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• W2148542994 abstract "Treatment with the peroxisome proliferator-activated receptor γ agonist rosiglitazone has been reported to increase HDL-cholesterol (HDL-C) levels, although the mechanism responsible for this is unknown. We sought to determine the effect of rosiglitazone on HDL apolipoprotein A-I (apoA-I) and apoA-II metabolism in subjects with metabolic syndrome and low HDL-C. Subjects were treated with placebo followed by rosiglitazone (8 mg) once daily. At the end of each 8 week treatment, subjects (n = 15) underwent a kinetic study to measure apoA-I and apoA-II production rate (PR) and fractional catabolic rate. Rosiglitazone significantly reduced fasting insulin and high-sensitivity C-reactive protein (hsCRP) and increased apoA-II levels. Mean apoA-I and HDL-C levels were unchanged following rosiglitazone treatment, although there was considerable individual variability in the HDL-C response. Rosiglitazone had no effect on apoA-I metabolism, whereas the apoA-II PR was increased by 23%. The change in HDL-C in response to rosiglitazone was significantly correlated with the change in apoA-II concentration but not to changes in apoA-I, measures of glucose homeostasis, or hsCRP. Treatment with rosiglitazone significantly increased apoA-II production in subjects with metabolic syndrome and low HDL-C but had no effect on apoA-I metabolism. The change in HDL-C in response to rosiglitazone treatment was unrelated to effects on apoA-I, instead being related to the change in the metabolism of apoA-II. Treatment with the peroxisome proliferator-activated receptor γ agonist rosiglitazone has been reported to increase HDL-cholesterol (HDL-C) levels, although the mechanism responsible for this is unknown. We sought to determine the effect of rosiglitazone on HDL apolipoprotein A-I (apoA-I) and apoA-II metabolism in subjects with metabolic syndrome and low HDL-C. Subjects were treated with placebo followed by rosiglitazone (8 mg) once daily. At the end of each 8 week treatment, subjects (n = 15) underwent a kinetic study to measure apoA-I and apoA-II production rate (PR) and fractional catabolic rate. Rosiglitazone significantly reduced fasting insulin and high-sensitivity C-reactive protein (hsCRP) and increased apoA-II levels. Mean apoA-I and HDL-C levels were unchanged following rosiglitazone treatment, although there was considerable individual variability in the HDL-C response. Rosiglitazone had no effect on apoA-I metabolism, whereas the apoA-II PR was increased by 23%. The change in HDL-C in response to rosiglitazone was significantly correlated with the change in apoA-II concentration but not to changes in apoA-I, measures of glucose homeostasis, or hsCRP. Treatment with rosiglitazone significantly increased apoA-II production in subjects with metabolic syndrome and low HDL-C but had no effect on apoA-I metabolism. The change in HDL-C in response to rosiglitazone treatment was unrelated to effects on apoA-I, instead being related to the change in the metabolism of apoA-II. The metabolic syndrome consists of a cluster of abnormalities that include hypertension, abdominal obesity, impaired fasting glucose, elevated fasting triglyceride levels, and low HDL-cholesterol (HDL-C). Patients with metabolic syndrome are at increased risk of cardiovascular disease and, as a result, recommendations have been made to reduce the risk in these patients. These recommendations include therapeutic lifestyle changes and, if treatment goals are not met, pharmacological intervention (1Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).J. Am. Med. Assoc. 2001; 285: 2486-2497Crossref PubMed Scopus (24453) Google Scholar). Currently, few drugs are available that are suitable for treating patients with two components of the metabolic syndrome, insulin resistance and low HDL-C. Among treatments available for improving insulin resistance are the thiazolidinediones (TZDs) rosiglitazone and pioglitazone, which activate the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). In addition to their insulin-sensitizing effects, TZDs have been shown to increase HDL-C levels in diabetic populations (2Chiquette E. Ramirez G. Defronzo R. A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors.Arch. Intern. Med. 2004; 164: 2097-2104Crossref PubMed Scopus (285) Google Scholar) by up to 14% for rosiglitazone and up to 19% for pioglitazone (3Goldberg R.B. Kendall D.M. Deeg M.A. Buse J.B. Zagar A.J. Pinaire J.A. Tan M.H. Khan M.A. Perez A.T. Jacober S.J. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia.Diabetes Care. 2005; 28: 1547-1554Crossref PubMed Scopus (718) Google Scholar). These changes in HDL-C compare favorably to HDL-C changes achieved with other drugs currently approved to treat low HDL-C levels (4Capuzzi D.M. Guyton J.R. Morgan J.M. Goldberg A.C. Kreisberg R.A. Brusco O.A. Brody J. Efficacy and safety of an extended-release niacin (Niaspan): a long-term study.Am. J. Cardiol. 1998; 82: 74U-81UAbstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar, 5Schaefer E.J. Asztalos B.F. The effects of statins on high-density lipoproteins.Curr. Atheroscler. Rep. 2006; 8: 41-49Crossref PubMed Scopus (40) Google Scholar, 6Barter P.J. Rye K.A. Is there a role for fibrates in the management of dyslipidemia in the metabolic syndrome?.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 39-46Crossref PubMed Scopus (127) Google Scholar, 7Hartweg J. Farmer A.J. Perera R. Holman R.R. Neil H.A. Meta-analysis of the effects of n-3 polyunsaturated fatty acids on lipoproteins and other emerging lipid cardiovascular risk markers in patients with type 2 diabetes.Diabetologia. 2007; 50: 1593-1602Crossref PubMed Scopus (94) Google Scholar). Although rosiglitazone and pioglitazone both activate PPARγ, they each have a characteristic metabolic response in regard to plasma lipid levels, with rosiglitazone also increasing plasma triglyceride levels in the relatively short term, whereas pioglitazone does not (8Goldberg R.B. Impact of thiazolidenediones on serum lipoprotein levels.Curr. Atheroscler. Rep. 2006; 8: 397-404Crossref PubMed Scopus (29) Google Scholar). The mechanisms responsible for the HDL-C-raising effects of TZDs are currently unknown. Studies that have measured apolipoprotein A-I (apoA-I) and apoA-II levels following rosiglitazone treatment have found that although HDL-C and apoA-II generally increase, levels of apoA-I remain unchanged (9Samaha F.F. Szapary P.O. Iqbal N. Williams M.M. Bloedon L.T. Kochar A. Wolfe M.L. Rader D.J. Effects of rosiglitazone on lipids, adipokines, and inflammatory markers in nondiabetic patients with low high-density lipoprotein cholesterol and metabolic syndrome.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 624-630Crossref PubMed Scopus (121) Google Scholar, 10Freed M.I. Ratner R. Marcovina S.M. Kreider M.M. Biswas N. Cohen B.R. Brunzell J.D. Effects of rosiglitazone alone and in combination with atorvastatin on the metabolic abnormalities in type 2 diabetes mellitus.Am. J. Cardiol. 2002; 90: 947-952Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, 11Wagner J.A. Larson P.J. Weiss S. Miller J.L. Doebber T.W. Wu M.S. Moller D.E. Gottesdiener K.M. Individual and combined effects of peroxisome proliferator-activated receptor and {gamma} agonists, fenofibrate and rosiglitazone, on biomarkers of lipid and glucose metabolism in healthy nondiabetic volunteers.J. Clin. Pharmacol. 2005; 45: 504-513Crossref PubMed Scopus (29) Google Scholar, 12Sarafidis P.A. Lasaridis A.N. Nilsson P.M. Mouslech T.F. Hitoglou-Makedou A.D. Stafylas P.C. Kazakos K.A. Yovos J.G. Tourkantonis A.A. The effect of rosiglitazone on novel atherosclerotic risk factors in patients with type 2 diabetes mellitus and hypertension. An open-label observational study.Metabolism. 2005; 54: 1236-1242Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 13Derosa G. Cicero A.F. Gaddi A. Ragonesi P.D. Fogari E. Bertone G. Ciccarelli L. Piccinni M.N. Metabolic effects of pioglitazone and rosiglitazone in patients with diabetes and metabolic syndrome treated with glimepiride: a twelve-month, multicenter, double-blind, randomized, controlled, parallel-group trial.Clin. Ther. 2004; 26: 744-754Abstract Full Text PDF PubMed Scopus (134) Google Scholar, 14Derosa G. Gaddi A.V. Piccinni M.N. Salvadeo S. Ciccarelli L. Fogari E. Ghelfi M. Ferrari I. Cicero A.F. Differential effect of glimepiride and rosiglitazone on metabolic control of type 2 diabetic patients treated with metformin: a randomized, double-blind, clinical trial.Diabetes Obes. Metab. 2006; 8: 197-205Crossref PubMed Scopus (35) Google Scholar). Weak, partial transactivation of PPARα by rosiglitazone (15Wurch T. Junquero D. Delhon A. Pauwels J. Pharmacological analysis of wild-type alpha, gamma and delta subtypes of the human peroxisome proliferator-activated receptor.Naunyn Schmiedebergs Arch. Pharmacol. 2002; 365: 133-140Crossref PubMed Scopus (35) Google Scholar, 16Sakamoto J. Kimura H. Moriyama S. Odaka H. Momose Y. Sugiyama Y. Sawada H. Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone.Biochem. Biophys. Res. Commun. 2000; 278: 704-711Crossref PubMed Scopus (279) Google Scholar) and pioglitazone (16Sakamoto J. Kimura H. Moriyama S. Odaka H. Momose Y. Sugiyama Y. Sawada H. Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone.Biochem. Biophys. Res. Commun. 2000; 278: 704-711Crossref PubMed Scopus (279) Google Scholar, 17Qin S. Liu T. Kamanna V.S. Kashyap M.L. Pioglitazone stimulates apolipoprotein A-I production without affecting HDL removal in HepG2 cells: involvement of PPAR-alpha.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 2428-2434Crossref PubMed Scopus (34) Google Scholar) has been demonstrated in vitro and may result in upregulation of the PPARα targets apoA-I and apoA-II, leading to an increase in the production rates (PRs) of these proteins. Consistent with these in vitro findings, Carreon-Torres et al. (18Carreon-Torres E. Rendon-Sauer K. Monter-Garrido M. Toledo-Ibelles P. Gamboa R. Menjivar M. Lopez-Marure R. Luc G. Fievet C. Cruz D. Rosiglitazone modifies HDL structure and increases HDL-apo AI synthesis and catabolic rates.Clin. Chim. Acta. 2009; 401: 37-41Crossref PubMed Scopus (25) Google Scholar) recently reported that rosiglitazone increased apoA-I production in rabbits. In contrast, a study in patients with type 2 diabetes demonstrated that treatment with pioglitazone had no effect on apoA-I kinetics (19Nagashima K. Lopez C. Donovan D. Ngai C. Fontanez N. Bensadoun A. Fruchart-Najib J. Holleran S. Cohn J.S. Ramakrishnan R. Effects of the PPARgamma agonist pioglitazone on lipoprotein metabolism in patients with type 2 diabetes mellitus.J. Clin. Invest. 2005; 115: 1323-1332Crossref PubMed Scopus (167) Google Scholar). To date, no studies have measured apoA-I kinetics in humans treated with roziglitazone, and no study has examined the effect of TZDs on the kinetics of apoA-II in humans. We conducted studies with rosiglitazone in subjects with metabolic syndrome and low HDL-C. These studies were conducted to test the hypothesis that rosiglitazone increases HDL-C by increasing apoA-I and apoA-II production in humans. Similar to what was reported for pioglitazone (19Nagashima K. Lopez C. Donovan D. Ngai C. Fontanez N. Bensadoun A. Fruchart-Najib J. Holleran S. Cohn J.S. Ramakrishnan R. Effects of the PPARgamma agonist pioglitazone on lipoprotein metabolism in patients with type 2 diabetes mellitus.J. Clin. Invest. 2005; 115: 1323-1332Crossref PubMed Scopus (167) Google Scholar), the results show that the metabolism of apoA-I was unchanged in response to rosiglitazone treatment, whereas there was a significant increase in the PR of apoA-II. The change in HDL-C in response to rosiglitazone was associated with the change in apoA-II levels, with those subjects increasing the plasma concentration of apoA-II having the greatest increase in HDL-C in response to rosiglitazone. Men and women between the ages of 18 and 75 years were recruited from the local area to participate in the study. All subjects had low HDL-C (<40 mg/dl for men, <50 mg/dl for women) and at least two additional risk factors for metabolic syndrome as defined by the Adult Treatment Panel III: abdominal obesity defined by increased waist circumference, hypertension or current treatment for hypertension, impaired fasting glucose without a diagnosis of diabetes, and fasting triglycerides >150 mg/dl and ≤800 mg/dl. Exclusion criteria included current treatment with statins or niacin; a history of cardiovascular disease including coronary artery disease or heart failure; a history of diabetes or recent treatment with diabetic medications; a history of renal disease or a serum creatinine level greater than 2.0 mg/dl; a history of testing HIV positive; being pregnant or lactating; a history of a major active rheumatologic, pulmonary, or dermatologic disease or an inflammatory condition; uncontrolled blood pressure (>180/100 mmHg); abnormal measures of thyroid function; levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, or total bilirubin greater than 2.0 times the upper limit of normal. All subjects gave written, informed consent. All protocols and procedures were approved by the Human Investigational Review Board at the University of Pennsylvania. This study was a single-site, single-blind, placebo-controlled, fixed-sequence study. A fixed-sequence design with placebo treatment followed by rosiglitazone treatment was selected to avoid potential carryover effects from rosiglitazone treatment. Eligible subjects visited the General Clinical Research Center (GCRC) at the University of Pennsylvania for baseline fasting blood collection. Prior to discharge, subjects were instructed to take placebo once daily for 8 weeks. At the end of the 8 week placebo treatment period, subjects were admitted to GCRC for an overnight kinetic study. Following the kinetic study, subjects were instructed to take rosiglitazone (8 mg) once daily for 8 weeks. At the end of the 8 week rosiglitazone treatment period, subjects returned to the GCRC for a second kinetic study. After this second kinetic study, the drug was discontinued and the subjects discharged. Apolipoprotein kinetics were measured as previously described (20Millar J.S. Brousseau M.E. Diffenderfer M.R. Barrett P.H. Welty F.K. Faruqi A. Wolfe M.L. Nartsupha C. Digenio A.G. Mancuso J.P. Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on apolipoprotein B100 metabolism in humans.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 1350-1356Crossref PubMed Scopus (65) Google Scholar). Briefly, subjects were fed a standardized meal representing 1/20th of their daily caloric intake hourly for 5 h. Participants were then given a bolus of [5,5,5-D3]leucine (10 µmol/kg) immediately followed by a constant infusion of [5,5,5-D3]leucine (10 µmol/kg/h). Hourly standardized meals were given throughout the kinetic study to maintain a constant rate of lipoprotein production. Blood samples were collected at various time points over a 15 h period, at which point the infusion was stopped. Lipoprotein fractions were isolated by sequential ultracentrifugation, and apolipoproteins were isolated by SDS-PAGE. Apolipoproteins were hydrolyzed, their amino acids derivatized, and their isotope enrichment analyzed by GC/MS. The fractional catabolic rates (FCRs) for HDL apoA-I and apoA-II were determined using the WinSAAM modeling program by fitting a rising monoexponential curve that incorporated a secretory delay to the HDL apoA-I and apoA-II [5,5,5-D3]leucine tracer data using a weighted least-squares approach (21Ikewaki K. Rader D.J. Schaefer J.R. Fairwell T. Zech L.A. Brewer Jr, H.B. Evaluation of apoA-I kinetics in humans using simultaneous endogenous stable isotope and exogenous radiotracer methods.J. Lipid Res. 1993; 34: 2207-2215Abstract Full Text PDF PubMed Google Scholar). The apoA-I and apoA-II liver precursor pool enrichment was assumed to be equal to the maximal estimated VLDL apoB-100 enrichment (i.e., VLDL apoB-100 enrichment plateau). Pool sizes for apoA-I and apoA-II were calculated as plasma concentration (mg/dl) multiplied by the estimated plasma volume (0.45 dl/kg body weight). PRs were calculated by multiplying the FCR by the pool size using the formula PR (mg/kg/day) = FCR (pools/day) • pool size (mg/kg body weight/pool). Plasma lipids were measured from EDTA plasma collected after a 12 h fast in a Centers for Disease Control and Prevention-standardized laboratory. Plasma total cholesterol (TC), VLDL-C (d < 1.006 g/ml fraction), HDL-C, and triglycerides were measured enzymatically on a Cobas Fara II autoanalyzer (Roche Diagnostic Systems, Inc.; Basel, Switzerland) using Sigma reagents (Sigma Chemical Co.; St. Louis, MO). LDL-C levels were determined by subtracting VLDL-C and HDL-C from the TC measurement. ApoA-I, apoB, apoC-II, apoC-III, apoE, and lipoprotein [a] (Lp[a]) were measured with immunoturbidemtric assays using Wako reagents (Wako Chemicals USA, Inc.; Richmond, VA). HDL particle sizes were measured using NMR (LipoScience; Raleigh, NC). High-sensitivity C-reactive protein (hsCRP) was measured with an ultra high-sensitivity latex turbidimetric immunoassay (Wako Chemicals USA, Inc.), and glucose and non­esterified FAs were measured using enzymatic reagents (Wako Chemicals USA, Inc.) on a Hitachi 912 autoanalyzer (Roche Diagnostics). Insulin levels were measured by radioimmunoassay (Linco Research, Inc). Insulin resistance was estimated with the homeostasis model assessment of insulin resistance (HOMA-IR) calculated as [plasma insulin (µIU/ml) × plasma glucose (mmol/l)]/22.5. Cholesterol efflux from Fu5AH rat hepatoma cells to patient HDL was obtained following precipitation of apoB-containing lipoproteins with polyethylene glycol, as previously described (22Zimetti F. Weibel G.K. Duong M. Rothblat G.H. Measurement of cholesterol bidirectional flux between cells and lipoproteins.J. Lipid Res. 2006; 47: 605-613Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar). Fu5AH cells efflux cholesterol primarily via the scavenger receptor class B type I (SR-BI) and aqueous diffusion pathways (23Rothblat G.H. de la Llera-Moya M. Atger V. Kellner-Weibel G. Williams D.L. Phillips M.C. Cell cholesterol efflux: integration of old and new observations provides new insights.J. Lipid Res. 1999; 40: 781-796Abstract Full Text Full Text PDF PubMed Google Scholar). Efflux was measured over a 4 h period on samples collected at the end of the placebo and rosiglitazone treatment periods. Differences between treatment groups were determined using a paired t-test. Differences for nonnormally-distributed data were determined using the Wilcoxon sign rank test. Analyses were performed using GraphPad Prism, Version 3.02 (GraphPad Software, Inc.). Stepwise multiple regression was conducted using Intercooled Stata, Version 9. A two-tailed P value of less than 0.05 was considered statistically significant. Seventeen subjects (nine male, eight female) enrolled in the study. The mean age of the subjects was 50.6 ± 10.5 years, with nine Caucasian and eight African-American subjects. Two subjects voluntarily withdrew from the study prior to initiating rosiglitazone treatment, and fifteen subjects completed all study-related visits. Baseline subject characteristics are shown in Table 1. Body mass index (BMI) ranged from 25.8 to 42.6 kg/m2, with the mean falling within the obesity range (>30.0 kg/m2). Five of the enrolled subjects were smokers.TABLE 1Baseline characteristics of the subjects enrolled in the studySubject characteristics (n = 17)Age (years), mean ± SD50.6 ± 10.5Male sex, n (%)9 (53)Race White, n (%)9 (53) African-American, n (%)8 (47)BMI (kg/m ), mean ± SD31.5 ± 4.0Current smoker, n (%)5 (29)BMI, body mass index. Open table in a new tab BMI, body mass index. Treatment with rosiglitazone (8 mg once daily) was well-tolerated and there were no serious adverse events reported. One subject was found to have trace edema in lower extremities after 8 weeks on rosiglitazone, which resolved within 2 weeks of drug discontinuation and was judged as possibly related to treatment. A second subject gained an unexplained 5.8 kg between baseline and 8 weeks on placebo and another 2.1 kg after being on rosiglitazone for 8 weeks that was judged as possibly related to treatment. Neither subject had symptoms of congestive heart failure or ischemic cardiovascular events. Because the second subject with unexplained weight gain was not in a steady state during the study period, the results for this subject were excluded from all analyses. The plasma lipid levels at the end of the placebo and rosiglitazone phases are shown in Table 2. There was an 11% increase in plasma TC in response to rosiglitazone that was due to a significant increase in the VLDL cholesterol level. There were no significant changes in triglyceride, LDL-C, or HDL-C levels following rosiglitazone treatment. Plasma nonesterified FA levels were significantly decreased (−36%) following rosiglitazone treatment. ApoA-I and apoB levels in plasma were unchanged following rosiglitazone treatment, whereas apoA-II, apoE, apoC-III, and Lp[a] levels in plasma were all significantly increased.TABLE 2.Plasma lipid, apolipoprotein, glucose, insulin, and high-sensitivity C-reactive protein levels in subjects completing the placebo and rosiglitazone treatment phases (n = 14)PlaceboRosiglitazone% ChangePTotal cholesterol (mg/dl)209 ± 51231 ± 6811%0.05Triglycerides (mg/dl)203 ± 98244 ± 15718%0.11VLDL-C (mg/dl)34 (24–39)41 (33–88)40%aMedian change.0.01LDL-C (mg/dl)141 ± 37138 ± 47−1%0.77HDL-C (mg/dl)34 ± 636 ± 74%0.22Lp[a] (mg/dl)25 (11–59)26 (12–63)34%aMedian change.0.04Nonesterified FAs (mEq/l)0.22 ± 0.060.14 ± 0.06−36%0.0002ApoA-I (mg/dl)94 ± 1486 ± 13−8%0.08ApoA-II (mg/dl)28 ± 433 ± 419%<0.0001ApoB (mg/dl)100 ± 22105 ± 325%0.76ApoE (mg/dl)5.3 ± 1.75.9 ± 2.012%0.009ApoC-II (mg/dl)5.8 ± 2.77.7 ± 3.937%0.0003ApoC-III (mg/dl)14.0 ± 6.216.7 ± 8.316%0.009Fasting glucose (mg/dl)86 ± 783 ± 8−3%0.30Fasting Insulin (mU/ml)17.6 ± 8.812.6 ± 4.6−22%0.02HOMA-IR3.7 ± 1.92.6 ± 1.0−23%0.02hsCRP (mg/l)1.9 (0.7–3.4)1.3 (0.3–3.4)−40%aMedian change.0.01Data are expressed as mean ± SD except for Lp[a] and hsCRP, which are median (interquartile range). ApoA-I, apolipoprotein A-I; HDL-C, HDL-cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; hsCRP, high-sensitivity C-reactive protein; LDL-C, LDL cholesterol; Lp[a], lipoprotein [a].a Median change. Open table in a new tab Data are expressed as mean ± SD except for Lp[a] and hsCRP, which are median (interquartile range). ApoA-I, apolipoprotein A-I; HDL-C, HDL-cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; hsCRP, high-sensitivity C-reactive protein; LDL-C, LDL cholesterol; Lp[a], lipoprotein [a]. Fasting glucose, insulin, and hsCRP levels at the end of the placebo and rosiglitazone phases are shown in Table 2. There was no change in fasting plasma glucose, whereas there were significant reductions in fasting insulin (−22%) and the HOMA-IR in response to rosiglitazone treatment. Plasma levels of hsCRP were significantly reduced following rosiglitazone treatment. We assessed HDL particle concentrations and particle size by NMR (Table 3). Consistent with the lack of change in the HDL-C concentration, there was no change in HDL particle concentration. There was, however, a change in the HDL size distribution, with an increase in medium-sized HDL and a decrease in small HDL.TABLE 3Effects of rosiglitazone on HDL particle concentration, size, and composition (n = 14)PlaceboRosiglitazonePTotal HDL particles (µmol/l)25.9 ± 3.524.5 ± 2.90.21Large HDL particles (µmol/l)2.7 ± 1.62.3 ± 1.90.16Medium HDL particles (µmol/l)2.2 ± 2.15.8 ± 4.10.0002Small HDL particles (µmol/l)21.0 ± 3.116.4 ± 4.20.003HDL size (nm)8.5 ± 0.28.5 ± 0.20.91Lipid composition (% lipid) Cholesterol28.1 ± 1.428.4 ± 2.40.66 Free cholesterol5.3 ± 0.45.3 ± 0.70.89 Cholesteryl ester22.8 ± 1.223.1 ± 2.10.62 Triglyceride12.5 ± 2.411.2 ± 2.70.10 Phospholipids59.4 ± 1.960.4 ± 2.30.04HDL apolipoproteins (mg/dl) apoE0.5 ± 0.40.7 ± 0.50.004 apoC-III2.2 ± 1.53.2 ± 2.40.12Data are expressed as mean ± SD. Open table in a new tab Data are expressed as mean ± SD. The lipid composition and apolipoprotein content of HDL isolated by ultracentrifugation was determined at the end of the placebo and rosiglitazone treatment periods (Table 3). Treatment with rosiglitazone significantly increased the percent phospholipid content and content of apoE in the HDL fraction. There was a trend toward the percent triglyceride content in HDL with rosiglitazone treatment being reduced. Treatment with rosiglitazone significantly increased the ability of HDL to promote cholesterol efflux from Fu5AH cells in in vitro studies. After 8 weeks of treatment with rosiglitazone, there was a 30% increase in the ability of HDL to promote cholesterol efflux (1.17 ± 0.41% efflux/4 h vs. 1.45 ± 0.44% efflux/4 h, placebo vs. rosiglitazone; P = 0.03). The percent change in HDL levels in response to rosiglitazone treatment was significantly correlated with the percent change in cholesterol efflux (r = 0.79; P = 0.0008). The results for changes in apoA-I and apoA-II metabolism in response to rosiglitazone are summarized in Table 4. There was no significant change in the apoA-I pool size following rosiglitazone treatment, as compared with placebo treatment, although there was a trend toward a lower pool size (−7%). There was also no significant change in the apoA-I PR or FCR in response to rosiglitazone treatment.TABLE 4ApoA-I and apoA-II kinetic parameters measured at the end of the placebo and rosiglitazone treatment periods (n = 14)PlaceboRosiglitazone% ChangePApoA-I pool size3,715 ± 8173,426 ± 808−7%0.14ApoA-I PR9.81 ± 2.479.47 ± 4.04−3%0.69ApoA-I FCR0.238 ± 0.0840.244 ± 0.0954%0.70ApoA-II pool size1,105 ± 2821,315 ± 35019%<0.0001ApoA-II PR2.33 ± 0.672.87 ± 0.9423%<0.0001ApoA-II FCR0.190 ± 0.0600.197 ± 0.0674%0.37Data are expressed as mean ± SD. FCR, fractional catabolic rate; PR, production rate. Open table in a new tab Data are expressed as mean ± SD. FCR, fractional catabolic rate; PR, production rate. In contrast, the apoA-II pool size was significantly increased in subjects treated with rosiglitazone. There was a significant increase in the apoA-II PR (23%) following rosiglitazone treatment, whereas the apoA-II FCR showed no significant change, although the individual changes in this variable ranged from −24% to 32%. Interestingly, the correlation between the percent change in the apoA-II PR and the percent change in the apoA-II pool size in response to rosiglitazone was not statistically significant (r = −0.17; P = 0.55) due to a concomitant increase in the apoA-II FCR in many subjects. Instead, there was a significant inverse correlation between the percent change in the apoA-II FCR and the percent change in the apoA-II pool size (r = −0.72; P = 0.004), indicating that the subjects with reduced or unchanged apoA-II FCR had the greatest change in apoA-II pool size. The HDL-C response to rosiglitazone treatment was heterogeneous, ranging from −20% to 35%. To attempt to identify the factors that determine the HDL-C response to rosiglitazone, correlations were conducted between the percent change in HDL-C and the percent change in the following variables: plasma apoA-I and apoA-II concentration, apoA-I and apoA-II FCR and PR, triglyceride, apoC-III, nonesterfied FAs, fasting insulin, fasting glucose, HOMA, and hsCRP (Table 5). Of these, the percent changes in the apoA-II concentration, the apoA-II FCR, the apoC-III concentration, and the nonesterfied FA concentration were significant correlates. When adjusting for BMI and smoking, only the percent changes in the apoA-II concentration and the nonesterfied FA concentration remained significant correlates with the change in HDL-C.TABLE 5.Correlations between the percent change in HDL-C and the percent changes in candidate HDL-C determinants in response to rosiglitazone treatment (n = 14)Correlation Coefficient,UnadjustedCorrelation Coefficient,Adjusted for BMI and SmokingApoA-I concentration0.350.44ApoA-I FCR−0.26−0.14ApoA-I PR0.000.18ApoA-II concentration0.80bP ≤ 0.001.0.83bP ≤ 0.001.ApoA-II FCR−0.53aP ≤ 0.05.−0.51ApoA-II PR−0.07−0.05Fasting insulin0.210.42Fasting glucose−0.25−0.23HOMA0.080.27HsCRP−0.11−0.14Triglyceride−0.45−0.50ApoC-III−0.60aP ≤ 0.05.−0.50Nonesterified FAs−0.66aP ≤ 0.05.−0.68aP ≤ 0.05.a P ≤ 0.05.b P ≤ 0.001. Open table in a new tab To determine whether the variables identified as significant correlates were independent predictors of the percent change in HDL-C levels, these variables were included in a stepwise regression model. When this was done, the percent change in the plasma apoA-II and apoC-III concentrations remained significant (P = 0.0001) and accounted for 75% of the change in the HDL-C concentration. When controlling for both BMI and smoking in the model, only the percent change in the plasma apoA-II remained a significant predictor of the percent change in HDL-C in response to rosiglitazone, accounting for 70% of the change, whereas apoC-III was of marginal significance i" @default.
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• W2148542994 title "Effect of rosiglitazone on HDL metabolism in subjects with metabolic syndrome and low HDL" @default.
• W2148542994 cites W1830141431 @default.
• W2148542994 cites W1965772460 @default.
• W2148542994 cites W1968948434 @default.
• W2148542994 cites W1977004017 @default.
• W2148542994 cites W1977386411 @default.
• W2148542994 cites W1980136960 @default.
• W2148542994 cites W1981576531 @default.
• W2148542994 cites W1982942348 @default.
• W2148542994 cites W1982990554 @default.
• W2148542994 cites W1998755810 @default.
• W2148542994 cites W2009004494 @default.
• W2148542994 cites W2021626647 @default.
• W2148542994 cites W2037447341 @default.
• W2148542994 cites W2037937153 @default.
• W2148542994 cites W2039401819 @default.
• W2148542994 cites W2042749152 @default.
• W2148542994 cites W2043466223 @default.
• W2148542994 cites W2055505113 @default.
• W2148542994 cites W2057106559 @default.
• W2148542994 cites W2059642795 @default.
• W2148542994 cites W2071558571 @default.
• W2148542994 cites W2074239164 @default.
• W2148542994 cites W2076752637 @default.
• W2148542994 cites W2086327217 @default.
• W2148542994 cites W2090809780 @default.
• W2148542994 cites W2093969743 @default.
• W2148542994 cites W2098509001 @default.
• W2148542994 cites W2100363598 @default.
• W2148542994 cites W2102675827 @default.
• W2148542994 cites W2109324665 @default.
• W2148542994 cites W2120156576 @default.
• W2148542994 cites W2121982383 @default.
• W2148542994 cites W2131265209 @default.
• W2148542994 cites W2131490500 @default.
• W2148542994 cites W2131669718 @default.
• W2148542994 cites W2149382475 @default.
• W2148542994 cites W2149426905 @default.
• W2148542994 cites W2149515208 @default.
• W2148542994 cites W2162261906 @default.
• W2148542994 cites W2167675508 @default.
• W2148542994 cites W2336386035 @default.
• W2148542994 cites W2336481777 @default.
• W2148542994 cites W4238251256 @default.
• W2148542994 cites W4244218181 @default.
• W2148542994 doi "https://doi.org/10.1194/jlr.p008136" @default.
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