Similar to fibrate hypolipidemic drugs, long
chain polyunsaturated fatty acids contained in fish oil are activators
of peroxisome proliferator-activated receptor
(PPAR
). The goal
of this study was to assess the contribution of PPAR
in mediating
the effect of fish oil on plasma lipid, lipoprotein, and apolipoprotein
levels. To this end, PPAR
-deficient mice and wild-type littermates
were fed isocaloric fish oil or coconut oil diets, the content of which varied reciprocally between 0, 3, 7, and 10% for 1 week. In both wild-type and PPAR
-deficient mice, fish oil feeding was associated with a dose-dependent decrease in triglycerides,
cholesterol, and phospholipids associated with lower levels of very low
density lipoprotein (VLDL) triglycerides and high density lipoprotein (HDL) cholesterol. The lowering of triglycerides and VLDL triglycerides was associated with a significant decrease of plasma apoC-III in both
genotypes. Fish oil treatment did not influence hepatic apoC-III
mRNA levels in either genotype indicating that apoC-III is not
under transcriptional control by fish oil. The lowering of HDL
cholesterol observed in both genotypes was associated with reduced
plasma apoA-II without changes in liver apoA-II mRNA levels. In
contrast, plasma apoA-I and liver apoA-I mRNA levels were decreased in wild-type but not in PPAR
-deficient mice after fish oil feeding indicating that PPAR
contributes to the effect of fish oil on apoA-I
gene expression. In conclusion, PPAR
is not rate-limiting for fish
oil to exert its triglyceride- and HDL-lowering action. Furthermore,
PPAR
mediates, at least partly, the decrease of apoA-I after fish
oil treatment, whereas apoC-III and apoA-II levels are affected in a
PPAR
-independent manner. Altogether, these results show major
molecular differences in action between fibrates and fish oil providing
a molecular rationale for combination treatment with these compounds.
 |
INTRODUCTION |
Fish oil treatment efficiently lowers lipids in patients with
hypertriglyceridemia (1, 2). In addition to its effect on
triglyceride-rich lipoproteins, fish oil decreases
HDL1 levels in rodents and to
a lesser extent in humans (2, 3). Fish oil acts by modulating the
activity of several enzymes of lipid and carbohydrate metabolism, such
as diacylglycerol acyltransferase, fatty-acid synthase, carnitine
palmitoyltransferase, glucose-6-phosphate dehydrogenase,
glucose-6-phosphatase, acetyl-CoA carboxylase and
9-desaturase (4). Fish oil and its major long
chain fatty acids, eicosapentaenoic (EPA) and docosahexaenoic (DHA)
acid, appear to affect most hepatic enzyme activities by regulating the
expression of their genes (4). The resultant effect is a decrease in
triglyceride synthesis (5) and an increase in fatty acid mitochondrial
-oxidation (6-8). This, in turn, results in decreased formation and
production of VLDL (9).
High fat diets also increase peroxisome proliferation in liver, kidney,
and heart of rodents (10). Coincident with an increase in the number of
peroxisomes, peroxisomal enzymes are induced by transcriptional
activation. Several of these enzymes are controlled by the peroxisome
proliferator-activated receptor
(PPAR
) (11-13). PPAR
belongs
to the superfamily of nuclear receptors that function as
ligand-activated transcription factors. In addition to PPAR
, the
PPAR family comprises PPAR
and PPAR
. PPARs heterodimerize with
the retinoid X receptor and alter transcription of target genes after
binding to peroxisome proliferator response elements. In
vitro PPAR is activated by fatty acids that bind to a ligand binding domain in its C-terminal region (14-20). In addition,
compounds such as fibrates, certain prostaglandins and leukotrienes,
and oxidized fatty acid derivates also bind to and activate PPARs. These observations suggest that fish oil may exert its metabolic and
lipid-lowering properties by activating PPARs. In agreement with this
hypothesis, studies in PPAR
-deficient mice have demonstrated that
PPAR
is necessary for fish oil to activate gene expression of
enzymes of fatty acid oxidation such as acyl-CoA oxidase and cytochrome
P450-4A2 but is not necessary to inhibit gene expression of fatty-acid
synthase and S14 protein (21, 22).
To date, the exact contribution of the PPAR
pathway to the lipid-
and lipoprotein-lowering properties of fish oil has not been defined.
Moreover, its contribution to the changes in circulating apolipoprotein
levels after fish oil treatment has not been described. Therefore, the
goal of the present study was to assess the role of the PPAR
pathway
in mediating the fish oil-dependent lipid, lipoprotein and
apolipoprotein alterations. To this end, the effects of increasing
consumption of fish oil on lipid and apolipoprotein levels were
assessed in wild-type and PPAR
-deficient mice. The results of the
present study indicate that PPAR
has a minor role in the fish
oil-induced lowering of triglyceride and HDL cholesterol levels in
mice. In this respect, fish oil acts differently than synthetic PPAR
activators such as fibrates.
 |
MATERIALS AND METHODS |
Animals--
The studies were performed with wild-type and
PPAR
-deficient mice (23) in the SV129 genetic background. Before
dietary experiments all animals were acclimatized for more than 2 weeks under conditions of controlled temperature (20 ± 1 °C) and
lighting (dark from 8 p.m. to 8 a.m.) in a room of low
background noise. The average age of the mice was 8 weeks.
Experiments--
For all experiments, male wild-type and
PPAR
-deficient mice were used. Before each dietary experiment a
blood sample was drawn for randomization on triglyceride levels.
Animals were housed in cages (2-3 per cage) and given free access to a
fat-free semi-purified diet (UAR, Villemoisson sur Orge, France)
supplemented with coconut oil, fish oil, or fenofibrate (Sigma). Fish
oil and coconut oil were obtained from menhaden and copra,
respectively, and were purchased from Sigma. Fish oil contained 30% of
n
3 fatty acid, and the EPA to DHA ratio was 1.2. Duration of experimental dietary exposure was 1 week in all
experiments. For experiment 1, three groups of 6 SV129 mice were
supplemented with an isocaloric diet containing either 10% (w/w)
coconut oil alone, 10% (w/w) coconut plus 0.2% (w/w) fenofibrate, or
10% (w/w) fish oil alone. For experiment 2, wild-type or
PPAR
-deficient mice were fed an isocaloric diet supplemented with
either 10% (w/w) coconut oil alone, 7% coconut oil plus 3% fish oil,
3% coconut oil plus 7% fish oil, or 10% fish oil alone. The other
major nutrient components were carbohydrate (50.4 g/100 g), casein (18 g/100 g), cellulose (4.8 g/100 g), salt mixture (5.6 g/100 g), and
vitamins (0.8 g/100 g). At the end of each dietary experiment, mice
were food-deprived for 4 h and were exsanguinated under diethyl
ether anesthesia by cardiac puncture. Blood samples were collected on
EDTA tubes.
Lipoprotein Separation and Measurements--
Plasma was
separated by centrifugation (630 × g) for 20 min at
4 °C. Lipids were determined enzymatically using commercially available kits for triglycerides (Triglycerides GPO-PAP, Roche Molecular Biochemicals), cholesterol (Cholesterol C System, Roche Molecular Biochemicals), and phospholipids (Phospholipids PAP 150, BioMérieux, Lyon, France). Plasma levels of mouse apoA-I, apoA-II, and apoC-III were measured by immunonephelemetric assays using
specific polyclonal antibodies in a fixed time method in a Behring
Nephelometric Analyzer (Behring Diagnostics, Marburg, Germany). For
these assays, the primary standard was a pool of sera from
normolipidemic C57BL/6 mice to which an arbitrary concentration of 100, 50, and 20 mg/dl was attributed for apoA-I, apoA-II, and apoC-III,
respectively. With this standard, the calibration curves cover the
ranges 1.25-40 mg/dl for apoA-I, 0.62-20 mg/dl for apoA-II, and
0.123-4 mg/dl for apoC-III. As the exact concentration of apolipoproteins of the standard is unknown, it was more convenient to
express the results of the experimental groups as percentage of the
control group. Accordingly, the correlations between apoA-I and HDL
were r = 0.96 and between apoC-III and triglycerides
were r = 0.80 in 20 serum samples. The variation
coefficients were below 6% for the 3 parameters including within and
between-day variation. Antibodies were raised in rabbit by immunization
with synthetic peptides reproducing a part of murine apoA-I sequence, the complete apoA-II sequence, and with native murine apoC-III prepared
by isoelectrofocusing.
Gel Filtration Chromatography (FPLC)--
Gel filtration
chromatography was performed using a Superose 6 HR 10/30 column
(Amersham Pharmacia Biotech) from 100 µl of plasma. The gel was
allowed to equilibrate with phosphate-buffered saline (10 mM) containing 0.01% EDTA and 0.01% 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 (Amersham Pharmacia Biotech). The effluents were
collected in 0.22-ml fractions. Triglycerides, cholesterol, and
phospholipids were measured in each collected fraction using
commercially available enzymatic kits (Triglycerides GPO-PAP or
Cholesterol C System, Roche Molecular Biochemicals and Phospholipid
Enzymatic PAP 150, BioMérieux, Lyon, France).
RNA Analysis--
Total cellular RNA was isolated from liver
tissue by the acid guanidinium thiocyanate/phenol chloroform method
(24). Northern and dot-blot hybridizations were performed exactly as
described previously (25). The rat apoA-I, apoA-II, apoC-III, acyl-CoA oxidase, CYP450, and human acidic ribosomal phosphoprotein 36B4 cDNA (25-27) were used as probes. All probes were labeled by
random primed labeling (Roche Molecular Biochemicals). Filters were
hybridized to 1 × 106
cpm·ml
1 of each probe as described (28).
They were washed in 300 ml of 75 mM NaCl, 7.5 mM sodium citrate, pH 7.4, and 0.1% SDS for 10 min at room
temperature and twice for 30 min at 65 °C and subsequently exposed
to x-ray film (Kodak X-Omat-AR, Eastman Kodak Co.). Autoradiograms were
analyzed by quantitative scanning densitometry (Bio-Rad GS670 Densitometer, Bio-Rad) in the linear range of film sensitivity. Curves
were plotted on a log/log scale relating the density measurements to
the amounts of mRNA in the corresponding dots. The relative amounts
of mRNA were calculated using the parallel, linear parts of these
curves as described elsewhere (28, 29).
Statistical Analysis--
Student's t test was used
to compare treatment effects within each genotype. The SPSS Software
release 7.5 for Windows was used (SPSS Institute Inc., Paris, France).
 |
RESULTS |
Effect of Fenofibrate and Fish Oil on Lipid Levels in SV129 Mice
Strain--
To test whether mice of the SV129 strain respond to
PPAR
activators, we tested the effect of fenofibrate (0.2% w/w) and
fish oil (10% w/w) on lipid metabolism in this mice strain. Plasma triglycerides, cholesterol, and phospholipids were lower in SV129 mice
supplemented with fish oil than in those on the coconut oil diet (Table
I). These effects were accounted
for by lower levels of both the large triglyceride-rich and the small
cholesterol-rich lipoprotein fraction as assessed by gel filtration
chromatography (data not shown). In contrast, fenofibrate decreased
triglyceride levels but not cholesterol and phospholipid concentrations
in the SV129 mice.
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|
Table I
Plasma lipid levels in SV129 mice treated with fenofibrate or fish oil
SV129 mice were treated for 1 week with 10% (w/w) coconut oil alone,
10% (w/w) coconut oil plus 0.2% (w/w) fenofibrate, and 10% (w/w)
fish oil alone. Lipids were analyzed as indicated under "Materials
and Methods." Values are means ± S.D. of six animals per group.
|
|
Effect of Fenofibrate and Fish Oil on Liver Acyl-CoA Oxidase,
ApoA-I, ApoA-II, and ApoC-III mRNA Levels in SV129 Mice
Strain--
To test whether mice of the SV129 strain respond to
PPAR
activators by peroxisomal proliferation and apolipoprotein gene expression changes, the effect of fenofibrate (0.2% w/w) and fish oil
(10% w/w) on liver acyl-CoA oxidase, apoC-III, apoA-I, and apoA-II
mRNA levels were analyzed (Fig. 1).
Liver acyl-CoA oxidase mRNA levels were higher in SV129 mice
treated with fenofibrate (approximately ×10) than in those
supplemented with coconut oil. In contrast, liver acyl-CoA oxidase
mRNA levels was mildly induced (approximately ×1.4) by fish
oil feeding. Liver apoC-III and apoA-I mRNA levels were lower in
the fenofibrate group than in the coconut oil group, whereas apoA-I,
but not apoC-III, was decreased by fish oil feeding in this mice
strain. Finally, liver apoA-II mRNA levels were markedly increased
by fenofibrate feeding but not affected by fish oil treatment.

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|
Fig. 1.
Liver acyl-CoA oxidase, apoC-III, apoA-I, and
apoA-II mRNA levels in SV129 mice fed 10% (w/w) coconut oil alone
(CO), 10% (w/w) coconut oil plus 0.2% (w/w)
fenofibrate (FENO), and 10% (w/w) fish oil alone
(FO) for 1 week. Each value represents mean of 6 mice per group. p values are for t test
comparison with coconut oil group: ***, p < 0.0001;
**, p < 0.001; *, p < 0.05.
|
|
Dose-dependent Effects of Fish Oil on Lipid and
Lipoprotein Levels in Wild-type and PPAR
-deficient Mice--
To
assess whether PPAR
mediates the effect of fish oil on plasma
lipids, a dose-response study was performed in wild-type and
PPAR
-deficient mice (Table II). Plasma
cholesterol, triglycerides, and phospholipids were lower in both
wild-type and PPAR
-deficient mice fed fish oil than in those fed
coconut oil (Table II). The lowering effect of fish oil on cholesterol,
triglyceride, and phospholipid levels was already discerned at 3%
(w/w) supplementation in both genotypes. The decrease in cholesterol,
triglyceride, and phospholipid levels was
dose-dependent and of similar amplitude in wild-type and
PPAR
-deficient mice. Triglyceride levels were lower in the large
FPLC plasma lipid fraction, corresponding to VLDL, of both wild-type
and PPAR
-deficient mice supplemented with increasing doses of fish
oil (Fig. 2). Cholesterol and
phospholipid peaks were lower in the small FPLC plasma lipid fraction,
corresponding to HDL, of wild-type and PPAR
-deficient mice fed fish
oil than in those fed coconut oil. Therefore, the decreases in plasma
triglyceride and cholesterol levels were accounted for by a lowering of
VLDL and HDL, respectively, in both genotypes.
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|
Table II
Plasma lipid levels in wild-type and PPAR -deficient mice fed an
isocaloric diet containing increasing amounts of fish oil
Wild-type and PPAR -deficient mice were fed the following diets for 1 week: fish oil 0% contained 10% (w/w) coconut oil; 3%, 3% (w/w)
fish oil plus 7% (w/w) coconut oil; 7%, 7% (w/w) fish oil plus 3%
(w/w) coconut oil; 10%, 10% (w/w) fish oil. Values are means ± S.D. of six animals per group.
|
|

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Fig. 2.
Plasma triglyceride and cholesterol
distribution of wild-type and PPAR -deficient
mice fed increasing proportions of fish oil (FO) (see
Table II for diet composition). Plasma lipoproteins were separated
by gel filtration chromatography (FPLC) using a Superose 6HR 10/30
column. Cholesterol and triglycerides were measured in eluted fractions
using enzymatic methods. Values are pools of six mice per treatment
group.
|
|
Effect of Fish Oil on Liver Acyl-CoA Oxidase and CYP450 mRNA
Levels--
To assess whether fish oil and PPAR
deficiency affect
peroxisomal proliferation, liver acyl-CoA oxidase and CYP450 mRNA
levels were measured (Fig. 3). Liver
acyl-CoA oxidase mRNA levels were induced by ~1.4-fold and in
liver CYP450 mRNA levels by 3-fold in wild-type but not in
PPAR
-deficient mice.

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Fig. 3.
Liver CYP450 mRNA levels of wild-type and
PPAR -deficient mice fed 10% coconut oil
(open bar) or 10% fish oil (dark
bar) for 1 week. Values are means of 11 mice per group.
p values are for t test comparison with coconut
oil group: ***, p < 0.0001; **, p < 0.001; *, p < 0.05.
|
|
Effect of Fish Oil on Plasma ApoC-III and Liver ApoC-III mRNA
Levels--
The effect of fish oil on circulating apolipoprotein C-III
levels in wild-type and PPAR
-deficient mice was assessed (Fig. 4). Plasma apoC-III levels were lower in
both PPAR
-deficient and in wild-type mice fed fish oil than in those
fed with coconut oil. There was no evidence for a statistically
significant effect of fish oil on liver apoC-III mRNA levels in
either genotype.

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Fig. 4.
Plasma apoC-III and liver apoC-III mRNA
levels of wild-type and PPAR -deficient mice
fed 10% coconut oil (open bar) or 10% fish oil
(dark bar) for 1 week. Values are means of 11 mice per group. p values are for t test
comparison with coconut oil group: ***, p < 0.0001;
**, p < 0.001; *, p < 0.05.
|
|
Effect of Fish Oil on Plasma and Liver mRNA Levels of
Apolipoprotein A-I and A-II--
Next, we examined the effect of fish
oil on the major HDL apolipoproteins (Fig.
5). Fish oil supplementation was
associated with a decrease in plasma apoA-I levels in both mice
strains. This decrease was less pronounced in the PPAR
-deficient
mice. Similarly, liver apoA-I mRNA levels were lower after fish oil feeding in wild-type but not in PPAR
-deficient mice suggesting that
PPAR
contributes to the fish oil-mediated lowering of plasma apoA-I
and liver apoA-I mRNA levels. Plasma apoA-II levels were lower in
both PPAR
-deficient and in wild-type mice fed with fish oil than in
those fed with coconut oil (Fig. 6).
However, fish oil had mild liver apoA-II mRNA levels raising effect
in both wild-type and PPAR
-deficient mice.

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Fig. 5.
Plasma apoA-I and liver apoA-I mRNA
levels of wild-type and PPAR -deficient mice
fed 10% coconut oil (open bar) or 10% fish oil
(dark bar) for 1 week. Values are means of 11 mice per group. p values are for t test
comparison with coconut oil group: ***, p < 0.0001;
**, p < 0.001; *, p < 0.05.
|
|

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|
Fig. 6.
Plasma apoA-II (upper panel)
and liver apoA-II mRNA levels (lower panel) of
wild-type and PPAR -deficient mice fed 10%
coconut oil (open bar) or 10% fish oil (dark
bar) for 1 week. Values are means of 11 mice per group.
p values are for t test comparison with coconut
oil group: ***, p < 0.0001; **, p < 0.001; *, p < 0.05.
|
|
 |
DISCUSSION |
The results of the present study show that fish oil has similar
effects on cholesterol, triglyceride, and HDL cholesterol levels in
wild-type and PPAR
-deficient mice suggesting that PPAR
is not
rate-limiting for fish oil to lower plasma lipid and lipoprotein levels. This finding is different to what is observed with fibrates (32) and suggests that fibrates and fish oil affect lipoprotein metabolism through different mechanisms of action. The lowering of
plasma triglyceride was associated with decreased levels of apoC-III in
both wild-type and PPAR
. Like fibrates, fish oil lowered apoA-I and
liver apoA-I mRNA level in wild-type but not in PPAR
-deficient
mice suggesting a contribution of PPAR
. These results indicate that,
in contrast to fibrates, fish oil has different molecular mechanisms of
action on triglyceride and HDL metabolism.
In contrast to fibrates, fish oil decreased triglyceride levels to a
similar extent in wild-type and PPAR
-deficient mice suggesting that
fish oil exerts its triglyceride-lowering properties through mechanisms
that are independent of PPAR
. There are a number of possible
hypotheses to explain these differences between fish oil and fibrates.
First, although long chain fatty acids, including EPA and DHA, bind and
activate PPAR
(14), the affinity and the ability of these fatty
acids to activate PPAR
is much smaller than that of pharmacological
activators such as fibrates (15-20). For example the effect of fish
oil on acyl-CoA oxidase expression is much lower than that of fibrates
suggesting that the contribution of fatty acid oxidation to the
triglyceride-lowering activity of fish oil treatment is minor in mice.
In fact, fish oil fatty acids might not be potent enough to activate
PPAR
to a level where it exerts a significant metabolic effect
in vivo. However, in our experiments fish oil treatment
regulated apoA-I, acyl-CoA oxidase, and CYP450 gene expression in a
PPAR
-dependent manner indicating that this hypothesis is
unlikely to be true. Second, fish oil may regulate the same genes
controlling triglyceride metabolism as fibrates through mechanisms of
actions independent of PPAR
. For example, the activity of a number
of lipogenic enzymes such as the S14 protein and fatty-acid synthase
which are conspicuously decreased by fish oil treatment (33, 34) are
under the control of the SREBP1 transcription factor (35, 36). Recent
studies have shown that SREBP1 expression is decreased by long chain
polyunsaturated fatty acids (36-39). Third, in contrast to fibrates
EPA and DHA activate PPAR
, which induces lipoprotein lipase in a
tissue-specific manner in adipose tissue, it is likely that a part of
the triglyceride-lowering activity of fish oil treatment occurs through
activation of this nuclear receptor in adipose tissue. Finally, PPAR
agonists and fish oil may affect different subsets of genes, by
currently unknown mechanisms, that are important for triglyceride metabolism.
ApoC-III plays a crucial role in triglyceride metabolism. Earlier
studies have demonstrated that apoC-III inhibits VLDL lipolysis and
uptake by cellular receptors (40-42) and that overexpression of
apoC-III in mice is associated with elevated levels of triglycerides due to a defective clearance of VLDL (43). Fibrate treatment has been
shown to decrease hepatic apoC-III mRNA and plasma apoC-III levels,
an effect contributing to the triglyceride-lowering activity of these
drugs. Interestingly, although plasma apoC-III concentrations are also
reduced by ~80% by fish oil, this diet did not decrease hepatic
apoC-III mRNA levels, an observation that is in sharp contrast to
fibrates (32). These observations further point out a difference
between fibrates and fish oil. Thus, the major reduction of plasma
apoC-III levels (
80%) as compared with the lack of effect of fish
oil on liver apoC-III mRNA suggests that nontranscriptional
mechanisms contribute to the lowering of plasma apoC-III after fish oil treatment.
Previous studies have shown that replacing saturated by polyunsaturated
fatty acids results in the lowering of HDL cholesterol in rodents as
well as in humans (44-46). The mechanism of this effect is not clear
since either decreased production rates or increased catabolic rates of
apoA-I were described depending on the experimental models, the type of
diets, and the metabolic parameters that were measured (47-50).
Moreover, hepatic apoA-I mRNA levels were either lowered or not
affected by the substitution of saturated by polyunsaturated fatty
acids in the diet (44, 48-53). In this study, fish oil supplementation
resulted in lower levels of HDL cholesterol and HDL phospholipids in
both genotypes, indicating a PPAR
-independent lowering action of
fish oil on HDL lipids. In contrast with this finding, plasma apoA-I
and liver apoA-I mRNA levels were decreased in wild-type mice, but
not in the PPAR
-deficient mice, after fish oil feeding. These
observations indicate that PPAR
contributes to the effect of fish
oil on apoA-I expression. Previous studies in our laboratory have shown
that fibrates decrease apoA-I gene transcription in rodents (25, 32,
54). This effect was shown to be due to the activation of PPAR
(32,
55). In the present study, the observation that fish oil requires
PPAR
to exert part of its apoA-I-lowering effect suggests that fish
oil and fibrates share, at least in part, a common molecular pathway of
apoA-I regulation. Furthermore, the dissociation between the effect of
fish oil on HDL lipids and apoA-I suggests that other or additional
proteins other than apoA-I regulate HDL lipids levels and that these
proteins are not under a major PPAR
control. In this respect,
apolipoprotein A-II is another major protein of HDL (56) whose
expression is transcriptionally induced by activation of PPAR
in
mice and humans (25, 32, 57). However, in contrast to fibrate
treatment, apoA-II levels were lowered by fish oil feeding as well in
wild-type and PPAR
-deficient mice. Furthermore and in contrast to
apoA-I, liver apoA-II mRNA levels were not affected by fish oil
treatment. The observed changes in plasma apoA-II concentrations might
be due to a (post) translational repression of its production or
secondary to intravascular metabolic changes. Although further studies
are required to elucidate the molecular mechanisms involved therein,
our results clearly demonstrate a distinct regulation of apoA-II by
fibrates and fish oil.
In conclusion, the results of the present study indicate that fish oil
decreases triglyceride and HDL levels to a similar extend in wild-type
and PPAR
-deficient mice suggesting that PPAR
is not rate-limiting
for fish oil to exert its lipid- and lipoprotein-lowering action. The
decrease in triglyceride levels was associated with a decrease in
plasma apoC-III which occurs independently of PPAR
. The lowering of
HDL cholesterol was accompanied by a decrease in plasma apoA-I,
apoA-II, and liver apoA-I mRNA. The effect on plasma apoA-I and
liver apoA-I mRNA levels was abolished by PPAR
deficiency
indicating a contribution of PPAR
to this effect. Altogether, these
data suggest that although fibrates and fish oil have a very similar
lipid- and apolipoprotein-lowering profile, they exert their
lipid-lowering action through different molecular mechanisms of action.
Published, JBC Papers in Press, October 24, 2000, DOI 10.1074/jbc.M008809200
The abbreviations used are:
HDL, high density
lipoprotein;
VLDL, very low density lipoprotein;
PPAR
, peroxisome
proliferator-activated receptor
;
EPA, eicosapentaenoic acid;
DHA, docosahexaenoic acid;
FPLC, fast protein liquid chromatography;
PIPES, 1,4-piperazinediethanesulfonic acid.
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