Published online before print June 19, 2008, doi: 10.1161/ATVBAHA.108.164541
© 2008 American Heart Association, Inc.
Clinical and Population Studies |
Extended-Release Niacin Alters the Metabolism of Plasma Apolipoprotein (Apo) A-I and ApoB-Containing Lipoproteins
From the Lipid Metabolism Laboratory (S.L.-F., M.R.D., A.B., M.N., K.V.H., B.F.A., S.O., M.A., E.J.S.), the Cardiovascular Nutrition Laboratory (N.R.M., A.H.L.), and the Mass Spectrometry Laboratory (G.G.D.), Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, and the Friedman School of Nutrition Science and Policy at Tufts University and Tufts University School of Medicine, Boston, Mass; and the School of Medicine and Pharmacology (P.H.R.B.), University of Western Australia, Perth, Australia.
Correspondence to Stefania Lamon-Fava, MD, PhD, Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research, Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111. E-mail stefania.lamon-fava{at}tufts.edu
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Abstract |
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Objectives— Extended-release niacin effectively lowers plasma TG levels and raises plasma high-density lipoprotein (HDL) cholesterol levels, but the mechanisms responsible for these effects are unclear.
Methods and Results— We examined the effects of extended-release niacin (2 g/d) and extended-release niacin (2 g/d) plus lovastatin (40 mg/d), relative to placebo, on the kinetics of apolipoprotein (apo) A-I and apoA-II in HDL, apoB-100 in TG-rich lipoproteins (TRL), intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL), and apoB-48 in TRL in 5 men with combined hyperlipidemia. Niacin significantly increased HDL cholesterol and apoA-I concentrations, associated with a significant increase in apoA-I production rate (PR) and no change in fractional catabolic rate (FCR). Plasma TRL apoB-100 levels were significantly lowered by niacin, accompanied by a trend toward an increase in FCR and no change in PR. Niacin treatment significantly increased TRL apoB-48 FCR but had no effect on apoB-48 PR. No effects of niacin on concentrations or kinetic parameters of IDL and LDL apoB-100 and HDL apoA-II were noted. The addition of lovastatin to niacin promoted a lowering in LDL apoB-100 attributable to increased LDL apoB-100 FCR.
Conclusion— Niacin treatment was associated with significant increases in HDL apoA-I concentrations and production, as well as enhanced clearance of TRL apoB-100 and apoB-48.
We investigated the effects of niacin (2 g/d), without or with lovastatin (40 mg/d) on apolipoprotein kinetics in 5 subjects. Niacin treatment significantly increased HDL apoA-I concentrations and production, as well as enhanced clearance of TG-rich lipoprotein apoB-100 and apoB-48. The addition of lovastatin to niacin further promoted an enhanced clearance of LDL apoB-100.
Key Words: apolipoprotein • high-density lipoprotein • kinetics • lipid-lowering medications • triglyceride
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Introduction |
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The cholesterol-lowering effect of the vitamin nicotinic acid, or niacin, was first reported by Altschul et al1 more than 50 years ago. Since then, treatment with pharmacological doses of niacin has been found to significantly lower the risk of coronary heart disease (CHD).2,3 Several trials have also tested the effect of niacin in combination with other lipid-lowering medications on CHD risk, overall showing a beneficial effect.4–6 Niacin primarily decreases plasma triglyceride (TG) levels and very low–density lipoprotein (VLDL) cholesterol (C) levels and increases plasma high-density lipoprotein (HDL)-C levels.2,7 It has been hypothesized that the reduction in TG and VLDL-C is mediated by the niacin-associated inhibition of free-fatty acid (FFA) release from the adipose tissue, which may lead to reduced substrate availability for TG synthesis and secretion in hepatic cells.8 However, a study conducted in 1 hypertriglyceridemic subject showed faster clearance of autologous 125I-labeled VLDL after niacin treatment.9 Niacin is one of the most potent HDL-C-raising agents currently available. Two previous studies have attempted to elucidate the effect of niacin on HDL metabolism in young normocholesterolemic subjects.10,11 The first study was conducted in 2 subjects and found an increase in HDL-C levels associated with a slower HDL catabolism with niacin.10 The second study, in 5 young healthy subjects, found a significant increase in plasma HDL-C and apolipoprotein (apo) A-I levels with niacin without significant effects on apoA-I kinetics.11
To date, very little is known about the mechanism by which niacin affects the metabolism of plasma lipoproteins in subjects with dyslipidemia, who are the ideal targets of niacin treatment. Therefore, the current study was designed to clarify the effects of extended-release niacin, without or with a statin, on the kinetics of apoA-I, apoA-II, apoB-100, and apoB-48 in plasma lipoproteins in subjects with combined hyperlipidemia.
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Subjects and Methods |
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Subjects
Five male subjects with combined hyperlipidemia were enrolled in this study (age range: 44 to 69 years; BMI range: 24.7 to 33.9 kg/m2). Plasma lipid criteria for enrollment into the study were: TG levels
150 mg/dL, LDL-C levels 130 mg/dL, and HDL-C levels 
40 mg/dL. Exclusion criteria were: age <40 years, myocardial infarction in the past 6 months, smoking, thyroid dysfunction, liver or kidney disease, liver cancer, diabetes mellitus, stroke, and current use of medications known to affect lipid metabolism. The study protocol was approved by the Institutional Review Board of Tufts University-New England Medical Center. Study candidates provided written informed consent.
Study Design
Subjects were instructed to follow the therapeutic lifestyle changes (TLC) diet (<30% of calories as total fat, <7% saturated fat, <200 mg/d cholesterol)12 throughout the study. The study had a randomized, double-blind, crossover design and consisted of 3 treatment phases, each lasting 12 weeks: placebo, extended-release niacin (Niaspan, KOS Pharmaceuticals), and extended-release niacin plus lovastatin (Advicor, KOS Pharmaceuticals). Niaspan tablets contained 500 mg extended-release niacin. Advicor tablets contained 500 mg extended-release niacin and 10 mg lovastatin. To avoid severe flushing, the dosage of Niacin was titrated according to the following schedule: 1 tablet during weeks 1 to 4, 2 tablets during weeks 5 to 8, and 4 tablets (corresponding to 2 g/d of extended-release niacin in the Niaspan phase and 2 g/d extended-release niacin and 40 mg/d lovastatin in the Advicor phase) during weeks 9 to 12 of each phase. Treatment phases were separated by a 4-week washout period. A 12-hour fast blood sample was obtained for the determination of plasma lipid levels on weeks 11 and 12 of each phase. Blood was centrifuged at 1000g for 30 minutes at +4°C and plasma was stored at –70°C until analyzed.
On week 12 of each phase, subjects underwent a 15-hour primed-constant infusion with 10 µmoles/kg body weight per hour of deuterated leucine (5,5,5-2H3-L-leucine; C/D/N Isotopes Inc), as previously described.13,14 Subjects were fed hourly for 20 hours with small identical meals, whose composition was complying with the TLC diet, starting 5 hours before and throughout the infusion period. Blood samples were collected into tubes containing EDTA (0.15%) just prior to the infusion (time 0), and at the following times during the infusion: 30, 35, and 45 minutes, and 1, 1.5, 2, 3, 4, 6, 9, 12, 14, and 15 hours.
Plasma Lipid and Lipoprotein Determinations
Lipids were measured both in plasma samples obtained after a 12-hour fast (week 11 and 12) and in nonfasting plasma samples obtained during the infusion (hour 0, 3, and 6 of infusion). Plasma TC and TG levels were measured by automated enzymatic assays.15 Plasma LDL-C and HDL-C concentrations were measured directly with kits from Equal Diagnostics and Roche Diagnostics, respectively.
Plasma apoA-I and apoA-II concentrations were measured using immunoturbidimetric assays, reagents, and calibrators from Wako Diagnostics. The concentration of apoB-100 in plasma and in lipoprotein fractions was measured with an enzyme-linked immunosorbent assay (ELISA).14 TRL apoB-48 was assessed with an ELISA assay (Shibayagi). Plasma HDL subpopulations were assessed by 2-dimensional gel electrophoresis, as previously described.16 Plasma concentrations of cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT) were assessed by ELISA (ALPCO Diagnostics). Remnant lipoprotein cholesterol concentrations were measured as previously described.17
Apolipoprotein Isotopic Enrichment and Kinetic Analysis
Five mL of plasma from each infusion time point were subjected to sequential ultracentrifugation in a Beckman ultracentrifuge (Beckman) for the isolation of triglyceride-rich lipoprotein (TRL), intermediate-density lipoprotein (IDL), LDL, and HDL fractions, as previously described.18 Lipoprotein fractions were subjected to gradient SDS polyacrylamide gel electrophoresis for separation of apolipoproteins and transferred to a Westran S polyvinylidene difluoride (PVDF) membrane.19 Each apo band was cut, and the leucine tracer/tracee ratio (percent) was determined as previously described.14,20 The Simulation Analysis and Modeling II (SAAM II) program was used to calculate the fractional catabolic rate (FCR) of each apolipoprotein using multicompartmental models previously described.14,21,22 Production rates (PR) of these apolipoproteins were determined by the following formula, estimating plasma volume as 4.5% of body weight: PR (mg/kg per day)=[FCR (pools/d) x apo concentration (mg/L) x plasma volume (L)]/body wt (kg).
Biochemical Assays
FFA levels in plasma were assessed with a colorimetric assay (Roche Diagnostics). Plasma glycated albumin, insulin, and adiponectin levels were assessed as previously described.23–25
Plasma concentrations of lathosterol and of the plant sterol β-sitosterol were assessed using a gas chromatography method.26
Statistical Analyses
A power calculation was performed and, based on the crossover design of the study, it was determined that 5 subjects were needed to have a >80% probability to detect a treatment difference at a 2-sided 0.05 significance level, if the difference in HDL-C levels between niacin and placebo is 28% and the standard deviation of the response is 11%.7 The SAS statistical package (SAS version 9.1) was used for statistical analyses. For normally distributed variables, means±SD were calculated. Nonnormally distributed variables were log-transformed to achieve normality before analysis, and the mean is expressed as geometric mean. The mixed model procedure (PROC MIXED) was used to test for differences in all outcome variables among phases. Analyses were adjusted for treatment sequence (Tukey-Kramer), and a probability value 0.05 was considered significant.
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Results |
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Treatment with extended-release niacin, relative to placebo, resulted in a significant increase in plasma HDL-C levels and a significant reduction in plasma TG levels, both in the fasted and fed state (Table 1). The combination of extended-release niacin and lovastatin produced a significant reduction in plasma LDL-C levels relative to both placebo and niacin, contributing to significant reductions in plasma TC levels with the combination treatment (Table 1).
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The kinetics of apolipoproteins in different lipoprotein fractions were assessed at the end of each treatment phase. Relative to placebo, extended-release niacin significantly increased plasma apoA-I concentrations (+15%; Table 2). This was associated with a significant increase in apoA-I PR (+24%), relative to placebo (Table 2). The effect of the combination of lovastatin and niacin on apoA-I concentrations and PR was similar to that of niacin alone. Neither niacin alone nor the combination treatment affected apoA-I FCR. Neither plasma apoA-II concentrations nor ApoA-II kinetic parameters were affected by niacin or the combination treatment, relative to placebo (Table 2). Analysis of the HDL subpopulation profile showed a significant increase in large HDL particle concentrations during niacin, relative to placebo, with significant increases in 
1, 2, pre 1, and pre 2 particles (Table 3). The addition of lovastatin to niacin had nonsignificant effects on the HDL subpopulation distribution. Plasma CETP and LCAT mass did not change significantly during treatment with niacin or the combination of niacin and lovastatin.
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The TRL apoB-100 concentration was significantly lowered (–28%) by niacin, relative to placebo, accompanied by a trend toward an increase in TRL apoB-100 FCR (+94%, P=0.06; Table 4 and Figure). No significant changes in the conversion of TRL apoB-100 to IDL (45% versus 53%, P=0.39) were observed. Niacin did not affect TRL apoB-100 PR (Table 4). In addition, niacin did not affect the plasma concentration or the kinetic parameters of apoB-100 in IDL and LDL. The addition of lovastatin to niacin resulted in a significant reduction in IDL apoB-100 concentrations accompanied by a significant increase in IDL apoB-100 FCR, and in a significant reduction in LDL apoB-100 concentrations with a significant increase in LDL apoB-100 FCR, relative to placebo (Table 4 and Figure). The significant effects of the combination treatment on LDL apoB-100 kinetic parameters were also maintained relative to niacin alone (Table 4). Similar to TRL apoB-100, treatment with niacin resulted in lower plasma TRL apoB-48 concentrations, accompanied by a significant increase in apoB-48 FCR and no change in PR (Table 5 and Figure). A trend toward an increase in TRL apoB-48 FCR was observed with the combination treatment.
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Plasma remnant lipoprotein cholesterol concentrations were significantly lowered, and plasma insulin and adiponectin levels were significantly increased by niacin, relative to placebo (supplemental Table I, available online at http://atvb.ahajournals.org), No effect of niacin on plasma FFA levels and markers of cholesterol homeostasis was observed (supplemental Table I). In contrast, lovastatin had a significant and independent effect on cholesterol homeostasis by lowering plasma lathosterol, a marker of cholesterol synthesis, and increasing plasma β-sitosterol, a marker of cholesterol absorption, relative to both placebo and niacin alone (supplemental Table I).
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Discussion |
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Treatment with extended-release niacin proved very effective in lowering high plasma TG levels and increasing low plasma HDL-C levels, consistent with the known effect of this medication.2,7,27 These changes were associated with significant reductions in remnant lipoproteins and a shift toward larger HDL subpopulation particles and point to a marked overall beneficial effect of this medication on the TG-HDL metabolism.
Our study indicates that the effect of extended-release niacin on plasma HDL-C concentrations is mediated in part by an increase in HDL apoA-I secretion. Our findings are different from the results of 2 previous studies.10,11 Blum et al10 studied the effect of 1g of niacin/3 times daily on apoA-I kinetics in 2 young normolipidemic subjects (a male and a female) using 125I-labeled autologous HDL and a multicompartmental model, and showed a slower catabolism of HDL particles.10 Shepherd et al11 studied 5 young normolipidemic subjects (3 males and 2 females) treated with niacin 1 g/3 times daily. Autologous HDL were labeled with 131I-apoA-I and 125I-apoA-II and the kinetic parameters of these apolipoprotein were calculated by mathematical models. Plasma apoA-I concentrations were increased by 7%, but no significant changes in apoA-I PR or FCR were observed.11 Previous in vitro studies in HepG2 cells have shown niacin to increase apoA-I concentration in the media and reduce apoA-I hepatic uptake without affecting apoA-I gene expression, suggesting that a reduction in apoA-I catabolism is the main mechanism in the regulation of HDL-C levels.28 In our study, extended-release niacin treatment significantly raised plasma apoA-I levels, mostly because of an increase in apoA-I PR. The discrepancy in the results between our study and the 2 previous kinetic studies may be explained by differences in the characteristics of the selected subjects and in the study methodology. In our study, subjects with abnormal plasma TG and HDL-C levels, ideal targets for niacin treatment, were selected. The metabolism of TG-rich lipoproteins and HDL may be affected differently by niacin in subjects who are young, healthy, and normolipidemic. In addition, in our study, apolipoproteins were endogenously labeled with a stable isotope, a method which has the advantages of labeling nascent particles and conserving the structure, metabolism, and binding characteristics of lipoproteins.29,30. The molecular mechanism that mediates the niacin-associated increase in apoA-I production is not known, however niacin can activate both the mitogen activated protein (MAP) kinase pathway and the peroxisome proliferator activated receptors (PPAR) transcription factors.31 Both MAP kinase and PPAR have been shown to affect hepatic apoA-I secretion.32,33
The analysis of HDL subpopulations by 2-dimensional gel electrophoresis suggests that niacin promotes the maturation of HDL into large particles, such as 1 and 2 and their corresponding pre particles. The mechanism that mediates this effect is not known, but a reduction in CETP activity, caused by the lowering in TG and TRL particle concentrations, may play a role. A niacin-associated change in HDL subpopulations to larger particles has been described previously with other methodologies.11,27 In the HATS study, the increase in plasma 1 particle levels associated with niacin plus simvastatin treatment was significantly related with slower coronary disease progression.34
Lovastatin had no significant independent effect on apoA-I kinetics, consistent with some previous reports of a lack of effect of statins on apoA-I kinetics.14,35
The plasma concentrations and kinetic parameters of apoA-II in HDL were not affected by treatment with niacin. This is in contrast with the report by Shepherd et al,11 where a significant reduction in plasma apoA-II levels, mostly explained by a reduction in apoA-II PR, was observed.
The reduction in plasma TG levels with niacin has been previously attributed to an inhibition of adipose tissue FFA release by this medication36: the reduced availability of fatty acids for hepatic TG synthesis would lead to an impaired hepatic VLDL assembly and reduced secretion. It has been shown, however, that the inhibition of FFA release by niacin lasts only a few hours and is followed by a marked rebound in FFA release that is already detectable 4 hours after extended-release niacin administration.37,38 In our study, a modest and nonsignificant increase in plasma FFA levels was observed approximately 9 hours after administration, consistent with a rebound phase. Previously, Wang et al38 have reported in normolipidemic women that the production of VLDL-TG was lowered by niacin, but the reduction was not fully explained by the effect of niacin on FFA levels. In vitro experiments have also suggested that niacin inhibits the activity of diglycerol acyl-transferase-2, the enzyme involved in TG synthesis in liver cells.39 In our study, niacin reduced the plasma concentration of TRL apoB-100. However, this reduction was not explained by TRL apoB-100 synthesis, but was mostly attributable to an almost significant increase in FCR. The same effect was observed for TRL apoB-48, where a significant increase in FCR was observed with niacin. This is consistent with the observation in 1 hypertriglyceridemic subject that autologous 125I-labeled VLDL underwent faster clearance after niacin treatment.9 The mechanism for the faster clearance of TRL is not clear. It is likely that it does not involve an increased expression of the LDL receptor, because niacin was not observed to affect the clearance of IDL and LDL apoB-100. Lipolysis may play a small role, as there was a slight trend toward an increased conversion of apoB-100 VLDL to IDL. The statin-induced effect on apoB-100 kinetics is consistent with several previous statin studies.14
In conclusion, in male subjects with elevated TG and low HDL-C levels, extended-release niacin induces beneficial changes in lipid and lipoprotein levels. The increase in HDL-C levels achieved with extended-release niacin is mediated in part by an increased production of apoA-I, whereas the reduction in plasma TG levels is mostly mediated by an increased clearance of both hepatic and intestinal TRL.
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Acknowledgments |
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Sources of Funding
This work was supported by an investigator-initiated research grant from KOS Pharmaceuticals to Dr Ernst Schaefer, and by the US Department of Agriculture under agreement No. 58-1950-4-401. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the US Department of Agriculture. Support was also provided by grant M01 RR00054 to Tufts Medical Center General Clinical Research Center, funded by the National Center for the Research Resources of the NIH. Dr P. Hugh R. Barrett is a senior research fellow of the National Health and Medical Research Council of Australia and is supported in part by the NIH (National Institute of Biomedical Imaging and Bioengineering grant P41 EB-00195).
Disclosures
Dr Ernst Schaefer has received grant support from KOS Pharmaceuticals, now part of Abbott, and from Abbott. He has been a consultant and in the Speakers’ Bureau for KOS Pharmaceutical and Abbott. Dr Bela Asztalos has received grant support from Abbott.
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Footnotes |
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Original received February 7, 2008; final version accepted June 5, 2008.
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References |
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G.F. Watts and D.C. Chan Of Mice and Men: Blowing Away the Cobwebs From the Mechanism of Action of Niacin on HDL Metabolism Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 1892 - 1895. [Full Text] [PDF]
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