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Effects of Atorvastatin on the Clearance of Triglyceride-Rich Lipoproteins in Familial Combined Hyperlipidemia

Department of Internal Medicine, St. Franciscus Gasthuis Rotterdam (M.C.C.), 3004 BA Rotterdam, The Netherlands; University Medical Center (M.C.C., S.M., D.W.E.), 3508 GA Utrecht, The Netherlands; Department of Nephrology, Leiden University Medical Center (C.V.), 2333 ZA Leiden, The Netherlands; and Department of Clinical Chemistry and Internal Medicine, Erasmus Medical Center (H.J.), 3000 DR Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. M. Castro Cabezas, Department of Internal Medicine, St. Franciscus Gasthuis Rotterdam, P.O. Box 10900, 3004 BA Rotterdam, The Netherlands. E-mail: m.castrocabezas{at}sfg.nl.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Familial combined hyperlipidemia (FCHL) patients have an impaired catabolism of postprandial triglyceride (TG)-rich lipoproteins (TRLs). We investigated whether atorvastatin corrects the delayed clearance of large TRLs in FCHL by evaluating the acute clearance of Intralipid (10%) and TRLs after oral fat-loading tests. Sixteen matched controls were included. Atorvastatin reduced fasting plasma TG (from 3.6 ± 0.4 to 2.5 ± 0.3 mM; mean ± SEM) without major effects on fasting apolipoprotein B48 (apoB48) and apoB100 in large TRLs. Atorvastatin significantly reduced fasting intermediate density lipoprotein (Svedberg flotation, 12–20)-apoB100 concentrations. After Intralipid, TG in plasma and TRL showed similar kinetics in FCHL before and after atorvastatin treatment, although compared with controls, the clearance of large TRLs was only significantly slower in untreated FCHL, suggesting an improvement by atorvastatin. Investigated with oral fat-loading tests, the clearance of very low density lipoprotein (Sf20–60)-apoB100 improved by 24%, without major changes in the other fractions. The most striking effects of atorvastatin on postprandial lipemia in FCHL were on hepatic TRL, without major improvements on intestinal TRLs. Fasting plasma TG should be reduced more aggressively in FCHL to overcome the lipolytic disturbance causing delayed clearance of postprandial TRLs.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
FASTING PLASMA HYPERTRIGLYCERIDEMIA is closely associated with the delayed postprandial clearance of chylomicrons and their remnants (1, 2, 3, 4, 5), as shown by Nestel 4 decades ago (6). One of the contributing factors is competition of chylomicrons and very low density lipoproteins (VLDL) for the same clearance mechanism (7, 8). The key factor in this catabolic process is lipolysis of triglyceride (TG)-rich lipoproteins (TRLs) by lipoprotein lipase (LPL), followed by receptor-mediated removal from the circulation (1). In addition, nonreceptor-dependent processes are involved, such as binding of TRLs and their remnants to proteoglycans (9).

Patients with familial combined hyperlipidemia (FCHL) characteristically show an increased production of hepatic VLDL, in part caused by enhanced hepatic free fatty acid (FFA) delivery (10, 11), and a decreased clearance of postprandial TRLs (4, 11, 12). The increased pool of VLDL has been held responsible for the delayed clearance of postprandial TRLs, causing enhanced postprandial lipemia in FCHL (4, 12). Other factors, such as plasma apolipoprotein CIII (apoCIII) (4) and an impaired response of postprandial complement component 3 (13), have been implicated in the delayed clearance of chylomicrons and their remnants in FCHL.

Reduction of fasting plasma TG usually results in improvement of postprandial lipemia in FCHL (4, 14, 15) and non-FCHL (16, 17, 18, 19, 20) subjects. It is believed that by reducing the pool of plasma VLDL, the catabolism of chylomicrons is enhanced, explaining the increased postprandial clearance of these lipoproteins.

Significant decreases in fasting plasma TG in FCHL have been achieved by monotherapy with statins (4, 14, 21), fibrates (21, 22, 23), or combinations of both (14, 24, 25). Atorvastatin is a potent inhibitor of hepatic cholesterol synthesis, which has been shown to inhibit the secretion of VLDL, thereby explaining the effective reduction of fasting plasma TG (26, 27, 28). Atorvastatin treatment has been shown to improve postprandial lipemia in animal models (29), in healthy subjects (30), and in patients with combined hyperlipidemia (17). We have investigated whether the acute clearance of large TRLs improves in FCHL after reduction of fasting plasma TG. For this purpose, FCHL subjects underwent an acute iv and an oral fat-loading test before and after treatment with atorvastatin, and TG kinetics were obtained.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

The independent ethics committee of University Medical Center Utrecht approved the study protocol, and written informed consent was obtained from each participant. Eighteen unrelated and untreated FCHL patients fulfilled the following criteria. They were known to have primary hyperlipidemia, and they all had elevated plasma apoB concentrations (>1.20 g/liter) when untreated. At least one first degree relative had a different hyperlipidemic phenotype, and each index subject had a positive family history of premature coronary heart disease defined as myocardial infarction or cerebrovascular disease before the age of 60 yr. In addition, the patients fulfilled the following inclusion criteria: absence of xanthomas and secondary factors associated with hyperlipidemia (such as disorders of thyroid, renal, or liver function and diabetes), body mass index (BMI) less than 30 kg/m², absence of apoE2/E2 genotype, and no use of more than 3 U alcohol/d.

Sixteen normolipidemic, healthy volunteers without a family history of cardiovascular disease, absence of apoE2/E2 genotype, BMI less than 30 kg/m², no use of more than 3 U alcohol/d, and not using drugs known to affect lipid metabolism were recruited by advertisement. Controls were matched to FCHL patients by age, waist to hip ratio, and BMI.

Treatment period

All FCHL patients stopped taking lipid-lowering drugs 4 wk before the first fat load, but they continued their usual low fat, low cholesterol diet. The FCHL patients were treated for 16 wk with atorvastatin. The initial dose of atorvastatin was 10 mg once daily. Every 4 wk, the patients visited the out-patient clinic, and fasting plasma TG and cholesterol were measured. When plasma TG concentrations were above 2 mM, and/or cholesterol levels were above 6.5 mM, the atorvastatin dose was doubled, up to a maximum dose of 80 mg after 12 wk. After 16 wk of atorvastatin, a second iv fat-loading test was performed. Control subjects received no treatment and underwent the fat-loading tests only once.

Intravenous fat loading test

Intralipid (10%; Pharmacia Biotech, Uppsala, Sweden) was used as the fat source; this emulsion is to some extent chylomicron-like, because its lipid droplets have a size and metabolic fate similar to those of chylomicrons (31). After an overnight fasting period of 12 h, Intralipid was given in a bolus of 0.1 g/kg body weight in one arm. Peripheral blood samples were obtained in sodium EDTA (2 mg/ml) before (–5 and 0 min) and at 1, 2, 3, 5, 10, 15, 20, 30, 40, 50, and 60 min after the bolus injection from the other arm.

Oral fat-loading test

All subjects visited our department after a 12-h fast and underwent a standardized oral fat-loading test containing 50 g fat and 3.75 g dextrose/m² body surface. After ingestion of the fat load, subjects were only allowed to drink water and sugar-free tea during the following 24 h. Peripheral blood samples were obtained in sodium EDTA (2 mg/ml) before the meal (0 h), at hourly intervals until 10 h after the meal, and at 12 and 24 h.

Analytical methods and laboratory techniques

Blood was placed on ice and centrifuged immediately for 15 min at 800 x g at 4 C. After centrifugation, a protease inhibitor was added to the plasma (final concentrations, 0.96 mg/ml EDTA, 1.25 mg/ml 6-aminohexanoic acid, 9.63 U/ml aprotinin, 0.05 mg/ml gentamicin, and 1 µg/ml sodium azide). Tetrahydrolipstatin (Roche, Basel, Switzerland) was also added to plasma that was used for FFA measurements to a final concentration of 1 mg/liter to prevent in vitro lipolysis (11). Plasma samples were stored at –20 C immediately after centrifugation. ApoE genotypes were determined as described previously (11, 12). TG and cholesterol were measured in duplicate by a commercial colorimetric assay (GPO-PAP and CHOD-PAP, respectively, Roche). High density lipoprotein (HDL) cholesterol was determined using the phosphotungstate/MgCl₂ method. TG-rich lipoproteins were subfractionated by ultracentrifugation as described in detail previously (12). Total plasma apoB and low density lipoprotein (LDL)-apoB were quantitated by immunoturbidimetry (11, 12). TRL-apoB was quantitated by gel electrophoresis and scanning as described previously (12). ApoAI was measured by nephelometry using apoAI monoclonal antibodies (OUED 14/15, Dade Behring Diagnostics NV, Leusden, The Netherlands). FFA were measured by a commercial enzymatic colorimetric assay (Wako Pure Chemical, Neuss, Germany) (11, 12). Postheparin LPL and hepatic lipase activities were determined by the release of FFA from ¹⁴C-labeled trioleoyl emulsion. Lipolytic activity is expressed as nanomoles of FFA per minute (milliunits) per milliliter of plasma.

Kinetic analyses

The apparent elimination half-life time (t_1/2) was calculated by applying the equation t_1/2 = ln²/elimination constant (Ke). The Ke was calculated by linear regression from the ln-transformed data on at least three points of the downslope of the curve, assuming first order kinetics.

Statistical methods

All values are expressed as the mean ± SEM. The absolute area under the curve (AUC) was calculated by the trapezoidal rule. Incremental AUCs were calculated after correction for fasting concentrations. Mean differences between FCHL subjects and controls were calculated by independent samples t test. Mean differences between untreated and treated FCHL subjects were calculated by paired samples t test. Differences in fasting TG values between FCHL and controls were calculated by Mann-Whitney U test. Changes in time were calculated by repeated measures ANOVA with least significant difference as the post hoc test. Statistical significance was reached at P < 0.05 (two-tailed test). Statistical calculations were performed using SPSS 10.0 (SPSS, Inc., Chicago, IL). Calculations of AUCs were performed with PRISM version 3.0 (GraphPad, Inc. San Diego, CA).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
General characteristics (Table 1)

FCHL patients and matched controls had similar anthropometric characteristics according to the inclusion criteria. Fasting plasma concentrations of TG, cholesterol, and apoB were significantly higher in untreated FCHL patients compared with controls. Plasma apoAI was significantly lower in FCHL. Fasting plasma FFA concentrations and HDL cholesterol were similar in both groups (Table 1). Fasting plasma insulin levels were higher in FCHL subjects (before and after atorvastatin), suggesting insulin resistance compared with controls.

Effects of atorvastatin treatment (Tables 1 and 2)

After 4 wk of treatment, all patients were using 10 mg atorvastatin; after 8 wk, six patients used 10 mg, and 12 patients used 20 mg atorvastatin. After 12 wk, four patients used 10 mg, five patients used 20 mg, and nine patients used 40 mg atorvastatin. After 16 wk of treatment, two patients used 10 mg, six patients used 20 mg, one patient used 40 mg, and nine patients used 80 mg atorvastatin.

Overall, FCHL had higher concentrations of TG, cholesterol, apoB100, and apoB48 than controls in all TRL fractions, and treatment did not affect these differences (Table 2). The cholesterol content in all TRL fractions decreased significantly, except in the largest Sf (Svedberg flotation) >400 fractions, without reaching the levels in controls. No significant changes were observed in fasting apoB100 or apoB48 in the three largest TRL fractions after treatment in FCHL. In Sf12–20, apoB100 was significantly reduced by 30% without any significant changes in apoB48.

TG kinetics after Intralipid in plasma and TRL (Figs. 1 and 2 and Table 3)

In both groups, maximal TG concentrations were reached 1 min after the bolus injection of Intralipid, followed by a gradual decline (Fig. 1A). The maximal concentration of plasma TG was higher in FCHL, before and after treatment (Table 3). Plasma FFA were not changed after atorvastatin in FCHL, and the curve was similar to that in the controls. Plasma cholesterol levels did not change after injection of Intralipid in any of the groups, but in FCHL the curve reached similar levels to controls after atorvastatin.

View larger version (15K): [in this window] [in a new window]   FIG. 1. Mean (±SEM) plasma changes during the iv fat load in TG (A), FFA (B), and cholesterol (C) in FCHL subjects before (•) and after () atorvastatin treatment and in controls ().

View larger version (15K): [in this window] [in a new window]   FIG. 2. Mean (±SEM) changes in TG in Sf>400 (A), Sf60–400 (B), and Sf20–60 fractions (C) in FCHL subjects before (•), and after () atorvastatin treatment and in controls ().

There were no major changes in plasma or chylomicron TG kinetics in FCHL patients after therapy compared with the untreated situation. The half-time, which was used as an estimation of the clearance rate of large TRLs, did not improve significantly in FCHL patients after atorvastatin treatment (Table 3); however after atorvastatin, plasma and chylomicron half-times did not reach statistical significance compared with the controls.

TG, cholesterol, and apoB kinetics after an oral fat load in plasma and TRL (Figs. 3–5 and Table 4)

Treatment with atorvastatin resulted in significantly decreased total postprandial plasma triglyceridemia when evaluated by oral fat-loading tests (Figs. 3 and 4 and Table 4), but there was no significant difference in incremental plasma triglyceridemia (data not shown). Atorvastatin treatment did not improve the postprandial TG and cholesterol changes in the separate lipoprotein fraction, and the AUCs remained elevated compared with controls. The clearance of apoB100 and apoB48 in each TRL fraction did not change significantly after atorvastatin, with the exception of Sf20–60-apoB100, which improved by 24%, although it remained elevated compared with control values (Fig. 5 and Table 4). Analyses of the incremental areas of the TRLs revealed overall similar results as the absolute areas, albeit without reaching statistical significance in most comparisons between patients and controls (data not shown).

View larger version (15K): [in this window] [in a new window]   FIG. 3. Mean (±SEM) changes during the oral fat load of TG in plasma (A), Sf>400 (B), Sf60–400 (C), and Sf20–60 fractions (D) in FCHL subjects before (•) and after () atorvastatin treatment and in controls ().

View larger version (14K): [in this window] [in a new window]   FIG. 4. Mean (±SEM) changes during the oral fat load of cholesterol in plasma (A), Sf>400 (B), Sf60–400 (C), and Sf20–60 (D) in FCHL subjects before (•) and after () atorvastatin treatment and in controls ().

View larger version (20K): [in this window] [in a new window]   FIG. 5. Mean (±SEM) changes during the oral fat load in apoB48 in Sf>400 (A), Sf60–400 (B), and Sf20–60 fractions (C) and in apoB100 in Sf>400 (D), Sf60–400 (E), and Sf20–60 fractions (F) in FCHL subjects before (•) and after () atorvastatin treatment and in controls ().

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

We were able to significantly reduce the total fasting plasma TG concentrations in FCHL, which was a consequence of small (nonsignificant) TG reductions in all TRL fractions. This small effect on total plasma TG by atorvastatin may be the reason for the lack of improvement in acute clearance of TRLs, which we had anticipated. It was expected that by reducing the amount of TRLs competing for the same clearance mechanism (essentially the lipolytic pathway represented by LPL), the clearance of TRLs would be enhanced. Several explanations are possible. Defects in the lipolytic cascade in FCHL may play a role. However, in vitro studies using TRLs from FCHL patients did not describe abnormal lipolysis compared with controls (34). A decade ago, our group showed that the postprandial clearance of chylomicron remnants in FCHL was closely associated with plasma apoCIII levels (4). Subsequently, other studies showed the importance of apoCIII in the phenotypic expression of FCHL (35). Because apoCIII is an inhibitor of lipolysis by LPL, this could be one of the defects involved in the persistent clearance defect of TRLs in vivo. However, it has been shown that the apoCIII content per particle is normal in FCHL compared with controls (34). Recent studies have clearly shown that the apoCI content of lipoproteins is closely associated with remnant clearance, and this may be a potential marker to detect subjects at risk of coronary artery disease (36). Future studies should address this issue in FCHL patients. Finally, the reduction of total plasma triglyceridemia by atorvastatin without changes in the large TRLs can be explained by the effect of the treatment on the Sf12–20 fraction. This was the only fraction in which a significant reduction of fasting lipoprotein mass (estimated by apoB100) was achieved by atorvastatin. Most likely, similar reductions may have occurred postprandially, although we did not quantitate this fraction in the postprandial samples.

Defective LPL activity and the genetic variance in the LPL gene have also been linked to FCHL and its phenotype (37, 38, 39, 40). In this study, the lipolytic activities were not changed after atorvastatin, and the individual lipolytic data did not show any major defects in FCHL compared with controls. Moreover, the plasma FFA curves in FCHL and controls were similar, and treatment did not change the response pattern in FCHL. Therefore, impaired lipolysis does not seem to explain the greater half-time for plasma TG and the largest TRL in FCHL. Another point of interest is the fact that the mean LPL activities in FCHL after atorvastatin reached levels significantly lower than those in controls, suggesting that treatment may have affected this enzyme. This effect has not been reported previously and deserves more attention.

Our results are in contrast with those reported by Boquist et al. (17) in 16 patients with premature atherosclerosis and combined hyperlipidemia. These researchers showed significant reductions of fasting TG in all lipoprotein fractions after atorvastatin (40 mg) treatment. In our 18 FCHL patients, TG concentrations were only significantly reduced in plasma, both fasting and postprandially, but the concentrations in the separate large TRLs did not change significantly fasting. Postprandial TRL cholesterol concentrations decreased significantly, suggesting that atorvastatin has a greater effect on the cholesterol content of TRL in FCHL, with a lesser effect on TG content. This may be specific for FCHL, because two different studies have now reported a reduction of TG in TRL fractions (mainly VLDL) in combined hyperlipidemia with atherosclerosis (17, 41) and in one animal model (42). In one study of six combined hyperlipidemic patients, a trend toward lowered VLDL-TG was reported without reaching significance (43). In addition, in a recent report describing the effect of atorvastatin on the clearance of chylomicron-like emulsions in a similar number of patients with atherogenic dyslipidemia, a significantly enhanced clearance of particles and TG was described (44), supporting the view that the results reported in the current paper may be specific for FCHL.

The most striking effects of atorvastatin in FCHL were on the hepatic TRLs. Atorvastatin appeared to have lesser effects on the intestinal lipoproteins, as reflected by the almost unchanged apoB48 data.

Finally, the decrease in fasting plasma TG achieved in the FCHL subjects was statistically significant but clinically less relevant, because fasting TG levels were still significantly higher than in controls. The treatment of FCHL subjects is difficult; especially, fasting plasma TG usually do not normalize after therapy (4, 14, 15, 21, 22, 23, 24, 25).

The lack of improvement in acute TRL clearance may in part have been caused by the insufficient decrease in fasting plasma TG and the elevated TG content of the large TRLs in FCHL. It is likely that the common lipolytic pathway (7, 8) was still overloaded in this situation. It remains to be investigated whether normalization of fasting plasma TG achieved by more aggressive interventions, such as combination therapy with fibrates or other TG-lowering interventions, will significantly improve postprandial TG metabolism in FCHL. Novel interventions directed to improve TG metabolism and reduce the TG content of TRLs in FCHL are needed.

	Acknowledgments

 
This paper is dedicated to the memory of Willem Erkelens, our beloved friend and colleague.

	Footnotes

 
This work was supported by an unrestricted educational grant from Pfizer, Inc.

Abbreviations: apo, Apolipoprotein; AUC, area under the curve; BMI, body mass index; FCHL, familial combined hyperlipidemia; FFA, free fatty acid; HDL, high density lipoprotein; LDL, low density lipoprotein; LPL, lipoprotein lipase; Sf, Svedberg flotation; TG, triglyceride; TRL, triglyceride-rich lipoprotein; VLDL, very low density lipoprotein.

Received July 31, 2003.

Accepted September 7, 2004.

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