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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION
Centre de Recherche en Nutrition Humaine, Institut National de la Santé et de la Recherche Médicale U539-Hôtel Dieu, Nantes, France (K.O., T.M., Y.Z., M.K.); Division of Clinical Nutrition, School of Medicine of Ribeirão Preto, São Paolo, Brazil (J.S.M.); Clinique d'Endocrinologie-Nutrition, Hôtel Dieu, Nantes, France (M.K., B.C.); and Pfizer Pharmaceutical Group Paris, Paris, France (H.L.)
Received January 10, 2003; accepted April 7, 2003.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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). Results of studies showing possible disturbances in LDL
metabolism are inconsistent (Howard,
1987). Previous studies have underlined that the insulin
resistance observed in type-2 diabetes is associated with an overproduction of
apoB100 containing lipoproteins and reduced LDL and VLDL catabolism
(Howard et al., 1987).
Atorvastatin is a strong competitive inhibitor of
3-hydroxy-3-methylglutaryl (HMG)-CoA reductase. In patients with familial
hypercholesterolemia and combined hyperlipidemia, the cholesterol-lowering
effects are related to reduction of LDL cholesterol and are explained either
by an increase in LDL receptor activity or by reduction of LDL apoB100
production with atorvastatin, as observed with other statins
(Aguilar-Salinas et al., 1998).
In addition to its cholesterol-lowering effect, atorvastatin also shows
significant triglyceride-lowering properties in hypertriglyceridemic subjects
(Lea and McTavish, 1997), but
conflicting results were reported concerning its effect on VLDL metabolism.
Various effect have been already reported on VLDL production with
atorvastatin: inhibiting effect in animal
(Burnett et al., 1997) or cell
models (Wilcox et al., 1999),
stimulating effect (Forster et al.,
1996) or no effect (Forster et
al., 2002) in combined hyperlipidemic subjects, and no effect in
insulin resistant patients with no diabetes mellitus
(Chan et al., 2002). It
appears, however, that statins could have an effect on VLDL production in
situations with high VLDL production
(Aguilar-Salinas et al.,
1998).
The aim of the present study was to evaluate metabolic changes induced by atorvastatin in patients with type-2 diabetes and marked hypertriglyceridemia. This study focuses on the apoB100-containing lipoproteins (VLDL, IDL, and LDL) in diabetic patients with combined dyslipidemia. We have studied apoB100 metabolism using endogenous labeling with deuterated leucine and multicompartmental modeling to analyze lipoprotein kinetics before and after atorvastatin treatment.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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). Five
normolipidemic obese subjects matched for age and body mass index with the
diabetic patients were also studied as controls. The study subjects were
instructed by a dietician to follow a weight-maintenance diet composed of 45%
carbohydrate, 35% fat, and 20% protein for at least 1 week before study
commencement. The experimental protocol was approved by the ethical committee
of Nantes University Hospital, and written informed consent was obtained
before the study was started.
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Experimental Protocol
Diabetic patients were treated for 2 months with atorvastatin (40 mg/day).
Kinetic studies of apoB100 metabolism were performed before and after
treatment. The endogenous labeling of apoB100 was carried out by constant
infusion of [D3]leucine in subjects fasted overnight for 12 h
before the study and who continued fasting during the entire procedure
(Maugeais et al., 2001).
Each subject received intravenously a prime of 10 µmol · kg–1 of tracer immediately followed by a constant tracer infusion (10 µmol · kg–1 · h–1) for 14 h. Venous blood samples were drawn into EDTA tubes (Venoject, Paris, France) at baseline and at 15, 30, 45 min, at 1, 1.5, 2, and 2.5 h, and then hourly until 14 h. Sodium azide, an inhibitor of bacterial growth, and Pefabloc SC (Interchim, Montluçon, France), a protease inhibitor, were added to blood samples at a final concentration of 1.5 and 0.5 mM, respectively.
Analytical Procedures
Isolation and Measurement of Enrichment of Lipoprotein Containing
apoB100. VLDL1 (Svedbery flotation rate 400–60) and VLDL2 (Svedbery
flotation rate 60–20) were separated by density gradient
ultracentrifugation (Gaw et al.,
1992) using a swinging bucket rotor at 40,000 revolutions/min for
24 h at 10°C (RPS 40T; Hitachi, Hialeah, FL). IDL (1.006 < density <
1.020 g/ml) and LDL (1.020 < density < 1.063 g/ml) were separated by
standard sequential ultracentrifugation methods
(Havel et al., 1955) using a
fixed-angle rotor at 40,000 revolutions/min for 22 h at 10°C (CP70;
Hitachi).
Isolation and measurement of leucine enrichment in apoB100 have been
described previously (Maugeais et al.,
2001). Briefly, apoB100 in lipoproteins was isolated by
SDS-polyacrylamide gel electrophoresis. Apolipoprotein bands were dried under
a vacuum and then hydrolyzed. The amino acids were purified by cation exchange
chromatography, then esterified, and derivatized. Electron-impact gas
chromatography-mass spectrometry was performed on a 5891A gas chromatograph
connected with a 5971A quadrupole mass spectrometer (Hewlett-Packard Co., Palo
Alto, CA). The isotopic ratio was determined by selected ion monitoring at
m/z of 282 and 285. Calculations of apoB100 kinetic
parameters were based on the tracer-to-tracee mass ratio
(Cobelli et al., 1992).
Measurements of Lipids and apoB100. Cholesterol and triglyceride
levels were measured using commercially available enzymatic kits (Boehringer
Mannheim GmbH, Mannheim, Germany) at three different sampling times. The
apolipoprotein AI concentration in plasma was measured by immunonephelemetry
(Behring, Rueil Malmaison, France) at the same sampling times. ApoB100
concentrations were obtained in lipoprotein fractions by combining selective
precipitation and mass spectrometry (Beghin
et al., 2000). The percentage recovery of cholesterol,
triglycerides, and apolipoprotein B100 after centrifugation was higher than
85%
Modeling. Kinetic analysis of tracer-to-tracee ratios was achieved
using computer software for simulation, analysis and modeling
(Barrett et al., 1998). The
model used (Fig. 1) is adapted
from a minimal model previously developed for apoB100 metabolism in
normolipidemic subjects (Maugeais et al.,
2001), but taking into account heterogeneity in VLDL as reported
in type-2 diabetics (Tilly-Kiesi et al.,
1996), e.g., large (VLDL1) and small VLDL (VLDL2), VLDL remnants
(VLDLR), and shunt between VLDL and LDL. In this model, apoB100 enters into
plasma through VLDL secretion and direct production of IDL and LDL. ApoB100
direct removal occurs from VLDL1 [k(0,10)], VLDL2 [k(0,20)], VLDLR [k(0,11)],
IDL [k(0,30)], and from LDL [k(0,40)]. ApoB100 transfer to higher density
lipoproteins occurs by delipidation for VLDL1 [k(20,10], k[11,10)], VLDL2
[k(30,20)], k[40,20)], and IDL [k(40,30)]. The use of more complex models did
not provide significant improvement in the fitting from the F test and Akaike
information criterion (Pont et al.,
1998). A forcing function, corresponding to the time course of
plasma leucine enrichment, was used to drive the appearance of leucine tracer
into apoB100 of the different lipoprotein fractions
(Maugeais et al., 2001).
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For comparison between the three groups (controls and diabetics subjects before and after treatment) the VLDL1, VLDL2, and VLDLR data were presented as VLDL delipidation rate and VLDL fractional catabolic rate (FCR), which represents the sum of delipidation and direct removal rate. The VLDL delipidation rate was calculated as VLDL2 delipidation flux divided by total VLDL mass. The VLDL direct removal was calculated as flux of VLDL1, VLDL2, and VLDLR direct removal divided by total VLDL mass.
As all our patients are obese, pools of apoB100 in plasma or in VLDL, IDL,
and LDL were calculated by multiplying the apoB100 concentration by 0.037
(l/kg), assuming a plasma volume of 3.7% of body weight
(Dagher et al., 1965). The
apoB100 production rate in milligrams per kilogram per hour represents the
product of FCR and pool size of apoB100 in lipoprotein fractions.
Statistical Analysis
Results are reported as the mean ± standard deviation. The
Mann-Whitney-test, performed with Statview F-4.5 (Abacus Concept, Berkeley,
CA) was used. A two-tailed probability level of 0.05 or less was accepted as
statistically significant.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Treatment with atorvastatin significantly decreased triglyceridemia (246.4 ± 116.4 versus 340.0 ± 167.0 mg/dl, P < 0.05) and cholesterolemia (189.3 ± 49.4 versus 269.7 ± 31.0 mg/dl, P < 0.05). Concentration of apoB100-VLDL decreased by 30% (P < 0.05). This decrease was significant in VLDL1 (P < 0.05) and VLDL2 (P < 0.05). Treatment also significantly decreased IDL and LDL apoB100 concentration, respectively, by 30% (P < 0.05) and 40% (P < 0.05). Routine biochemical and hematological examinations were unaffected by atorvastatin administration (not shown), with no change in the body mass index, fasting plasma glucose, HOMA, or hemoglobin A1c concentrations.
Lipoproteins Kinetics. Representative curves for a control (subject C1) and for a diabetic patient (subject D2) before and after atorvastatin treatment are shown in Fig. 2. Model fitted lines and experimental points showed close agreement. Values of B100 masses in each compartment calculated with the model from steady state were in close agreement with chemically measured values (differences between predicted and measured values were of 5 to 20%, data not shown). Methods provided identified values ± standard deviation as obtained by iterative least-squares fitting for individual kinetic parameters. Standards deviation were less than 30% for most of the parameters (data not shown).
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At baseline a dramatic increase of total apoB100 production was observed in type-2 diabetic patients compared with controls (240% of controls, P < 0.005) (Table 3). This was related to a higher apoB100-VLDL production (P < 0.005), with no change for other lipoproteins. VLDL FCR was lower (67% of the controls but not significantly) related to decreased delipidation rate (one-third of the controls, P < 0.005). IDL FCR was also decreased (P < 0.005) related to a lower delipidation rate (P < 0.05). In contrast to low LDL apoB100 FCR (57% of the controls, P < 0.05), the diabetic patients had no consistent perturbations in LDL-apoB100 production compared with controls (increased in two subjects, with no change in two subjects, and decreased in three subjects).
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Treatment with atorvastatin significantly reduced overall production of apoB100 by 20% (0.91 ± 0.41 versus 1.17 ± 0.59 mg/kg/h, P < 0.05) (Table 3). This decrease was related to VLDL-apoB100 production (P < 0.05), with no significant change in direct production for IDL and LDL. The most dramatic change induced by atorvastatin treatment was the normalization of IDL and LDL FCR (2-fold increase compared with baseline, P < 0.05) with no change of VLDL FCR or delipidation rate. The increase of IDL FCR was related to significant increase of delipidation rate to LDL (P < 0.05).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Effect of Diabetes on apoB100 Metabolism. Studied type-2 diabetic
patients showed hypertriglyceridemia related to an increased VLDL
concentration (both VLDL1 and VLDL2). This was linked to a higher VLDL
production rate in all the patients and lower delipidation rate of VLDL
resulting in a low total FCR of VLDL in most of the subjects. Previous kinetic
studies have shown increased VLDL production rate in type-2 diabetes
(Kissebah et al., 1982;
Cummings et al., 1995). In rat
hepatocytes, insulin inhibits apoB100 secretion by stimulating degradation of
newly synthesized apoB100 (Sparks and
Sparks, 1990). Then, hepatic VLDL-apoB100 overproduction in type-2
diabetes could result from impaired action of insulin. In animal models,
resistance to insulin action increased intracellular stability of nascent
apoB100 and enhanced expression of microsomal triglyceride transfer protein,
which facilitated the assembly and secretion of apoB100-containing lipoprotein
particles (Taghibiglou et al.,
2000).
The observed decrease in VLDL delipidation rate compared with controls
results in normal (Cummings et al.,
1995) or lower (Kissebah et
al., 1982) FCR of VLDL. The decrease of VLDL delipidation rate
reported in type-2 diabetes (Taskinen et
al., 1990) is related to insulin resistance
(Eckel, 1989). Another
possible cause could be the physical changes of VLDL making these lipoproteins
a poor substrate for LPL (lipoprotein lipase)
(Saheki et al., 1993).
Hypercholesterolemia was related to a high concentration of LDL in all the
patients. This high concentration of LDL apoB100 was induced by a low FCR of
LDL in most of the patients compared with controls. This decrease of LDL FCR
already reported (Howard et al.,
1987) could be explained by an insulin stimulating effect on LDL
receptor activity (Taskinen et al.,
1990) and a glycosylation of LDL particles that can alter binding
to these receptors (Hiramatsu et al.,
1985).
In type-2 diabetic patients, compared with controls, VLDL was less
channeled toward conversion into LDL than direct removal (data not shown), as
previously reported in other studies
(Howard et al., 1987;
Taskinen et al., 1990). This
is related to the decreased VLDL delipidation rate discussed above. Such a
situation could explain the lack of high concentrations of LDL frequently
observed (Howard et al., 1987)
in spite of low LDL catabolism. Both perturbations with contradictory effects
on LDL concentrations could explain the inconsistent increase of LDL amount
reported in type-2 diabetes.
Effect of Atorvastatin on apoB100 Metabolism in Diabetic Subjects.
Atorvastatin treatment lowered VLDL total concentration by lowering VLDL
production rate with no change in FCR. The low VLDL delipidation rate did not
increase with treatment. This process, catalyzed by LPL
(Olivecrona and Olivecrona,
1995), appears to be associated to insulin resistance, which was
not improved by the treatment as seen by the HOMA index, which did not change
after treatment.
Atorvastatin decreased the production rate of VLDL apoB100 in spite of
insulin resistance. The production rate of VLDL is controlled by liver
cholesterol availability and particularly from de novo synthesis
(Watts et al., 1995) through
possible effect on translocation, intracellular apoB100 degradation, ACAT
activity, and microsomal triglyceride transfer protein activity
(Huff and Burnett, 1997).
Statins through their effects on HMG-CoA reductase inhibition decrease the
intrahepatic free cholesterol concentration. It has been previously reported
in cellular models that atorvastatin, but not simvastatin, decreased the
production of VLDL apoB100 (Wilcox et al.,
1999). This effect could be only observed for the most potent
statins because it was shown in animals that the magnitude of decrease in
hepatic VLDL apoB100 secretion is determined by the extent of HMG-CoA
reductase inhibition (Burnett et al.,
1999). The mechanisms possibly involved a defect of translocation
of apoB100 into the lumen of the endoplasmic reticulum, increasing by this way
the amount of apoB100 degraded within the cell
(Mohammadi et al., 1998).
Atorvastatin could decrease cholesterol synthesis and availability of
cholesterol and cholesterol ester for the normal assembly of apoB100
containing lipoprotein particles. Using lovastatin
(Arad et al., 1990;
Cuchel et al., 1997) and
pravastatin (Vega et al.,
1990), it was shown a decrease in VLDL production. Nevertheless,
it has recently been reported no atorvastatin effect on VLDL production rate
in moderate combined hyperlipidemic subjects
(Forster et al., 2002) and
insulin resistant patients with no diabetes and less marked VLDL
overproduction (Chan et al.,
2002). These apparently conflicting results could come from
studying patients with different metabolic profiles and specially different
level of VLDL production (Illingworth,
1991; Aguilar-Salinas et al.,
1998).
Opposite results were found for effect of treatment on delipidation rate of
IDL and VLDL. Delipidation process of IDL is catalyzed by hepatic lipase
(Olivecrona and Olivecrona,
1995) and was normalized by treatment. As discussed above,
activity of lipoprotein lipase appears to be modulated by insulin resistance
activity but hepatic lipase could be independent of insulin action and
essentially modulated by changes of IDL composition. Whatever the mechanisms
of the contradictory effects of atorvastatin on delipidation process, our
results suggest that delipidation rates of VLDL and IDL are not regulated by
the similar pathways, as previously reported
(Peinado-Onsurbe et al.,
1992).
The main change induced by the treatment concerned LDL. Treatment with a
statin is reported to decrease LDL production rate and/or to increase LDL
catabolism. For example, in combined hyperlipidemia
(Cuchel et al., 1997),
lovastatin decreased LDL production rate without change of catabolism. In
another form of familial combined hyperlipidemia
(Aguilar-Salinas et al., 1997),
pravastatin increased LDL FCR with no change of production rate. The same
result was reported in normolipidemic volunteers during simvastatin treatment
(Malmendier et al., 1989).
This inconsistency could result from the dose used (and potency of the statin
used) and from the studied pathological situation
(Aguilar-Salinas et al., 1998).
In the present study, atorvastatin normalized LDL concentration by normalizing
FCR through stimulating LDL receptor activity, as previously demonstrated with
simvastatin (Malmendier et al.,
1989).
In conclusion, our kinetic data demonstrated the various effects of atorvastatin on dyslipidemia in type-2 diabetes and underlined the usefulness of this treatment even in case of increase of triglycerides and moderate increase of LDL cholesterol.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: LDL, low-density lipoprotein; ApoB100, apolipoprotein B100; VLDL, very low-density lipoprotein; HMG, 3-hydroxy-3-methylglutaryl; IDL, intermediate density lipoprotein; HOMA, homeostasis model assessment; FCR, fractional catabolic rate; VLDLR, very low-density lipoprotein remnant; LPL, lipoprotein lipase.
Address correspondence to: Khadija Ouguerram, Centre de Recherche en Nutrition Humaine, INSERM U539-Hôtel Dieu, France. E-mail: khadija.ouguerram{at}sante.univ-nantes.fr
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W. L. Isley, J. M. Miles, B. W. Patterson, and W. S. Harris The effect of high-dose simvastatin on triglyceride-rich lipoprotein metabolism in patients with type 2 diabetes mellitus J. Lipid Res., January 1, 2006; 47(1): 193 - 200. [Abstract] [Full Text] [PDF]
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M. Myerson, C. Ngai, J. Jones, S. Holleran, R. Ramakrishnan, L. Berglund, and H. N. Ginsberg Treatment with high-dose simvastatin reduces secretion of apolipoprotein B-lipoproteins in patients with diabetic dyslipidemia J. Lipid Res., December 1, 2005; 46(12): 2735 - 2744. [Abstract] [Full Text] [PDF]
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M. C. Nierman, B. H.C.M.T. Prinsen, J. Rip, R. J. Veldman, J. A. Kuivenhoven, J. J.P. Kastelein, M. G.M. de Sain-van der Velden, and E. S.G. Stroes Enhanced Conversion of Triglyceride-Rich Lipoproteins and Increased Low-Density Lipoprotein Removal in LPLS447X Carriers Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2410 - 2415. [Abstract] [Full Text] [PDF]
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K. Ouguerram, M. Chetiveaux, Y. Zair, P. Costet, M. Abifadel, M. Varret, C. Boileau, T. Magot, and M. Krempf Apolipoprotein B100 Metabolism in Autosomal-Dominant Hypercholesterolemia Related to Mutations in PCSK9 Arterioscler. Thromb. Vasc. Biol., August 1, 2004; 24(8): 1448 - 1453. [Abstract] [Full Text] [PDF]
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), VLDL2 (*), IDL (
) and LDL (+).