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,
2
*
INSERM U-325, 59019 Lille, France;
Département d'Athérosclérose, Institut Pasteur de Lille, 59019 Lille, France;
**
Laboratoire de Lipochimie Alimentaire, ISTAB, Université Bordeaux I, 33 405 Talence, France; and
INSERM U-508, 59019 Lille, France
2To whom correspondence should be addressed: Dr Jean Dallongeville, Département d'Athérosclérose, Institut Pasteur de Lille, 1 rue du Professeur Calmette, 59019 Lille Cedex, France.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • apolipoprotein E-deficient mice • atherosclerosis • diet • lipoprotein • Pinus pinaster oil
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The current guidelines recommend lipid intake to be
limited to 30% of the energy needs with 7% saturated, 14%
monounsaturated and 9% polyunsaturated fatty acids in the diet
(National Cholesterol Education Program 1994
). Numerous
studies in experimental animals clearly demonstrated that oils which
differ in their fatty acid composition have unequal lipid-lowering
properties (Chang and Huang 1999
, Harris 1997
, Hayes and Khosla 1992
, Jeffery et al. 1997
, Lu et al. 1996
). The identification of
new sources of oil with beneficial potential for health might help to
promote and improve compliance to lipid-lowering diets in humans.
The Mediterranean diet and olive oil have been favorably considered in
the medical community and received much attention for their potential
benefit in cardiovascular disease prevention (Kushi et al. 1995a
and Kushi et al. 1995b
).
Conifer seeds such as Pinus koraiensis, P.
cembra, P. cembroides, P. edulis, P.
pinea, P. sibirica and P. monophylla seeds
are currently consumed as condiments in food preparation (Nuts 1995
, Wolff and Bayard 1995b
). Recent studies
indicate that oils extracted from some of these conifer seeds have
substantial lipid-lowering potential in rodents (Ikeda et al. 1992
, Sugano et al. 1994
). Earlier studies
in rats showed that P. pinaster (maritime pine) seed oil
(Wolff 1995a
) lowers triglycerides,
VLDL-triglycerides and VLDL-cholesterol compared to a diet
enriched in oleic acid (Asset et al. 1999
). The latter
findings indicated that P. pinaster seed oil may be useful in lipid-lowering diets.
Transgenic animals expressing targeted alterations of lipoprotein
metabolism have proven fruitful models to the investigation of
lipoprotein metabolism and atherosclerosis (Breslow 1996
, Paigen et al. 1994
). In this respect,
apolipoprotein E (apo E)-deficient mice show markedly elevated plasma
cholesterol due to the accumulation of VLDL + IDL3
in their bloodstream (Nakashima et al. 1994
,
Plump et al. 1992
, Plump and Breslow 1995
, Zhang et al. 1992
). These particles are
mainly cholesterol-rich remnants of chylomicron and VLDL. Apo
E-deficient mice develop atherosclerotic lesions of all phases of
evolution throughout the arterial tree (Nakashima et al. 1994
, Plump 1997
, Zhang et al. 1992
).
The goal of our study was to assess whether P. pinaster seed oil could prevent atherosclerosis. To this end, the lipid-lowering and antiatherogenic properties of P. pinaster seed oil were assessed in apo E-deficient mice. This animal model was chosen because it develops aortic lesions that resemble those of humans.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Studies were performed with apo E-deficient mice (Zhang et al. 1992
). These mice were obtained in C57BL/6J background
after multiple back-crosses (Transgenic Alliance; IFFA CREDO,
L'Arbresle, France). They were acclimated for 1 wk under conditions of
controlled temperature (20 ± 1°C) and lighting (dark from 2000–0800 h) in a room of low background noise before dietary studies.
Dietary experiments in apoE-deficient mice.
Before each dietary experiment, a blood sample was drawn for group
assignment based on cholesterol levels. Mice were housed in cages (2–3
per cage) and were given free access to a fat-free semipurified
diet4
(UAR, Villemoisson sur Orge, France) which was supplemented with either
lard (Eurogat, Saint Denis, France), P. pinaster oil
(D'ANOSTE, Vendays-Montalivet, France) or sunflower oil (BERTIN,
Lagny le Sec, France) according to the experimental design (Table 1
). Lard was used as control diet to mimic the Western-type diet. Mice
of similar age (±1 wk) were used in each experiment. Weight gain was
monitored throughout the studies.
|
Histological studies and comparison with Sunflower oil.
To assess whether P. pinaster oil supplementation protects
against atherosclerosis, a long-term comparative study with
sunflower oil and lard was carried out in 9-wk-old apoE-deficient
mice, at a time when atherosclerotic lesions were mild
(Nakashima et al. 1994
). Thirty mice, 10 females per
group, were fed either lard, sunflower oil or P. pinaster
oil (10 g/100 g) for 4 mo. At the end of the dietary intervention, mice
were food-deprived for 4 h and were exsanguinated under
diethylether anesthesia by cardiac puncture. The heart and vascular
tree of each mice were perfused in situ with 9 g/L saline, dissected
and stored in 10% formaldehyde solution until they were processed.
Kinetic studies of triglycerides. To investigate the mechanism underlying triglyceride concentration changes, triglyceride production and fractional catabolic rates were determined using Triton WR1339. Thirty female apoE-deficient 8-mo-old mice (10 per group) were supplemented for 3 wk with lard, sunflower or P. pinaster oil (10 g/100 g). At the end of the dietary intervention, mice were food-deprived for 4 h and the kinetic study was started.
Lipoprotein separation and measurements.
Plasma was separated by centrifugation (630 x g) for
20 min at 4°C. VLDL + IDL were separated by ultracentrifugation,
using a Beckman TL100 ultracentrifuge (Beckman Instruments France SA,
Gagny, France), from 150 µL of plasma by a single centrifugation at
density 1.019 kg.L-1 (Traber et al. 1987
).
Briefly, 850 µL of 1.019 kg.L-1 KBr solution and 6 µL
of 1.34 kg.L-1 KBr solution was added to 150 µL of
plasma and centrifuged in a polycarbonate tube (400,000 x g, 10°C) with a Beckman TLA-100.2 rotor (Beckman
Instruments France SA) during 2.5 h (Brousseau et al. 1993
). The tube was sliced and the remaining 300 µL infranate
fraction (d > 1.019 kg.L-1) was analyzed for lipids.
Lipids concentration in the VLDL fraction (d < 1.019
kg.L-1) were determined by subtracting infranate values
from total plasma values according to the Lipid Research Clinic
protocol (Lipid Research Clinics Program 1974
). Lipids
were determined enzymatically using commercially available kits for
triglycerides (Triglycerides GPO-PAP; Boehringer Mannheim, Mannheim,
Germany), cholesterol (Cholesterol C System, Boehringer Mannheim) and
phospholipids (Phospholipids PAP 150; BioMérieux, Lyon, France).
To assess the lipid composition of the VLDL + IDL fraction, a
sample of the d < 1.019 kg.L-1 lipoprotein fraction
was kept for lipid analyses. The results of lipid composition are
expressed in relative terms (percentage of total lipids). To assess
whether dietary oil supplementation normalizes the lipid composition of
apoE-deficient mice lipoproteins, the VLDL + IDL lipid
composition of 10 male C57BL/6 wild-type mice was determined for
comparison.
Gel filtration chromatography.
Gel filtration chromatography was performed using a Superose 6 HR 10/30 column (Pharmacia; Pharmacia LKB Biotechnology, S-751 82 Uppsala, Sweden). The gel was allowed to equilibrate with phosphate buffered saline (10 mmol/L) containing 0.1 g/L of EDTA and 0.1 g/L of sodium azide; 200 µL of plasma were eluted with the buffer at room temperature at a flow rate of 0.2 mL.min-1. Elution profiles were monitored at 280 nm and recorded with an analog-recorder chart tracing system (Pharmacia; Pharmacia LKB Biotechnology). The effluents were collected in 0.24 mL fractions. Triglycerides or cholesterol were measured in each collected fraction using commercially available enzymatic kits (Triglycerides GPO-PAP or Cholesterol C System, Boehringer Mannheim).
Agarose gel electrophoresis.
Agarose gel electrophoresis was performed according to Noble
(Noble 1968
) with a Beckman Paragon system (Beckman
Instruments France SA). Briefly, plasma (5 µL) was applied on a 0.5%
agarose gel (Paragon LIPO lipoprotein electrophoresis; Beckman
Instruments France SA). Electrophoresis was performed for 30 min in a
barbital buffer (pH 8.6) at 100 V. Gels were stained with Sudan black
B.
Measurement of fatty streak lesions.
The hearts were sectioned just below the atria. The base of the heart
plus the aortic root were taken for analysis. Tissue was dipped
overnight in OCT liquid (Tissue-Tek; Sakura Finetek U.S.A., Torrance,
CA). The following day, the heart was placed in fresh OCT liquid on a
cryostat plate (Cryostat 3050; Leïca microsystémes S.A.,
Rueil-Malmaison, France) with the apex of the heart facing the
plate and frozen at -25°C. The heart was sectioned perpendicular to
the axis of the aorta and working in the direction of the apex of the
heart. Each 10-µm section was mounted on gelatinized slides until the
disappearance of aortic valve leaflets. Sections were air-dried
overnight and rinsed briefly in 60% isopropyl alcohol. Sections were
then stained with oil red O, counter stained with Harris haematoxylin
and sealed with aquamount Gurr®. A total of 10 sections was used for
quantification of atherosclerosis lesions. By definition, the first
section used for quantification was the one that allows the
identification of two leaflets on the apex side of the heart. The next
section was the one located 100 µm toward the base and so on up to a
total of 10 sections. Each section was recorded using a Nikon
microscope (Diaphot; Nikon France S.A, Champigny sur Marne, France) and
a color video camera (Sony CCD IRIS DXC 107 AP; SONY France, Paris,
France). Color images were acquired using a PC fitted with a
framegrabbing board (Snappy, Video Snapshot; HCS MISCO, Verri
es
le Buisson, France). Quantification of atherosclerosis lesion areas was
performed using Scion Image software.
In vivo hepatic triglycerides production using Triton WR1339.
Each mouse was injected in the tail vein with 500 mg/kg body weight of
Triton WR1339 (Sigma-Aldrich Chimie, Saint Quentin Fallavier, France)
as a 150 g/L solution in 9 g/L NaCl as described (Li et al. 1996
). Blood samples of 100 µL were drawn before Triton
WR1339 injection and at 10, 15, 30, 45 min after. Plasma triglycerides
were measured in each sample. Triglyceride production and fractional
catabolic rate were calculated as described previously (Naka et al. 1998
) after adjusting for mice weight. Results are
expressed as triglyceride secretion rate (PR, mg.h-1) and
fractional catabolic rate (FCR, pool.h-1).
Lipolysis.
At 0800 h, 8 nonpurified diet-chow-fed C57BL/6 wild-type mice were given intragastrically a bolus of 600 µL lard or P. pinaster oil, and blood samples were taken 2 h after. Triglyceride-rich lipoproteins (TRL: d < 1.006 kg/L) were isolated by ultracentrifugation from the pooled plasma. C57BL/6 wild-type were used for this experiment because their VLDL are relatively enriched in triglycerides compared to VLDL from apoE-deficient mice. TRL were incubated at four concentrations (range 0.06–0.35 mmol/L) for 5 min at 37°C in a 200 µL final volume of solution containing: 0.1 mol/L Tris/HCl, pH 8.5, 12 g/L Nonesterified Fatty Acid-free BSA (Sigma-Aldrich Chimie) and 0.27 unit of commercial bovine lipoprotein lipase (E.C. 3.1.1.34; Sigma Diagnostics, St. Louis, MO). The reaction was stopped by the addition of 100 µL of ice-cold stop-buffer (50 mmol/L KH2PO4, 1 mL/L Triton X-100, pH 6.9) and tubes were placed on ice. A blank sample was prepared for each concentration by adding the stop-buffer before the lipoprotein lipase, and the difference was regarded as the amount of TRL-triglycerides hydrolyzed. Nonesterified fatty acids (NEFA) were quantified using the NEFA-C kit (Wako Chemicals GmbH, Neuss, Germany) according to the manufacturer's instructions.
Statistical analysis.
One-way ANOVA was used to compare the effects of oils on lipid and lipoprotein levels as well as on lipid composition and kinetic study parameters. Two-way ANOVA was used to assess the susceptibility of TRL to lipoprotein lipase-mediated lipolysis: one factor was the TRL concentration in the incubation media, the second factor was the type of oil. When the F-test was significant (P < 0.05), the Scheffé test was used for post hoc analysis. The SPSS Software release 7.5 for Windows was used (SPSS Institute Inc., Paris, France).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Total cholesterol and phospholipids were lower in the P.
pinaster- than in the lard-fed mice (Table 2
). Lower levels of VLDL + IDL-cholesterol and -phospholipids,
respectively, accounted for these effects. In contrast, total
triglycerides and VLDL + IDL-triglycerides were higher in the
P. pinaster-fed mice than in those fed lard. Gel
filtration chromatography profiles confirmed these findings (data not
shown). In the P. pinaster oil-fed mice, the cholesterol
was lower in the large and intermediate lipoprotein fractions and
triglyceride concentration was higher in the large lipoprotein fraction
than in lard-fed mice. These differences resulted in a
dose-dependent alteration of VLDL + IDL lipid composition
(Table 3
). VLDL + IDL from P. pinaster-supplemented mice were
enriched in triglycerides and low in cholesterol and phospholipids
compared to those of lard-supplemented mice. Therefore, the VLDL
+ IDL lipid compositions of P. pinaster-treated
mice were intermediate between those of wild-type C57BL/6 mice and
lard-fed apo E-deficient mice. There was no evidence for
difference in electrophoretical mobility on agarose gel of lipoprotein
fractions among diets (data not shown).
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Plasma cholesterol, phospholipids, VLDL + IDL-cholesterol and
VLDL + IDL-phospholipids were lower in both the sunflower- and
P. pinaster-fed than in the lard-fed mice
(Table 4
). In contrast, triglycerides and VLDL + IDL-triglyceride levels
were higher in the P. pinaster-supplemented mice than in
the sunflower- and lard-fed mice. There were no significant
differences in triglyceride and VLDL + IDL triglyceride levels
between sunflower- and lard-fed mice. The gel filtration
chromatography profiles of the VLDL + IDL lipoprotein fraction
indicated that cholesterol in both the large VLDL-sized and small
IDL-sized fraction were lower in both P. pinaster- and
sunflower oil-supplemented mice than in the lard-fed mice
(Fig. 1
). The lipid composition analysis of VLDL + IDL showed no significant
difference between lard- and sunflower oil-treated mice, whereas
the VLDL + IDL lipoprotein fraction of P.
pinaster-treated mice was enriched in triglycerides compared
to lard- and sunflower-supplemented mice (Table 5
).
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Mean affected area increased progressively from the base of leaflets to
reach a peak value at about 500 mm downstream and then decrease
progressively further down (Fig. 2A
). This pattern of lesion distribution was not different among lard-,
sunflower- and P. pinaster-fed mice. Although there was
a tendency for lower mean affected surface area in the P.
pinaster-supplemented apo E-deficient mice compared to
lard- and sunflower oil-fed mice, this difference was not
significant (Fig. 2B)
.
|
The triglyceride production rates (Table 6
) tended to be lower in P. pinaster- and
sunflower-supplemented mice than in lard-fed mice (P
< 0.06). The fractional catabolic rate of triglycerides was
significantly lower in P. pinaster-supplemented mice
than in lard- and sunflower oil-fed mice (P < 0.0001). There was no significant difference in fractional catabolic
rated between the sunflower- and the lard-supplemented mice.
|
Fatty acid release from TRL of P. pinaster-fed mice was
significantly (P < 0.015) lower than that of the
lard-fed mice (Fig. 3
).
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|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In mice, apo E deficiency results in marked alterations of
lipoprotein profile characterized by increased levels of VLDL + IDL cholesterol (Plump et al. 1992
, Zhang et al. 1992
). These particles contain apo B48, are
cholesterol-enriched and triglyceride-depleted and represent
predominantly chylomicron and VLDL remnants. The lipoprotein
accumulation results from the defect of the final step of chylomicron
and VLDL clearance; namely the apo E-mediated cellular uptake. As
the result of lipoprotein alterations, apo E-deficient mice develop
spontaneously atheromatous vascular lesions that resemble those found
in humans. Therefore, apo E-deficient mice appear to be a model for
assessing the lipid-lowering and antiatherogenic properties of
diets (Breslow 1996
, Plump and Breslow 1995
).
VLDL + IDL-cholesterol, the most atherogenic lipoprotein
fraction, was lower in apo E-deficient mice fed P.
pinaster oil than in those fed lard. VLDL + IDL-cholesterol were lower in both the large VLDL and the
remnant-sized VLDL. These differences were observed in all
experiments, regardless of the percentage of fat in the diet and
duration of supplementation. Compared to lard, P. pinaster
and sunflower oil had similar VLDL + IDL-cholesterol-lowering
effects, likely due to their elevated polyunsaturated fatty acids
content (Lichtenstein 1996
). These results are
consistent with the effect of fish oil in patients with
dysbetalipoproteinemia. In this metabolic disorder, which is
characterized by the accumulation of atherogenic chylomicron- and
VLDL-remnants (Schmitz et al. 1985
), VLDL + IDL-cholesterol levels decrease in response to fish oil
supplementation (Dallongeville et al. 1991
,
Fainaru et al. 1982
). In this respect, the effect of
P. pinaster in the apo E-deficient mice resembles the
effect of (n-3) fatty acids in humans.
The findings concerning triglycerides were unequivocal. Triglyceride levels were higher in the P. pinaster oil-fed mice than in the lard- or sunflower oil-fed mice. Greater triglycerides levels were accounted for exclusively by VLDL-triglyceride accumulation. The differences in VLDL + IDL-cholesterol and -triglycerides resulted in VLDL + IDL that had a lipid composition which was intermediate between wild-type and apo E-deficient mice lipoproteins. Therefore, the P. pinaster diet, but not the sunflower or lard diets, produced VLDL + IDL in the apo E-deficient mice that resemble those of wild-type mice, suggesting an improvement in this lipoprotein fraction composition. However, the overall lipid composition of VLDL + IDL was far from being normalized.
To understand the mechanism of triglyceride accumulation, the synthetic and fractional catabolic rates of triglycerides were measured in P. pinaster oil and lard-fed apo E-deficient mice. The triglyceride synthetic rate tended to be lower (P < 0.06), and the fractional triglyceride catabolic rate was significantly lower in the P. pinaster seed oil-fed group than in the lard group. Therefore, P. pinaster oil supplementation has contrasting effects on triglyceride metabolism: (i) a favorable tendency to lower triglycerides synthesis and (ii) an unfavorable influence on fractional catabolic rate. The latter effect is compatible with higher VLDL-triglyceride levels in P. pinaster oil-fed mice.
To further understand the mechanism of the slower fractional catabolic
rate in P. pinaster oil-fed mice, the ability of
lipoprotein lipase to hydrolyze VLDL-triglyceride from P.
pinaster oil- or lard-fed mice was measured. Schematically,
VLDL clearance is a two-step process, which starts with
triglyceride hydrolysis by lipoprotein lipase followed by apo E- and
cellular receptor-mediated VLDL remnant uptake. In apo
E-deficient mice, the second step of the clearance process is
impaired due to the lack of apo E. Therefore, the most likely
explanation for the lower triglyceride fractional catabolic rate levels
in the P. pinaster oil-supplemented mice was a defect in
lipoprotein lipase-mediated hydrolysis of triglycerides. Previous
in vitro studies showed inconsistent results in the effect of oils
serving as substrate for lipoprotein or hepatic lipase activities with
either decreased, unchanged or increased affinity of lipolytic enzymes
(Botham et al. 1997
, Ekstrom et al. 1989
,
Melin et al. 1991
, Morley and Kuksis 1977
, Oliveira et al. 1997
). In the present
study, VLDL-triglycerides of wild type mice, rather than those of
apo E-deficient mice, were obtained after a single bolus of
P. pinaster oil or lard to assess the ability of lipoprotein
lipase to hydrolyze triglycerides. These particles contain more
triglycerides and less cholesterol and therefore resemble nascent liver
VLDL which are subjected to lipoprotein lipase hydrolysis. In contrast,
VLDL from apo E-deficient mice are cholesterol-enriched and
triglyceride-depleted and represent predominantly chylomicron and
VLDL remnants (Plump et al. 1992
). VLDL obtained after a
single bolus of P. pinaster oil were hydrolyzed less than
those produced after a single bolus of lard. This result suggests,
although does not prove, that a less efficient hydrolysis of
triglycerides could contribute to the increased triglyceride levels in
P. pinaster-fed apoE-deficient mice. The decrease
affinity of VLDL for lipoprotein lipase might be related to the fatty
acid composition of the triglycerides as well as to changes in lipid or
apolipoprotein composition.
There were at least two reasons to expect a beneficial effect of
P. pinaster oil supplementation on atherosclerosis in the
apo E-deficient mice. First, the lowering of circulating
lipoproteins was due mainly to the atherogenic VLDL + IDL
lipoprotein fraction. Second, the composition of VLDL + IDL,
although not completely normalized, was intermediate between apo
E-deficient and wild-type mice. Despite, these beneficial
differences, the atherosclerosis lesion areas included foam cells,
extracellular matrix and proliferative smooth muscle cells with
numerous cholesterol clefts. Aortic lesions developed in the valve
cusps and were most abundant at about 500 mm of the valve base in the
direction of the aortic arch. Then, affected area decreased
progressively further downstream. There was a tendency (ns) for a
smaller affected surface area and for fewer lesions in the distal aorta
in P. pinaster oil-fed mice compared to lard or
sunflower oil-supplemented mice. This observation is consistent
with a recent study that showed no benefit of docosahexaenoic acid over
safflower oil on atherosclerosis development in apo E-deficient
mice (Adan et al. 1999
). A number of reasons may explain
the lack of difference among the three diet groups. First, the
differences in circulating lipoprotein levels among the diet groups
might not be sufficient to produce significant differences in
atherosclerosis lesions. Second, the metabolic defect in apo
E-deficient mice might be too marked to respond to dietary
intervention. Third, apo E might be necessary for polyunsaturated fatty
acids to exert their protective effects. Finally, fatty acids affect
not only circulating lipoproteins but also other variables such as
eicosanoids, platelet aggregation and membrane fluidity. The peculiar
fatty acids of P. pinaster oil, namely cis 5,9,12-18:3 and
cis 5,11,14-20:3, may not be properly metabolized by mouse enzymes to
promote these beneficial effects.
In conclusion, the results of the present study indicated that P. pinaster oil diet is associated with lower levels of cholesterol and VLDL + IDL-cholesterol and higher levels of triglycerides and VLDL-triglycerides than lard in apoE-deficient mice. These differences have no preventive effect on atherosclerosis lesion formation in this mouse model. Therefore, additional studies in other animal models are necessary to clarify the potential benefits of P. pinaster oil supplementation on lipoprotein metabolism and atherosclerosis. In this view, the findings of a powerful VLDL + IDL-lowering potential in the apo E-deficient mice are promising.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: apo, apolipoprotein; IDL, intermediary density lipoprotein; NEFA, nonesterified fatty acids; TRL,
triglyceride-rich lipoproteins.
4 The fat-free semipurified diet contains 630 g of carbohydrate, 225 g of casein, 60 g of
cellulose, 70 g of salt mixture and 10 g of vitamins per kg.
Manuscript received April 22, 1999. Initial review completed May 28, 1999. Revision accepted August 17, 1999.
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