1 Division of Clinical Nutrition, National Institute of Health and Nutrition, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8636; and 2 Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
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ABSTRACT |
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Fish oil rich in n-3
polyunsaturated fatty acids has been shown to reduce the risk of
cardiovascular diseases partly by reduction of blood triglyceride
concentration. This favorable effect mainly results from the combined
effects of inhibition of lipogenesis by decrease of SREBP-1 and
stimulation of fatty acid oxidation by activation of peroxisome
proliferator-activated receptor- (PPAR
) in liver. However,
because fish oil is easily peroxidized to form hydroperoxides and
increases oxidative stress, some defense mechanism(s) against oxidative
stress might occur. To understand these complex effects of fish oil
diet, the gene expression profile of mice liver was analyzed using
high-density oligonucleotide arrays. High-fat diet (60% of total
energy intake) as either safflower oil or fish oil (tuna) was given to
mice. After 6 mo of feeding, expression levels of a total of 6,521 genes were analyzed. In fish oil diet compared with safflower oil diet,
immune reaction-related genes, antioxidant genes (several glutathione
transferases, uncoupling protein 2, and Mn-superoxide dismutase), and
lipid catabolism-related genes upregulated, whereas cholesterol and
fatty acid synthesis-related genes and 17-alpha hydroxylase/C17-20
lyase and sulfotransferases related to production of endogenous PPAR
ligands and reactive oxygen species (ROS) downregulated markedly.
Because upregulation of these antioxidant genes and downregulation of
sulfotransferases were also observed in mice administered fenofibrate,
altered gene expression related to antioxidant system observed in fish
oil feeding was mediated directly and indirectly by PPAR
activation. However, downregulation of 17-alpha hydroxylase/C17-20 lyase was not due to PPAR
activation. These data indicate that fish oil feeding downregulated the endogenous PPAR
-activation system and increased antioxidant gene expressions to protect against ROS excess.
n-3 fatty acids; fibrate; sulfotransferase; glutathione transferase; dehydroepiandrosterone
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INTRODUCTION |
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IN RODENTS, FISH OIL
FEEDING showed less obesity and lower blood triglyceride levels
relative to other dietary oils (4, 13). In humans,
increased intake of fish oil showed protective effects against
cardiovascular disease (27), but concern remains that
increased intake of fish oil may lead to increased lipid peroxidation
(23). Contained in fish oil are n-3 polyunsaturated fatty
acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid
(DHA), which are taken into the body, are mostly delivered to liver
(29), and are easily peroxidized to form hydroperoxides and their secondary degradation products (9). These are
considered to be deleterious to tissues (37). Thus liver
is the primary target organ for oxidative stress in fish oil feeding.
Fish oil administration and fibrate, which are peroxisome
proliferator-activated receptor- (PPAR
) activators, manifest
substantial increase in expression of
H2O2-generating peroxisomal fatty acyl CoA
oxidase, the first enzyme of the classic peroxisomal fatty acid
-oxidation system, and of microsomal Cyp 4A1 and 4A3 genes
(41). Disproportionate increases in
H2O2-generating enzymes and
H2O2-degrading enzyme catalase and reductions
in glutathione peroxidase activity by peroxisome proliferators lead to
increased oxidative stress in liver. However, the results of fish oil
feeding to animals showed slight increases in the tissue level of
thiobarbituric acid reactive substances (33). Thus fish
oil feeding may enhance the hepatic antioxidant defense with several mechanism(s).
To identify genes responsible for metabolic alterations and antioxidant
systems of fish oil feeding, the gene expression profile of 6,521 genes
using oligonucleotide arrays in high-carbohydrate diet, high-safflower
oil diet, and high-fish oil diet-fed mice was examined in mice liver.
In addition, to examine whether the altered gene expression of fish oil
feeding is via PPAR activation, mRNA levels of liver from mice
administered fenofibrate were examined by Northern blotting.
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MATERIALS AND METHODS |
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Diet experiment. Female C57BL/6 mice were obtained from Tokyo Laboratory Animals Science (Tokyo, Japan) at 7 wk of age and fed a normal laboratory diet for 1 wk to stabilize the metabolic conditions. Mice were exposed to 12:12-h light-dark cycle and maintained at a constant temperature of 22°C.
For gene-chip analysis, mice were divided into three groups (n = 5-6 in each group). The first group was given a high-carbohydrate diet that, on a calorie basis, contained 63% carbohydrate, 11% fat, and 26% protein. In the high-carbohydrate diet, safflower oil was used as source of fat. The second group was given a high-safflower oil-rich diet containing 14% carbohydrate, 60% safflower oil, and 26% protein. Safflower oil used here was high-oleic type, containing 46% oleic acid (18:1n-9) and 45% linoleic acid (18:2n-6) from total fatty acids. The third group was given a high-fish oil diet containing 14% carbohydrate, 60% fish oil, mainly from tuna, and 26% protein. Fish oil contained 7% EPA (20:5n-3) and 24% DHA (22:6n-3) and was kindly provided by NOF (Tokyo, Japan). In this study, to elucidate the effects of fish oil feeding, we used a very high-fat diet (60% of total energy intake). The materials and methods of preparation and fatty acid composition of diet were the same as those used in our previous studies (15, 38). Mice were fed each diet for 6 mo. At the end of the experiments, animals were anesthetized at about 10:00 AM by intraperitoneal injection of pentobarbital sodium (0.08 mg/g body wt, Nembutal; Abbot, North Chicago, IL). Liver was isolated immediately, weighed, and homogenized in guanidine-thiocyanate, and RNA was prepared by the method described by Chirgwin et al. (3). RNAs were used for gene-chip analysis and Northern blotting. To confirm the results of gene-chip analysis and to examine whether up- and downregulation of these genes by 6 mo fish oil feeding were also observed in a short-term feeding period and were due to activation of PPARGene-chip analysis of gene expression. Poly (A)+ RNA was prepared from pooled total RNA from five animals of each group by using an mRNA purification kit (Amersham Pharmacia Biotech, Piscataway, NJ). Double-stranded cDNA (Superscript Choice System, GIBCO BRL) was made from 1 µg of mRNA with a T7-(dT)24 primer containing T7 RNA polymerase promoter site (Amersham Pharmacia). Biotinylated complementary RNA was made from 1 µg of cDNA using BioArray high-yield RNA transcript labeling kit (Enzo) and then fragmented to ~100-200 nucleotides. Ten micrograms of these in vitro transcripts were hybridized to Affymetrix Mu 6500 microarray for 16 h at 45°C with constant rotation at 60 rpm (21). Chips were washed and stained with streptavidin-phycoerythrin (10 µg/ml, Molecular Probes) and biotinylated goat antistreptavidin (3 µg/ml, Vector Laboratories) using tEukGE-WS2 protocol on Affymetrix fluidics station. Chips were scanned using Hewlett-Packard confocal laser scanner and visualized using Affymetrix Gene Chip 3.1 software (Affymetrix). Fluorescence intensity from the safflower oil- and fish oil-fed groups was normalized to that from the carbohydrate-fed group by equating the overall fluorescence intensity for the entire chip of each group. The average values were scaled to 100 so that all chips could be directly compared, and the data were imported into File Maker Pro (File Maker).
In order of fold-change levels in gene expression in liver from fish oil-fed mice relative to safflower oil-fed mice, genes increased more than twofold and decreased less than twofold are listed and examined. Difference call, which defines genes increased or decreased, is derived from this software and is classified in five stages: transcript has increased, decreased, marginally increased, marginally decreased, or has exhibited no change in expression level. Fold-change calculation was carried out as an indication of the relative change of each transcript represented on the probe array. Differentially expressed genes were identified using the following criteria. Absolute call is present, and average difference was >150. Absolute call, which was calculated by this software using several markers, is an indicator of the presence or absence of each gene transcript. The average difference value is a marker of abundance of each gene obtained by comparing the intensity of hybridization to 20 sets of perfectly matched 25-mer oligonucleotides relative to 20 sets of mismatched oligonucleotides using Affymetrix Gene Chip 3.1 software.Preparation of cDNA probe for Northern blot. The cDNA fragments for cytochrome P-450 17-alpha hydroxylase/c17-20 lyase, sulfotransferases, kappa-immunoglobulin (constant region), gelsolin, and glutathione transferase theta-class type 2 were obtained by PCR from first strand cDNA using mouse liver total RNA. First strand cDNA was prepared using a first-strand cDNA synthesis kit (Amersham Pharmacia Biotech) primed with oligo(dT). The PCR primers used were as follows: cytochrome P-450 17-alpha hydroxylase/c 17-20 lyase, 5' primer, 5'-CTACACCTGGCTGCCATGT-3', and 3' primer, 5'-GCCTGATACGAAGCACTTCT-3'; hydroxysteroid sulfotransferase, 5' primer, 5'-AGGAACGAACTGGCTGAATG-3', and 3' primer, 5'-CTTGGGCTACTGTGAAGTGA-3'; phenol/aryl form sulfotransferase, 5' primer, 5'-CCACATTGCAAAGCCTACAC-3', and 3' primer, 5'-CATTAGCTTGGCATAGTGGG-3'; kappa-immunoglobulin (constant region), 5' primer, 5'-GATGCTGCACCAACTGTATC-3', and 3' primer, 5'-AACAGTGGTAGGTCGCTTGT-3'; gelsolin, 5' primer, 5'-GCACTATGGTGGTGGAGCA-3', and 3' primer, 5'-CGTTGGCAATGTGGCTGGA-3'; glutathione transferase theta-class type 2 primer, 5'-GCTTGCTGTTATCGAACGCA-3', and 3' primer, 5'-TGGTCAGACCACTCAAGGAA-3'. PCR was performed with Taq DNA polymerase (Takara, Shiga, Japan). Amplification was made by using the following program: segment 1: 94°C, 1 min; segment 2: 30 cycles of 98°C for 20 s, 68°C for 2 min; and segment 3: 72°C for 10 min. The amplified products were subcloned into pGEM-T Easy vector (Promega, Madison, WI) and verified by sequencing. The cDNA probes for rat glutathione transferase Ya subunit were kindly provided by Dr. Nakagawa at Kitasato University, and rat Mn-SOD was provided by Dr. Ookawara at Hyogo Medical University. These cDNA were used as probes for Northern blotting.
Northern blotting.
A portion of RNA (15 µg/lane) was denatured with glyoxal and dimethyl
sulfoxide and analyzed by electrophoresis in 1% agarose gels. After
transfer to Nylon membranes (New England Nuclear, Boston, MA) and
ultraviolet cross-linking, RNA blots were stained with methylene blue
to locate 28S and 18S rRNAs and to ascertain the amount of loaded RNAs
(35). The blots were hybridized overnight at 42°C with
cDNAs that had been labeled with [32P]dCTP (New England
Nuclear) by a random prime labeling kit (Amersham Pharmacia Biotech).
The filters were washed several times with 1× SSC, 0.1% SDS at room
temperature, washed twice at 50°C, and then exposed to X-ray film at
80°C.
Statistics. Statistical comparisons of the groups were made by one-way ANOVA, and when they were significant, each group was compared with the others by Fisher's protected least-significant differences test (Statview 5.0 Abacus Concept, Berkeley, CA). Statistical significance is defined as P < 0.05. Values are means ± SE.
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RESULTS |
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Phenotypic comparison of mice fed three different diets for 6 mo.
The difference of body and tissue weights, blood lipid concentrations,
and other metabolic parameters after 5-6 mo feeding are described
in our previous studies (13, 15, 38). Briefly, compared
with carbohydrate diet, safflower oil diet resulted in two- to
threefold increase of wet parametrial white adipose tissue weight with
concomitant 40% increase of body weight, but fish oil feeding did not
increase white adipose tissue and body weight. The average energy
intake of mice fed each diet was not significantly different; energy
intakes of mice fed carbohydrate diet, safflower oil diet, and fish oil
diet were 7.4 ± 0.5, 7.7 ± 0.9, 7.9 ± 0.5 kcal · day1 · mouse
1,
respectively, when they were measured at 12-13 wk feeding. Liver weight from fish oil-fed mice was 60% greater than that from
carbohydrate-fed mice, possibly through peroxisomal proliferation. Fish
oil feeding decreased liver triglyceride and cholesterol concentration
by 62% and 35%, respectively, compared with safflower oil feeding.
Altered gene numbers among three different diets.
Table 1 shows the number
of liver genes whose expression levels were altered after a 6-mo
feeding period. Of the 6,521 genes, including 3' expressed sequence
tags (ESTs), analyzed, 1,669; 1,925; and 1,928 were expressed
at significant levels (absolute call is present), and 975; 1,039; and
992 were expressed at substantial levels (absolute call is present, and
average difference is >150) in carbohydrate-, safflower oil-, and fish
oil-fed female mice, respectively. Of these, in safflower oil- and fish
oil-fed mice, compared with carbohydrate-fed mice, 132 (13%), and 117 (12%) genes, respectively, significantly and substantially upregulated (difference call is increased, and its average difference is >150), whereas those of 14 (1%) and 48 (5%) genes, respectively,
downregulated significantly (difference call is decreased, and average
difference of carbohydrate-fed mice is >150). Within fat diet-fed
groups, numbers of up- and downregulated genes in fish oil feeding
compared with safflower oil feeding were 63 (6%) and 102 (10%),
respectively.
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Upregulated genes of fish oil feeding.
Of 63 genes that upregulated in fish oil feeding compared with
safflower oil feeding, 24 genes showed increase greater than twofold.
In order of the fold increase, they are listed in Table 2 with their average differences
(corresponding to expression level) and putative function. When they
are classified into subgroups according to their functions, genes
related to immune reaction, fat oxidation, and antioxidant emerge
(Table 3). Enzymes related to fatty acid
oxidation, such as fatty acid transport protein, Cyp 4a-10, long-chain
fatty ACS, and carnitine palmitoyltransferase II, upregulated in fish
oil-fed mice. Compared with carbohydrate-fed mice, Cyp 4a-10,
long-chain fatty ACS also upregulated in safflower oil-fed mice, but
their increase in safflower oil-fed mice was smaller than those in fish
oil-fed mice. The different expression levels of these genes among
three groups might be to the levels of PPAR activation. In fish
oil-fed mice, testosterone 16-alpha-hydroxylase related to steroid
degradation also upregulated by 4.3-fold. Upregulation of these genes
is mostly mediated by PPAR
activation (17). In other
genes, alpha 2 type IV collagen, beta-tubulin, insulin-like growth
factor-binding protein 2, and biglycan related to cell proliferation
and formation of connective tissues also upregulated. However, their
physiological roles of upregulation in fish oil feeding have not been
elucidated.
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Fish oil feeding upregulates immune-reacted genes in a long-term feeding period. Largest increases were observed in immune-reacted genes (Table 2). Components of immunoglobin such as immunoglobin kappa chain and immunoglobin heavy-chain constant region µ (b) markedly upregulated 37- and 24-fold, respectively. Because µ-type heavy chain is found in IgM, an increase of IgM is anticipated. Indeed, in rats, compared with safflower oil-fed group, fish oil feeding enhanced the serum IgM level (12). In relation to immune response, gelsolin involved in phagocytosis of neutrophils and macrophages (36) also upregulated by 10-fold. Leukocyte elastase inhibitor that inactivates enzymes related to immune reaction (34) also upregulated by ninefold. These immunological reactions observed in fish oil-fed mice were not due to hepatocyte injury, because there were no increases of serum glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) concentrations (data not shown).
To examine whether upregulation of these genes by 6 mo, fish oil feeding was also observed in a short-term feeding period and was related to activation of PPAR
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Fish oil or fenofibrate administration upregulates antioxidant genes. In this gene-chip analysis, genes having antioxidant activities, such as uncoupling protein-2 (UCP-2), theta-class glutathione transferase type 2, glutathione transferase, glutathione transferase Ya subunit, and manganese superoxide dismutase (Mn-SOD) upregulated by two- to fourfold (Tables 2 and 3). UCP-2 and Mn-SOD, which are located in mitochondria, reduced superoxide formation (6, 26). A recent study of UCP-2 knockout mice revealed an important role of UCP-2 in macrophage-mediated immunity and ROS generation (1). Glutathione transferases in cytosol promoted conjugation of toxic electrophilic xenobiotics to glutathione (22). However, expression levels of other genes related to antioxidant systems, such as Cu-Zn SOD (M60798), cellular (AA123700) and plasma (U13705) glutathione peroxidase, and catalase (L25069), did not alter in fish oil-fed mice (data not shown).
To examine whether upregulation of these genes by 6-mo fish oil feeding was also observed in a 1-wk feeding period and was related to activation of PPAR
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Downregulated genes in fish oil feeding.
Of 102 genes that downregulated in fish oil feeding compared with
safflower oil feeding, 25 genes showed a decrease less than twofold. In
order of fold decrease, they are listed in Table
4 with their average differences and
putative function. Of 25 genes, 6 genes were related to cholesterol and
fatty acid synthesis. They were stearoyl-CoA desaturase, ATP
citrate-lyase, fatty acid synthase, squalene epoxidase, farnesyl
pyrophosphate synthetase, and low-density lipoprotein receptor. In
agreement with our previous findings (15), parallel with
decreases of these enzymes, a marked reduction of SREBP-1c may be
responsible for downregulation of cholesterol and fatty acid synthesis.
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Fish oil or fenofibrate administration downregulates genes related
to induction of endogenous PPAR activator.
Fish oil feeding downregulated the expression of cytochrome
P-450 17-alpha hydroxylase/C17-20 lyase and
sulfotransferases (Tables 3 and 4). Cytochrome P-450
17-alpha hydroxylase/C17-20 lyase catalyzes formation of
dehydroepiandrosterone (DHEA) from pregnenolone (25).
Because the sulfated form of DHEA by hydroxysteroid sulfotransferase is
a peroxisomal proliferator (39), marked reduction of both
17-alpha hydroxylase/C17-20 lyase and hydroxysteroid sulfotransferase may be an adaptive response to decrease production of
endogenous PPAR
activators. In addition, hydroxysteroid and phenol/aryl form sulfotransferases produce ROS (10).
Sulfation by sulfotransferase is a common final step in the
biotransformation of xenobiotics and is traditionally associated with
inactivation. However, the sulfate group is electron withdrawing and
may be cleaved off heterolytically in some molecules, leading to
electrophilic cation (10).
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DISCUSSION |
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By using gene-chip analysis, we have studied genes that were
markedly altered in expression levels by fish oil feeding. Although we
have selected some genes in limited number of genes, we could show not
only that the well-known genes related to fatty acid oxidation and
triglyceride synthesis, but also new classes of genes related to
PPAR activation and ROS production are markedly altered by fish oil feeding.
Fatty acids, particularly eicosanoids and their metabolites
(42), constitute one class of endogenous PPAR
activators, whereas steroid DHEA and its metabolites constitute another
class of naturally occurring PPAR
activators. When DHEA is
administrated to rodents, this androgen precursor acts as a strong
peroxisome proliferator (7, 40) and inducer of liver
peroxisomal enzyme expression and Cyp 4A gene transcription
(31). However, DHEA is effective in inducing each gene of
these mRNAs in rat liver in vivo (31), but this steroid
has no effect in cultured cells (32). This suggests that
DHEA per se is not an active inducer but that this metabolite is more
active inducer. In rat primary hepatocytes, DHEA-3
sulfate (DHEA-S),
a DHEA metabolite produced by steroid sulfation (14),
increases in peroxisomal enzyme and Cyp 4A expression levels at
physiologically relevant concentrations of DHEA (10 µM)
(32). In addition, because DHEA-S is unable to induce a liver peroxisome proliferative response in vivo when administrated to
PPAR
gene knockout mice (30), it is evident that
peroxisome proliferative response by DHEA-S is mediated by PPAR
. Our
finding that fish oil feeding resulted in marked reductions of two
important enzymes for DHEA-S formation, namely 17-alpha
hydroxylase/C17-20 lyase that catalyzes the conversion of
pregnenolone to DHEA and hydroxysteroid sulfotransferase that catalyzes
the conversion of DHEA to DHEA-S, indicates an operation of a
negative-feedback system to reduce endogenous ligand formation for
PPAR
activation against increased activation of PPAR
caused by
fish oil feeding (Fig. 4). Thus fish
oil-mediated PPAR
activation may inhibit steroid-mediated PPAR
activation to prevent some PPAR
-mediated deteriorative effects such
as ROS production and cancer formation (41). However, to
prove this hypothesis, it is necessary to identify endogenous ligands
for PPAR
activation and to show that fish oil feeding results in a
reduction of PPAR
ligands derived from the steroid pathway.
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Sulfotransferase is not only related to PPAR activation but also to
ROS production. Sulfotransferases are phase II drug-metabolizing enzymes that sulfoconjugate a variety of endogenous and exogenous compounds such as biogenic amines, steroid hormones, bile acids, drug,
and carcinogens (11, 16). However, the sulfate group is
electron withdrawing and may be cleaved off heterolytically in some
molecules, leading to an electrophilic cation (10). Fish
oil feeding and fenofibrate administration downregulate hydroxysteroid and phenol/aryl form sulfotransferase. Both types of sulfotransferases are related to ROS production. Thus downregulated hydroxysteroid and
phenol/aryl form sulfotransferase by fish oil feeding may contribute to
a decrease of ROS production.
In this line of evidence, fish oil feeding and fibrate administration
upregulated antioxidant genes such as UCP-2, glutathione transferase,
and Mn-SOD. Glutathione S-transferases (GST) are a multigene family;
four classes of protein, , µ,
, and
, have been demonstrated
(2). In mouse,
-class GST consists of two subunits Ya
and Yc. Glutathione transferase (L06047) in Table 2 corresponds to
4-type, which abundantly expresses in lung tissues
(43). Ya subunit gene expression is induced by planar aromatic compounds and electrophiles (8), and antioxidant
response element is found in the 5'-flanking region of this gene
(28). Fish oil feeding upregulated Ya,
4-, and
-types of GST to quench ROS in cytosol, whereas it upregulated UCP-2
and Mn-SOD to quench ROS in mitochondria (Fig.
5).
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Because fish oil-mediated alterations of gene expression related to ROS
production were also observed in fenofibrate-administered mice, it is
conceivable that alterations of these genes are mediated by PPAR
activation. However, altered gene expressions observed in fenofibrate
administration are due to the direct effects mediated by peroxisome
proliferator responsive elements or the indirect effects of other
cis-elements by PPAR
-activated gene products or
PPAR
-unrelated effects. Most of the fenofibrate effects are considered to be mediated directly and indirectly by PPAR
(17, 18), but it is not ruled out that in case of some genes, similar alterations of gene expression between fenofibrate administration and
fish oil feeding were merely coincident and were not related to PPAR
activation.
In this study, to clarify the effects of fish oil feeding, we used a
very high-fat diet (60% of total energy intake). We have observed that
there was a linear, dose-dependent effect of fish oil on upregulation
of PPAR-activated genes such as ACS, LPL, and UCP-2 mRNAs; 10% of
fish oil showed a significant increase of ACS, LPL, and UCP-2 mRNAs
(data not shown). Thus we expected that alterations of gene expression
observed in 60% oil diet would also be observed in the range of daily
intake of fish.
Another finding of gene-chip analysis is that immunological reaction
was observed in fish oil feeding, but this effect was not observed in
PPAR activator. Because lipid peroxidation products, which are
specific to fish oil feeding, are a potent chemostatic factor for
neutrophils (5), it is possible that fish oil feeding increases lipid peroxidation products and induces neutrophil migration and activation in liver tissues. Thus increased immunological reaction
as well as induction of antioxidant genes might be an adaptive reaction
against increased oxidative stress.
In summary, gene-chip analysis revealed that activators of PPAR,
such as fish oil and fenofibrate, altered gene expression profiles to
defend against excess PPAR
activation and ROS production.
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ACKNOWLEDGEMENTS |
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We are grateful to NOF for the supply of fish oil and to Dr. Nakagawa at Kitasato University for the supply of rat GST Ya subunit cDNA and to Dr. Ookawara at Hyogo Medical University for the supply of rat Mn-SOD cDNA.
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FOOTNOTES |
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This work was supported in part by Special Coordination Funds for Promoting Science and Technology from the Japanese Science and Technology Agency (Tokyo) and by research grants from the Japanese Ministry of Health, Labor, and Welfare (Tokyo) and the Japanese Ministry of Education, Culture, Sports, Science, and Technology (Tokyo).
Address for reprint requests and other correspondence: O. Ezaki, Division of Clinical Nutrition, National Institute of Health and Nutrition, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8636, Japan (E-mail: ezaki{at}nih.go.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpgi.00376.2001
Received 24 August 2001; accepted in final form 19 October 2001.
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