a
significant increase in HDL cholesterol (+13%) and apo A-I
(+11%) levels. Triglyceride levels decreased by 24%;
however, this difference did not reach statistical significance
(P=.07).
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Lovastatin had a dramatic effect on the rates of de novo
cholesterol synthesis. Drug treatment resulted in a
significant reduction in both C-FSR (-40%; P=.04) and C-PR
(-42%; P=.03) (Table 3).
Both total cholesterol and LDL cholesterol
levels were positively correlated with C-FSR (r=.992,
P<.001 and r=.879, P=.050,
respectively) and C-PR (r=.972, P=.005 and
r=.877, P=.051, respectively) during treatment
with lovastatin. No correlation was found between total
cholesterol and LDL cholesterol levels and
C-FSR (r=.362, P=.550 and r=.446,
P=.452, respectively) and C-PR (r=.409,
P=.494 and r=.565, P=.321,
respectively) during treatment with placebo. These data suggest that
reduced levels of plasma total and LDL cholesterol observed
after treatment of the combined hyperlipidemic subjects
with lovastatin were a result, in part, of reduced rates of
de novo cholesterol synthesis.
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Apo B-100 plasma concentration and kinetic parameters are
shown in Tables 4, 5, and 6
for VLDL, IDL, and LDL, respectively. The plots of the model fit to the
apoB-100 kinetic data for each subject on drug and placebo treatments
are shown in the Figure. Mean VLDL apo B
concentrations (Table 4) were reduced after treatment with
lovastatin compared to treatment with the placebo. However,
the mean differences between the two periods did not reach statistical
significance (P=.071). There was no significant effect of
lovastatin on VLDL apoB-100 FCR (P=.892) or PR
(P=.150). The conversion rate of VLDL to IDL averaged 88%
and was unaffected by drug treatment. It should be noted that after
drug treatment VLDL apoB-100 PR was decreased in four of five of the
subjects. Subject 5 had a somewhat different response than that of the
other four subjects. His VLDL apoB PR increased (from 26.7 to 30.6
mg/kg/d) and the conversion rate of VLDL to IDL decreased
(from 85% to 50%) after drug treatment. Analysis of the
subgroup of subjects 1 to 4 suggested that lovastatin
tended to decrease VLDL apoB-100 PR in these subjects (placebo
23.0±6.8, lovastatin 14.7±2.7 mg/kg/d,
P=.060) and had no significant effect on the conversion of
VLDL to IDL.
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Treatment with lovastatin resulted in a significant
reduction in IDL apo B concentrations in the study subjects
(P=.009) (Table 5
). The kinetic data suggest that there was
a decrease in IDL apo B-100 PR (P=.010) rather than a change
in the IDL apo B-100 FCR (P=.340). A subgroup
analysis of subjects 1 to 4 did not change the interpretation
of the results. The decrease in IDL apo B-100 PR that was observed
after lovastatin treatment in all the study subjects was
attributable to a decrease in VLDL apo B-100 PR with no change in the
percentage of VLDL converted to IDL in subjects 1 to 4 (Table 4). In
subject 5, the reduction in IDL apo B-100 PR seemed to be primarily due
to an increased direct removal of VLDL from plasma.
Treatment with lovastatin resulted in a significant
reduction in LDL apo B concentrations in all subjects
(P=.044) (Table 6). The kinetic data suggest that this
reduction was contributed to primarily by a decrease in LDL apo B-100
PR (P=.019). These differences were maintained after subject
5 was eliminated from the analysis. There was no change in the
percentage of IDL converted to LDL after lovastatin
treatment as compared with the data after placebo treatment (Table 5).
Apo B-100 kinetic parameters of the patients during the
placebo and lovastatin treatment periods were compared with
those parameters of a comparable age-matched group of
normolipidemic male subjects not taking medications known to alter
plasma lipid levels (Table 7 and 8). Relative to the normolipidemic
subjects, the hyperlipidemic patients tended to have
lower VLDL apo B-100 FCR both during the placebo and
lovastatin periods, with the differences approaching
statistical significance (P=.07 and P=.07,
placebo and lovastatin periods, respectively) (Table 7).
There were no significant differences in IDL or LDL apo B-100 FCR
between the normolipidemic subjects and the
hyperlipidemic patients either on or off drug
therapy.
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During the placebo period hyperlipidemic patients had IDL and LDL apo B-100 PR that were significantly higher than those of the normolipidemic subjects (P=.01 and P=.01, IDL and LDL, respectively). Treatment with lovastatin resulted in a reduction in these rates so that they were statistically indistinguishable from those of the normolipidemic subjects (P=.81 and P=.55, IDL and LDL, respectively).
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Discussion |
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Treatment of combined hyperlipidemic male patients with lovastatin for a 6-week period resulted in significantly lower plasma levels of total cholesterol, VLDL cholesterol, LDL cholesterol, and apo B relative to the period when the patients were treated with a placebo drug. Kinetic studies in our patients suggest that the reduction in circulating levels of cholesterol and apo B were contributed to by both a decrease in the rate and amount of cholesterol synthesized de novo and a decrease in the amount of newly synthesized apo B-100 incorporated into IDL, LDL, and possibly VLDL. The percentage of conversion of VLDL to IDL and LDL was not significantly changed. We found no evidence that the rate of catabolism of apo B-100-containing lipoproteins from plasma was increased. Whereas during the placebo period the PR of apo B-100 in IDL and LDL of the hyperlipidemic subjects were elevated relative to those of age- and sex-matched control subjects, after lovastatin treatment the PR of the hyperlipidemic subjects was similar to those of the control subjects.
In the current study, the C-FSR and C-PR of de novo synthesized cholesterol were dramatically reduced (40% and 42%, C-FSR and C-PR, respectively) after the 6-week lovastatin treatment period relative to the placebo period. The magnitude of the reductions is similar to that observed in the previous studies assessing the effect of HMG CoA reductase inhibitors on cholesterol synthesis in patients with heterozygous familial hypercholesterolemia,14 15 16 17 and patients with gallstone disease40 and cholesteryl ester storage disease.23 The current work, using a direct method to calculate the de novo cholesterol synthesis, extends the previous findings to patients with other forms of dyslipoproteinemia and suggests that the reductions in plasma cholesterol levels observed are independent of type of hyperlipidemia and are probably due to a common mechanism.
The mean VLDL apo B-100 PR of subjects was lower, but not significantly so (P=.15), after treatment with lovastatin. Interpretation of the VLDL apo B-100 data is complicated by the aberrant response of patient 5. Patient 5's VLDL apo B-100 PR increased by 15% after lovastatin treatment despite a 62% decrease in the C-PR and in contrast to the other four subjects, who all showed declines in the VLDL apo B-100 PR of 21% to 54%. IDL and LDL apo B-100 were significantly reduced during lovastatin treatment for all the subjects. This was due to a decrease in VLDL apo B-100 PR, with the exception of patient 5. In this patient, we observed a decrease in the percentage of conversion of VLDL to IDL, indicating an increased removal from plasma that accounted for his reduced IDL apo B-100 PR. Precedence for this variability in response to an HMG CoA reductase inhibitor on lipoprotein kinetics has been noted previously.10
In contrast to the consistent observations on the effect of HMG
CoA reductase inhibitors on rates of de novo
cholesterol synthesis, the data on the
metabolism of apo B-containing lipoproteins is more varied
(Table 9). Similar to the findings of the
current study, Grundy and Vega,10 25 Ginsberg et
al,23 Arad et al,11 Vega et
al,21 Watts et al,24 and Aguilar-Salimas et
al26 reported that, independent of the type of
dyslipidemia, the decreased concentrations of LDL
cholesterol were primarily attributable to a decrease in
PR. The decrease in the PR of LDL apo B-100 was due to either an
increased uptake of VLDL remnants (VLDL and/or IDL) or a decreased
hepatic secretion of apo B-containing lipoproteins. Focusing on
patients with familial dysbetalipoproteinemia, Vega et
al13 concluded that both decreased PR and increased FCR of
lipoproteins contributed to the decrease in VLDL and LDL apo B-100
observed as a result of lovastatin therapy. Finally, in a
comprehensive assessment of the effect of simvastatin on
apo B metabolism and lipoprotein subfractions, Gaw et
al22 concluded that the resultant kinetic changes were
associated with an increase in the direct catabolism of
VLDL2 and IDL and consequent decreased PR of LDL.
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In contrast with the findings of the current study, Bilheimer et al18 and Arad et al11 have reported that treatment of familial hypercholesterolemic patients with lovastatin resulted in an increased receptor-mediated clearance of LDL. Similarly, Malmendier et al19 and Parhofer et al20 reported that treatment of normolipidemic and mixed hyperlipoproteinemic subjects, respectively, with HMG CoA reductase inhibitors resulted in an increase in LDL apo B-100 catabolic rates.
Recent studies focusing on the mechanism of apo B secretion from hepatic cells have suggested that the secretion rate of apo B-containing particles is dependent on lipid substrate availability (for reviews, see 41 42 ). Some of these in vitro studies suggest that cholesteryl ester availability is one of the most important determinants in the secretion of apo B-containing particles.43 44 Cianflone and colleagues43 demonstrated that HepG2 cells incubated in the presence of lovastatin showed a decreased cholesteryl ester synthesis and a significant reduction in apo B secretion. Tanaka and colleagues44 showed in a rabbit hepatocyte culture system that incubation with pravastatin caused a decrease in de novo cholesterol synthesis, cholesteryl ester content in the cells, and apo B secretion. Moreover, in their experiments pravastatin increased intracellular degradation of apo B, which suggests that the reduction in intracellular cholesteryl ester content accelerates intracellular degradation of apo B and decreases apo B secretion.44 A decreased acyl CoA cholesterol acyltransferase activity during incubation with lovastatin has been demonstrated in intestinal cells.45 These studies support the hypothesis that a decrease in de novo cholesterol synthesis could result in a decrease in the availability of cholesterol for incorporation into newly synthesized lipoprotein particles, with a consequent decrease in apo B-100-containing lipoprotein secretion, as suggested by our study. Relating the findings of the in vitro systems to that of the in vivo work should be done cautiously, however, because complex compensatory mechanisms in vivo may not be operating in vitro.
The results of the current study suggest that treatment of combined hyperlipidemia subjects with lovastatin caused a reduction in the concentrations of total, VLDL, and LDL cholesterol and apo B-100. A reduction in both the rate of de novo cholesterol synthesis and a decrease in the PR of apo B-containing lipoproteins appear to contribute to these changes. No evidence suggesting that a change in the FCR of VLDL, IDL, and LDL, or direct catabolism of VLDL and IDL contribute to the lower levels of blood lipids observed after drug treatment. The current study also found that treatment of the combined hyperlipidemic subjects with lovastatin resulted in a normalization of the PR for apo B-100-containing lipoproteins similar to those observed in normocholesterolemic control subjects. The decrease in cholesterol synthesis rather than increase in direct uptake of apo B-100-containing lipoproteins may have contributed to the decrease in the PR.
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Acknowledgments |
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This work was supported by a General Clinical Research Center grant from the National Institutes of Health, 5M01RR00054, and a grant from Merck, Sharp & Dohme. We thank the staff of the Clinical Study Unit for their expert technical assistance. We also gratefully acknowledge the cooperation of the study subjects, without whom this investigation would not have been possible.
Received September 25, 1996; accepted February 5, 1997.
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