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Original Article |
Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 551 (M.G., P.E., W.L.G., C.S., M.J.C.), Dyslipoproteinemia and Atherosclerosis, Hôpital de la Pitié, 75651 Paris, France; and Pfizer (R.D.), 75668 Paris, France
Address all correspondence and requests for reprints to: Dr. Maryse Guerin, INSERM Unité 551, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83, boulevard de l’Hôpital, 75651 Paris Cedex 13, France. E-mail: mguerin{at}infobiogen.fr.
Abstract
The effect of atorvastatin, at 10 mg or 40 mg for 6 wk, on lipid and lipoprotein metabolism during the postprandial phase in subjects (n = 11) displaying type IIB hyperlipidemia was evaluated. The postprandial increment in area under the curve above baseline concentrations in type IIB subjects was significantly decreased by atorvastatin for plasma triglyceride (A10: -42% and A40: -55%, P < 0.01), chylomicrons (CMs) (A10: -24% and A40: -40%, P < 0.03) and VLDL-1 (A10: -54% and A40: -52%, P < 0.02). Before atorvastatin therapy, postprandial cholesteryl ester (CE) transfer from high-density lipoprotein (HDL) to CMs (2.5-fold; P < 0.005), very low-density lipoprotein (VLDL)-1 (1.8-fold; P < 0.005), VLDL-2 (1.4-fold; P < 0.05), and intermediate-density lipoproteins (1.4-fold; P < 0.05) were significantly increased 4 h postprandially. Following statin treatment, the postprandial transfer of CE from HDL to triglyceride-rich lipoproteins (TRLs) at the 4-h time point was significantly reduced at 10 mg/d (-26%; P < 0.05) and at 40 mg/d (-24%; P < 0.05), compared with that before treatment. Such postprandial increase in CE transferred from HDLs to TRLs arose exclusively from accelerated CE transfer from HDLs to CMs (2.5-fold; P < 0.005). In conclusion, atorvastatin attenuates the abnormal intravascular remodeling of postprandial TRL particles via marked reduction in CE transfer in type IIB hyperlipidemia and diminishes the postprandial formation and accumulation of CMs and VLDL-1.
POSTPRANDIAL LIPID METABOLISM has received considerable attention since it was proposed that postprandial triglyceride (TG)-rich lipoproteins are implicated in atherogenesis. Indeed, TG-rich lipoproteins favor the development of coronary artery disease (1). Furthermore, elevated levels of chylomicron (CM) remnants containing apolipoprotein (apo) B48 have been associated with the presence and progression of atherosclerosis (2). The intimate relationship between postprandial lipemia and atherosclerosis clearly suggests that the relationship between lipoprotein metabolism, and atherosclerosis can no longer be considered exclusively on the basis of fasting lipid levels (3). Therefore, lipid-lowering therapy, whose aim is to reduce atherogenesis, should be targeted at least in part to lipid and lipoprotein metabolism in the postprandial state.
Several studies of the effect of inhibition of endogenous cholesterol synthesis by 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors, including lovastatin and simvastatin, on postprandial metabolism have been described (4, 5, 6, 7, 8). The common primary feature of these studies concerns the effect of statin therapy on postprandial TG concentration, which appears to correlate with the degree of reduction in fasting plasma TG (9). In miniature pigs, atorvastatin induces greater reduction in plasma TG levels over the postprandial phase than that observed at baseline (10). More recently, Parhofer et al. (11) reported that postprandial lipoprotein metabolism is enhanced in normolipidemic subjects under atorvastatin therapy as a result of elevated catabolism of CM remnants and/or decreased conversion of CMs to CM remnants; by contrast, the formation and secretion of CMs was not affected. This statin is highly effective in reducing plasma low-density lipoprotein (LDL)-cholesterol (12, 13); equally, atorvastatin mediates marked reduction in plasma TG concentrations (14, 15). The lowering of TG levels mediated by atorvastatin results from two indirect mechanisms, one that limits hepatic very low-density lipoprotein (VLDL) production (16) and the second that enhances the clearance and fractional catabolic rate of circulating TG-rich lipoproteins (10). Furthermore, the effect of atorvastatin on apoB-containing lipoproteins, VLDLs, intermediate-density lipoproteins (IDLs), and LDLs, is mediated in part by the preferential reduction of cholesteryl ester transfer protein (CETP)-mediated cholesteryl ester (CE) transfer from high-density lipoproteins (HDLs) to apoB- containing lipoproteins and principally to large VLDL-1 particles (17).
The common hyperlipidemia of phenotype IIB is typically associated with an increased risk of premature coronary artery disease (18) and is characterized by concomitant elevation of circulating levels of atherogenic apoB-containing, TG-rich (VLDL) and cholesterol-rich lipoproteins (VLDL remnants, IDLs, and LDLs, including small dense LDLs) (19). With the objective of reducing the atherosclerotic burden in type IIB hyperlipidemia during the postprandial phase, we evaluated the impact of atorvastatin (10 and 40 mg/d) on postprandial apo B- and apoAI-containing lipoprotein subspecies and on CETP-mediated CE enrichment of TG-rich apoB-containing lipoproteins in subjects displaying this dyslipidemic phenotype.
Patients and Methods
Patients
Eleven males aged between 35 and 66 yr (mean 51 ± 3 yr) and displaying the type IIB lipid phenotype (i.e. with fasting plasma levels of cholesterol more than 6.5 mmol/liter, TGs more than 1.70 mmol/liter and less than 4.58 mmol/liter, and apoB more than 140 mg/dl) were selected for the study (Table 1
). Patients were excluded if they displayed dysbetalipoproteinemia; diabetes mellitus; secondary causes of hyperlipidemia such as uncontrolled hypothyroidism, renal impairment, or nephrotic syndrome; or known liver or muscle disease. Other exclusion criteria included uncontrolled hypertension or any major cardiovascular event (myocardial infarction, severe or unstable angina pectoris, angioplasty, or cardiovascular surgery). None of the subjects was obese (body mass index, <30 kg/m2; mean 27 ± 1) or consumed more than 17 g alcohol per day. Nine patients displayed the apoE3/E3 phenotype, one the apoE3/E4 heterozygous phenotype, and one the apoE4/E4 phenotype.
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Adverse events were recorded at each clinic visit, and 16 adverse events were reported. The most common adverse events reported were headache (n = 4) and myalgia (n = 2). The adverse events were generally mild and transient. No serious adverse events were reported, and no clinically important elevations in creatine phosphokinase and aminotransferase or aspartate aminotransferase were noted. The study was performed in accordance with the ethical principles set forth in the Declaration of Helsinki. The study protocol and amendment were reviewed and approved by an ethics committee and met national institutional requirements. Written informed consent was obtained from all patients.
Postprandial time course
Subjects were asked to abstain from alcohol and vigorous exercise for 24 h before the day of the test. For each subject, an overnight fasting blood sample was collected at 0800 h. After ingestion of a standardized breakfast (300 kcal, containing 12% protein, 70% carbohydrates, and 18% fat) at 0830 h, the subjects consumed the test meal at 1130 h. Plasma samples were obtained immediately before the test meal (baseline) and at 2, 4, and 8 h after ingestion of the meal. Blood was collected into sterile EDTA-containing tubes (final concentration of EDTA, 1 mg/ml), and plasma was separated immediately by low-speed centrifugation (2500 rpm) for 20 min at 4 C. The standardized breakfast of low caloric content was consumed by type IIB subjects 3 h before initiation of the postprandial study to avoid a metabolic background involving high free fatty acid levels and low insulin concentrations after prolonged fasting overnight. It is important to note that no significant variation in plasma TG, cholesterol, and apoB levels was detected between blood samples taken at 0800 h after an overnight fast and those obtained at baseline (1130 h), 3 h after ingestion of the standardized breakfast (Table 1
).
The test meal consisted of freshly prepared commercially available foods: instant mashed potatoes mixed with oil (two thirds sunflower oil and one third rapeseed oil), beef steak, cheese, bread, and apple. This meal represented a typical Western meal of a total 1200 kcal and consisted of 14% protein, 38% carbohydrates, and 48% fat, providing 66 g of fat and 142 mg of cholesterol (20). The fatty acid composition of this meal was as follows: 16:0, 13%; 18:1, 36.4%; 18:2, 31.8%, and 18:3, 2.2%.
Lipid and protein analyses
The lipid content of plasma and isolated lipoprotein fractions was quantified enzymatically by using kits from Roche Molecular Biochemicals (Meylan, France) for total cholesterol (TC) and free cholesterol. CE mass was calculated as (TC-FC) x 1.67 and, thus, represents the sum of the esterified cholesterol and fatty acid moieties (21). Kits from Bio-Mérieux (Marcy-l’Etoile, France) were used for determination of TGs and phospholipids. Bicinchoninic acid assay reagent (Pierce Chemical Co., Rockford, IL) was used for protein quantification. Lipoprotein mass was calculated as the sum of the mass of the individual lipid and protein components for each lipoprotein fraction. Fasting plasma LDL- cholesterol was calculated using the Friedewald formula. Plasma apoAI and apoB concentrations were determined by immunodiffusion using commercial gels (Sebia, Issy-les-Moulineaux, France). ApoE phenotype was determined by isoelectric focusing as described earlier (22).
Isolation of plasma lipoprotein subfractions
CMs (Sf >400) were isolated by centrifugation at 20,000 rpm for 45 min at 15 C using a SW41 Ti rotor in an XL70 ultracentrifuge (Beckman Instruments, Gagny, France) (20). Each plasma sample (3 ml) was overlayered with 4 ml of a d = 1.006 g/ml solution. After flotation, CMs were collected in one fraction of 2 ml. Subfractions of TG-rich lipoproteins, i.e. VLDL-1 (Sf 60–400), VLDL-2 (Sf 20–60), and IDL (Sf 12–20) were isolated from CM free plasma (2 ml) by nonequilibrium density gradient ultracentrifugation as previously described (23). LDL and HDL subfractions were isolated from CM free plasma (3 ml) by density gradient ultracentrifugation by a slight modification of the method of Chapman et al. (21) as previously described (17). With this procedure, LDLs were separated into three major LDL subclasses, light LDL (LDL-1 + LDL-2; d:1.019–1.029 g/ml), intermediate LDL (LDL-3; d:1.029–1.039 g/ml), and small dense LDL (LDL-4 + LDL-5; d: 1.039–1.063 g/ml). HDLs were separated into two major fractions, HDL-2 (d:1.063–1.110 g/ml) and HDL-3 (d: 1.110–1.179 g/ml).
Determination of CE transfer from HDL to TG-rich lipoproteins
Determination of CE transfer from HDL to TG-rich lipoproteins was assayed by modification of the method of Guérin et al. (24), which estimates net physiological CE transfer between endogenous lipoprotein donor and acceptor particles in plasma from each patient. Radiolabeled 3H-HDL were isolated from the plasma fraction (1 ml) (d > 1.063 g/ml) as previously described (24). Radiolabeled HDL preparations displayed a specific radioactivity that ranged from 5,000 to 14,500 cpm/µg CE. CE transfer was determined after incubation of whole plasma (3 ml) from individual subjects at 37 C or 0 C for 3 h in the presence of radiolabeled HDL (equivalent to 1% of the total HDL-CE mass present in 1 ml of the subject’s plasma) and iodoacetamide (final concentration 1.5 mmol/liter) for inhibition of lecithin:cholesterol acyltransferase. After incubation, CMs were isolated by ultracentrifugation at 20,000 rpm for 45 min. The plasma sample (3 ml) was overlayered with 5 ml of d = 1.006 g/ml solution. After centrifugation, CMs were collected in one fraction of 2 ml. CM free plasma (2 ml) was used to isolate VLDL-1, VLDL-2, and IDL as described above. The radioactive CE content of each isolated lipoprotein fraction was quantified by liquid scintillation spectrometry with a Rack-ß 1209. The rate of CE transfer was calculated from the known specific radioactivity of radiolabeled HDL-CE after its addition to plasma and is expressed in micrograms CE transferred per hour per milliliter plasma (24).
Statistical analysis
The data were analyzed using SAS software (SAS Institute, Cary, NC). The paired t test was applied for changes observed in plasma lipid and lipoprotein subfraction levels and on CE transfer from HDL to TG-rich lipoproteins after atorvastatin therapy. Postprandial lipemia was quantified by calculating the area under the curve (AUC) and the incremental AUC (iAUC) for plasma TG and lipoprotein subfractions. The iAUC represents the increase in area following the response of the test meal above baseline concentrations. Repeated-measure ANOVA was performed to assess changes in plasma TG levels, lipoprotein concentrations, and CE transfer from HDL to TG-rich lipoproteins during the postprandial phase. Results were considered statistically significant at P values less than 0.05. Values are given as means ± SEM.
Results
Effects of atorvastatin on fasting plasma lipid levels in type IIB hyperlipidemia
Before atorvastatin treatment (A0), all subjects displayed plasma lipid levels characteristic of the IIB phenotype as defined in the inclusion criteria in Patients and Methods (Table 1). Following atorvastatin therapy at 10 mg/d (A10) and 40 mg/d (A40) for 6 wk at each dose, we observed significant reductions in both fasting levels of plasma TG (-50%, P < 0.002 at A10 and -49%, P < 0.003 at A40) and TC (-33%, P < 0.0001 at A10 and -43%, P < 0.0001 at A40), compared with corresponding levels in the same type IIB subjects before treatment. Similar dose-dependent reductions in plasma LDL-cholesterol (-35% and -49%, P < 0.0005) and in apoB (-36% and -47%, P < 0.0001) levels were observed at 10 mg and 40 mg atorvastatin, respectively, indicating a marked reduction in numbers of circulating atherogenic apoB-containing particles under statin therapy. No significant changes in HDL-cholesterol levels were noted, however, in atorvastatin-treated patients, whereas an increase in apo AI concentration occurred at 10 mg atorvastatin (+17%); this elevation was maintained and statistically significant (P < 0.05) at the 40-mg dose (+19%).
Effects of atorvastatin on postprandial TG levels
The net change in plasma TG level over the 8-h postprandial time course following ingestion of a typical Western meal in type IIb hyperlipidemic patients (n = 11) before (A0) and after atorvastatin (10 mg/d, A10 and 40 mg/d, A40) treatment is presented in Fig. 1. For comparison purposes, a representative postprandial time course for TGs in normolipidemic subjects is also shown. A progressive postprandial decrease in plasma TG levels occurred from 4–8 h in type IIB subjects before statin treatment; nonetheless, plasma TG concentrations remained significantly elevated in such nonstatin-treated subjects (+40%; P < 0.05) 8 h postprandially, compared with baseline levels. By contrast, after atorvastatin treatment at either 10 or 40 mg/d, TG concentrations had fallen at the 8-h time point to levels that were not significantly different from those seen before meal intake. Both the AUC and the iAUC for plasma TG from 0–8 h significantly decreased (-48% and -42%, respectively, P < 0.01) following a 6-wk period of atorvastatin therapy at 10 mg/d and by 48% and 55%, respectively (P < 0.01) after atorvastatin at 40 mg/d (Table 2). Interestingly, the iAUC from 0–2 h for plasma TG levels were significantly reduced by 38% (P = 0.019) and 43% (P = 0.016) at A10 and A40, compared with values before atorvastatin treatment (A0).
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Plasma levels of CM-TG increased in a similar manner (2.5-fold) 2 h postprandially both in the absence of statin treatment and after statin therapy at 10- and 40-mg doses (Fig. 2A). Subsequently, CM-TG levels rose progressively to attain a maximum 4 h postprandially in type IIB subjects both before statin treatment and after treatment with 10 mg statin (1.4 ± 0.2 mmol/liter and 1.1 ± 0.2 mmol/liter at A0 and A10, respectively). By contrast, at the 40-mg statin dose (A40), maximal CM-TG levels were attained earlier, i.e. 2 h after meal intake (1.0 ± 0.1 mmol/liter); in addition, plasma CM-TG levels were significantly reduced (-36%; P = 0.035) 4 h postprandially (0.9 ± 0.2 mmol/liter, A40), compared with the nontreatment level at this time point (1.4 ± 0.2 mmol/liter, A0).
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and Table 2, both the AUC and iAUC for plasma CMs from 0–8 h were significantly reduced by this statin (26% and 24%, respectively, P = 0.015 at A10; 30% and 40%, respectively, P = 0.03 at A40), whereas the iAUC for plasma CMs from 0–2 h was not influenced by lipid-lowering therapy. Effects of atorvastatin on postprandial VLDL-1 levels
As shown in Fig. 3A, baseline levels of VLDL-1-TG were significantly lower (-48%, P < 0.0005) in type IIB subjects (n = 11) following drug therapy, compared with those before treatment (A0: 0.79 ± 0.06 mmol/liter; A10: 0.41 ± 0.05 mmol/liter and A40: 0.41 ± 0.05 mmol/liter). Following atorvastatin therapy, mean reductions of 58% (P < 0.0005) in plasma VLDL-1-TG concentrations relative to levels in the same type IIB subjects before statin treatment were observed at each time point of the postprandial phase (2, 4, and 8 h). Moreover, 2 h after ingestion of the mixed meal, plasma VLDL-1-TG levels increased by 1.6-fold (P < 0.0005) in nontreated type IIB patients and by 1.3-fold (P < 0.005) in all subjects independently of statin dose.
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and in Fig. 3B, the postprandial AUC for VLDL-1 levels was significantly reduced (-47% and -51%, P < 0.0005) after a 6-wk period of statin therapy at 10 mg/d and 40 mg/d, respectively. Over the complete postprandial phase (0–8 h), the iAUC for VLDL-1 concentration was significantly reduced by 54% (P = 0.016) at A10 and 52% (P = 0.017) at A40, compared with the iAUC for VLDL-1 determined in type IIB subjects before atorvastatin therapy (A0). In addition, the iAUC from 0–2 h after meal intake for plasma VLDL-1 was significantly reduced under atorvastatin therapy by 54% (P = 0.015) at A10 and 43% (P = 0.03) at A40. These findings suggest that atorvastatin primarily acts to reduce the production rates of VLDL-1 particles during the early phase of the postprandial response. Effects of atorvastatin on postprandial VLDL-2 and IDL levels
As shown in Fig. 4, baseline VLDL-2-TG levels were reduced by 36% (P < 0.0005) at the lower dose of atorvastatin relative to nontreated type IIB subjects (0.22 ± 0.02 mmol/liter and 0.14 ± 0.01 mmol/liter at A0 and at A10, respectively) and by 41% (P < 0.0005) at the highest dose (0.13 ± 0.01 mmol/liter at A40). Furthermore, the AUC for VLDL-2 levels was significantly reduced by 38% (P < 0.005) and 46% (P < 0.0005) after a 6-wk period of atorvastatin therapy at 10 mg/d and 40 mg/d, respectively (Table 2). In addition, no significant variation in the iAUC for plasma VLDL-2 levels from 0–8 h was induced by atorvastatin therapy.
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Effects of atorvastatin on postprandial LDL and HDL subfraction levels
The effects of atorvastatin on LDL and HDL subfraction concentrations over the postprandial phase in the type IIB phenotype are presented in Table 3. The postprandial AUC for total LDL (d: 1.019–1.063 g/ml) levels was significantly reduced by 34% (P < 0.0005) and 49% (P < 0.0005) after a 6-wk period of atorvastatin therapy at 10 mg/d and 40 mg/d, respectively. Interestingly, plasma levels of each LDL subfraction, i.e. light (d:1.019–1.029 g/ml), intermediate (d:1.029–1.039 g/ml), and dense LDL (d:1.039–1.063 g/ml), were markedly reduced by atorvastatin therapy as reported earlier (25). Moreover, the most marked atorvastatin- induced reduction was observed in dense LDL after each period of drug therapy (-44% after 6 wk at 10 mg/d, P = 0.0009 and -55% after 6 wk at 40 mg/d, P = 0.0001). Over the postprandial period, minor but nonetheless significant reductions in total LDL concentrations were observed. Thus, 2 h postprandially, plasma LDL levels were significantly reduced both in the absence of statin treatment (-7%, P = 0.001) and after atorvastatin therapy at 10 mg (-7%, P = 0.02) and 40 mg (-3%, P = 0.05) doses, compared with levels before meal intake. As shown in Table 3, no significant change in fasting total plasma HDL mass or HDL-2 and HDL-3 concentrations was detected as a consequence of drug treatment. Interestingly, postprandial lipemia in our type IIB patients was associated with a minor but significant reduction (-5%, P < 0.0005) in postprandial plasma HDL levels, which resulted primarily from a significant decrease (-16%, P < 0.05) in HDL-3 levels, thereby suggesting that remodeling of HDL-3 may occur during the postprandial phase.
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Before statin treatment, the mean net postprandial transfer of radioactive CE from HDL to TG-rich lipoproteins (CMs + VLDL-1 + VLDL-2 + IDL) in our type IIB subjects was significantly increased at 4 h (+68%, P < 0.0005), compared with baseline (Fig. 5). This increment was associated with marked elevation in postprandial CE mass transferred from HDL to individual TG-rich lipoprotein subfractions: CMs (2.5-fold, P < 0.005), VLDL-1 (1.8-fold, P < 0.005), VLDL-2 (1.4-fold, P < 0.05), and IDL (1.4-fold, P < 0.05). At the 4-h postprandial time point before statin therapy, CE transfer to CMs and VLDL-1 was maximal (Figs. 6 and 7).
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), whereas rates of CE transfer from HDL to VLDL-2 and IDL were not significantly modified at baseline by statin therapy (VLDL-2: 3.8 ± 0.8, 4.1 ± 0.6, and 3.6 ± 0.4 µg CE transferred per hour per milliliter before and after atorvastatin therapy at 10 mg and 40 mg, respectively; IDL: 5.2 ± 0.9, 5.7 ± 0.6, and 6.0 ± 0.5 µg CE transferred per hour per milliliter before and after atorvastatin therapy at 10 mg and 40 mg, respectively).
Following statin treatment, the mean net postprandial transfer of radioactive CE from HDL to TG-rich lipoproteins was significantly reduced by 26% (P < 0.05) at 10 mg/d and 24% (P < 0.05) at 40 mg/d 4 h postprandially, compared with that before treatment (Fig. 5). Interestingly, after atorvastatin therapy at 10 mg/d, postprandial transfer of CE from HDL to TG-rich lipoproteins was significantly increased at 4 h by 42% (P < 0.05), compared with baseline. A similar postprandial elevation in CE transfer from HDL to total TG-rich lipoproteins (+53%, P < 0.05) was observed after atorvastatin therapy at 40 mg/d. However, this increment was exclusively associated with marked elevation in postprandial CE mass transferred from HDL to CMs (2.5-fold, P < 0.005) in atorvastatin-treated patients from both groups (A10 and A40) (Fig. 6). In addition, the postprandial rate of CE transfer from HDL to CMs increased progressively over the period from 0–4 h in type IIB subjects in all three groups (nonstatin treated, A10 and A40) and to a similar degree. Moreover, CE transfer to CMs was significantly reduced at the 8-h time point by atorvastatin (A10: -51%, P < 0.05 and A40: -53%, P < 0.05), compared with the 8-h time point before statin therapy. By contrast, the rate of CE transfer from HDL to VLDL-1 (Fig. 7), VLDL-2, and IDL (data not shown) remained essentially unchanged over the postprandial phase.
Discussion
The present study has revealed for the first time that atorvastatin, a potent HMGCoA reductase inhibitor, significantly reduces postprandial accumulation of atherogenic TG-rich lipoprotein subspecies including CMs and VLDL-1 in type IIB hyperlipidemia, a dyslipidemia frequently associated with premature atherosclerosis. Equally, we demonstrate that atorvastatin induces marked reduction in the CETP-mediated transfer of CE from HDL to VLDL-1 particles during the postprandial phase in the type IIB phenotype.
Atorvastatin treatment normalized the initial accumulation of TGs during the postprandial phase in the type IIB phenotype. Indeed, the increment in plasma TG levels during the initial period (0–2 h) of the postprandial response resembled that described for a normolipidemic population after ingestion of the same typical Western meal (20) (Fig. 1). By contrast, the decrement observed in plasma TG levels from 2–8 h appeared to be delayed in both nontreated and atorvastatin-treated type IIB patients, compared with normolipidemic subjects. Subfractionation of TG-rich lipoproteins revealed that the 0- to 8-h iAUC for plasma CMs was significantly reduced on atorvastatin therapy (-25%, P = 0.015 at A10 and -40%, P = 0.03 at A40), whereas the 0- to 2-h iAUC for plasma CMs was not influenced by lipid-lowering treatment. These observations strongly suggest that atorvastatin did not influence the intestinal production rate of CMs in our dyslipidemic subjects but may induce an acceleration of the catabolism of CMs and their remnants. In addition, the initial postprandial accumulation of CMs from 0–2 h in type IIB patients before and after statin therapy was similar to that observed in normolipidemic subjects (20) (Fig. 2B). Moreover, use of 10- and 40-mg doses indicated that atorvastatin tends to normalize the intravascular catabolism of CMs and/or CM remnants in a dose-dependent manner. These findings are entirely consistent with those previously reported by Parhofer et al. (11), who observed that atorvastatin increases catabolism of CM remnants, decreases conversion of CMs to CM remnants, or both in normolipidemic subjects without any effect on CM formation and secretion.
The iAUC for plasma VLDL-1 from 0–2 h after meal intake was significantly reduced under statin therapy (-54%, P = 0.015 at A10 and -43%, P = 0.03 at A40), suggesting that atorvastatin not only reduces but also normalizes the initial postprandial accumulation of VLDL-1 particles (Fig. 3B). Atorvastatin therapy does not therefore normalize the intravascular catabolism of VLDL-1 particles, which remains delayed in comparison with normolipidemic subjects. Nonetheless, atorvastatin can inhibit in vitro hepatic VLDL secretion by the limited availability of endogenous cellular cholesterol (25, 26).
Earlier studies of the effects of lipid-lowering drugs on postprandial lipid metabolism have revealed that reduction in postprandial lipemia is closely related to the drug-induced decrease in fasting TG concentrations (4, 5, 6, 7, 8, 11, 27, 28, 29, 30). Fibrates, which have a more pronounced effect on fasting TG levels than statins, significantly reduce postprandial triglyceridemia in dyslipidemic subjects (27, 28, 29, 30). By contrast, HMGCoA reductase inhibitors, which tend to reduce fasting TG levels to a lesser degree than fibrates, have a less reproducible effect on postprandial lipid levels (4, 5, 6, 7, 8). It has been proposed that lipid-lowering drugs may affect CM metabolism as a direct consequence of reduction in plasma VLDL levels; in this case, CM lipolysis is enhanced as a result of increased availability of lipoprotein lipase. In this context, it is relevant that our experimental procedure for the isolation of VLDL-1 (Sf 60–400) does not exclude the possibility that part of this fraction may correspond to CM remnants of intestinal origin. However, Karpe et al. (31) has demonstrated a major contribution of liver-derived, TG-rich lipoproteins to postprandial triglyceridemia. Indeed, these authors observed that the intestinally derived apoB48-containing Sf 60–400 fraction accounted for less than 20% of the total postprandial Sf 60–400 fraction and that at least 80% of lipoprotein particles isolated in the Sf 60–400 fraction at the postprandial peak corresponded to liver-derived apoB100-containing lipoprotein particles in both normotriglyceridemic and hypertriglyceridemic subjects (31).
Interestingly, we observed a dose-dependent effect of atorvastatin on postprandial LDL and its subfractions (Table 3), whereas no major difference between the two doses of atorvastatin used was detected in postprandial levels of TGs, CMs, or VLDL and its subfractions. HMGCoA reductase inhibitors such as atorvastatin act primarily in the liver by inhibiting de novo cholesterol synthesis, which results in an up-regulation of the expression of the cellular LDL receptor (32). A dose-dependent reduction of LDL-cholesterol has been demonstrated with doses of atorvastatin up to 80 mg/d, whereas doses from 80–160 mg/d do not result in any further reduction in LDL-cholesterol levels; these findings suggest a plateau effect indicative of maximal inhibition of cholesterol synthesis at a dose of 80 mg/d (33). Therefore, the observed dose-dependent effect of atorvastatin on postprandial LDL and its subfractions may result from an enhanced removal of circulating LDL particles via a dose-dependent up-regulation of hepatic LDL receptors.
Finally, we presently demonstrate that CETP-mediated CE transfer to TG-rich lipoprotein particles, and notably to CMs and VLDL-1, is enhanced during postprandial lipemia in type IIB hyperlipidemia as a result of an elevation in their mass and particle number. By this mechanism, the formation and accumulation of potentially atherogenic CE-enriched lipoprotein particles, primarily involving CMs and VLDL-1, are enhanced in the postprandial phase in type IIB hyperlipidemia. In addition, our data indicate that atorvastatin treatment significantly reduces CE transfer from HDL to VLDL-1 particles during the postprandial phase. We therefore conclude that atorvastatin reduces postprandial formation and accumulation of potentially atherogenic TG-rich lipoprotein subspecies, which primarily include CMs and VLDL-1, and acts to normalize the intravascular remodeling of postprandial TG-rich lipoprotein particles via reduction in CE transfer from HDL in type IIB hyperlipidemia. In acting to potentiate the normalization of the qualitative and quantitative anomalies of postprandial lipid metabolism in type IIB dyslipidemia, this potent HMGCoA reductase inhibitor therefore reduces the atherosclerotic burden in this common metabolic disorder.
Acknowledgments
We are indebted to INSERM and Pfizer, Inc. France for support of these studies.
Footnotes
This work was supported by the Association Claude Bernard (to P.E.) and a Research Fellowship from the French Ministry of Research and Technology (to W.L.G.).
Abbreviations: apo, Apolipoprotein; AUC, area under the curve; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; CM, chylomicron; HDL, high-density lipoprotein; HMGCoA, 3-hydroxy-3-methylglutaryl coenzyme TC, total cholesterol; iAUC, incremental AUC; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; TG, triglyceride; VLDL, very low-density lipoprotein.
Received February 25, 2002.
Accepted July 22, 2002.
References
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A. Kontush, P. Therond, A. Zerrad, M. Couturier, A. Negre-Salvayre, J. A. de Souza, S. Chantepie, and M. J. Chapman Preferential Sphingosine-1-Phosphate Enrichment and Sphingomyelin Depletion Are Key Features of Small Dense HDL3 Particles: Relevance to Antiapoptotic and Antioxidative Activities Arterioscler Thromb Vasc Biol, August 1, 2007; 27(8): 1843 - 1849. [Abstract] [Full Text] [PDF]
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), after a 6-wk period of 10 mg/d atorvastatin (A10, •), and after a second 6-wk period of 40 mg/d atorvastatin (A40, 
). The dotted line represents the evolution in plasma TG levels in normolipidemic subjects following consumption of the same Western meal (
, P < 0.05 and 
) and 4 h after meal intake (
) in type IIB hyperlipidemic subjects (n = 11) before (A0) and after atorvastatin at 10 mg/d (A10) or 40 mg/d (A40). Values are mean ± SEM. 
