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Unité d’Expression des Gènes Eucaryotes, Institut Pasteur, Paris, France;
*
Departamento de Bioquimica y Biologia Molecular, Universidad de Leon, Leon, Spain; and
U545 Inserm, Institut Pasteur and Faculté de Pharmacie, Univ. Lille II, Lille, France
2To whom correspondence should be addressed. E-mail: mostos{at}pasteur.fr.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • fructose • transgenic mice • apolipoprotein gene expression.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–4
). Furthermore, fructose feeding has frequently been used to induce hyperinsulinemia, euglycemia and insulin-resistance (IR)3
in rats (5
,6
). However, this was not observed in the only mouse model studied to date. Indeed, Merat et al. (7
) found that a diet rich in fructose resulted in a marked hypercholesterolemia, but did not induce IR in LDL receptor–deficient mice (LDLR-/-). However, these mice developed more extensive atherosclerosis than the fat-fed LDLR-/- mice. This atherosclerotic increase was not accompanied by an increase in advanced glycation end products or oxidation-specific epitopes in the atherosclerotic lesions, indicating that other mechanisms such as a decrease in reverse cholesterol transport or an elevated blood pressure may be involved. Fructose intake has increased steadily during the past two decades due to its introduction as sweetener in pharmaceuticals and in mainstream food applications such as carbonated beverages, canned fruits, jams, jellies and dairy products. This has led to an increased interest in the study of diets rich in this nutrient.
The apolipoprotein (apo) AI-CIII-AIV gene cluster is involved in lipid metabolism and atherosclerosis (8
,9
). Overexpression of apo CIII in mice causes hypertriglyceridemia and induces atherogenesis (10
,11
), whereas overexpression of apo AI or apo AIV, the main components of HDL, protects against atherosclerosis (12
–15
). Expression of the three genes is controlled by a series of elements that are distributed throughout and extend beyond the cluster. These elements seem to coordinately regulate the transcription of all three genes (16
–18
). We recently generated transgenic (Tg) mice for the human apo AI-CIII-AIV gene cluster using a 33-kb genomic fragment containing the three genes and flanking sequences (19
). In these mice, the three genes of the cluster are expressed in hepatic and intestinal tissues. Transgenic mice exhibit gross hypertriglyceridemia and accumulation of apo B48–rich lipoproteins of d < 1.006 kg/L, but are protected against atherosclerosis. They are therefore an adequate model with which to study the effect of different nutrients on the expression of the three human genes.
The purpose of this study was to investigate in vivo the consequences of long-term fructose consumption on lipid metabolism and in human apo AI, CIII and AIV gene expression.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Male Tg mice for the human gene cluster apo AI-CIII-AIV (line 12) generated in our laboratory (19
) were used. The Tg line was established and maintained in the C57BL/6 genetic background (Charles River, Saint Aubin les Elbeuf, France). Nontransgenic littermates were used as controls. Mice were housed in a temperature-controlled room with alternating 12-h light (0700–1900 h) and dark periods (1900–0700 h). The mice consumed water ad libitum, and a cholesterol-free nonpurified diet containing (g/kg) the following: protein, 214; lipid, 51; carbohydrate, 517; and sucrose and fructose < 5 (Standard diet A03, UAR, Toulouse, France). At 2 mo of age, the nonfructose groups were provided with tap water and the fructose groups with a 250 g/L fructose solution. The calculated average daily intake of fructose per mouse was 
1.5 g. For 9 mo, control and Tg mice were allowed free access to the food and water or sugar solution. All procedures involving animal handling and care were conducted in accordance with Pasteur Institute Guidelines for Husbandry of Laboratory Mice.
RNA isolation and Northern blot experiments.
After overnight food deprivation, mice were killed by cervical dislocation and tissues (liver and small intestine) were removed and frozen (-80°C). Total RNA was extracted with RNA-plus (Quantum, Illkirch, France) and samples were purified, separated by electrophoresis (20 µg total RNA/lane) on a 1% agarose gels containing formaldehyde, blotted onto Hybond-N+ membrane (Amersham Pharmacia Biotech, Saclay, France) and hybridized in quickHyb solution (Stratagene, La Jolla, CA) with 32P-labeled cDNA probes for each human apolipoprotein, as previously reported (19
). The human ubiquitin probe (Clontech Laboratories, Palo Alto, CA) was used as a control. Hybridization was carried out according to the QuickHyb Hybridization Solution instruction manual (Stratagene). Autoradiographs were scanned with NIH Image program. Signals were normalized according to the ubiquitin signal. The results were analyzed with the Statview computer program. Differences were tested by ANOVA, and P < 0.05 was considered significant.
Apolipoprotein quantification.
Human apo A-I and C-III concentrations in plasma were quantified by gel agarose immunoelectrophoresis with highly specific polyclonal antibodies (Hydragels SEBIA, Issy-les-Moulineaux, France); mouse apoproteins did not cross-react at detectable levels. Human apo A-IV plasma concentration was determined using an antibody-sandwich ELISA assay.
Apo B48 and apo B100 were quantified in different lipoprotein fractions. They were separated by SDS-PAGE in 4–15% gradient polyacrylamide PhastGels (Amersham Pharmacia Biotech). Gels were silver stained, scanned and analyzed using a videodensitometer scanner and NIH image software; results were normalized by total protein concentration in each fraction. Protein concentrations were determined using a Micro BCA Protein Assay Kit (Pierce, Rockford, IL). Analyses were repeated three times for each different group of mice.
Glucose, insulin and lipid determination.
Blood from mice deprived of food for 8 h was obtained by retroorbital bleeding under isofluorane anesthesia, before the sugar supply, and once a month during the treatment. Plasma triglycerides and cholesterol levels were determined enzymatically using commercial kits (Peridochrom Triglycerides GPO-PAP and Cholesterol CHOD-PAP, Boehringer Mannheim, Mannheim, Germany). All assays were calibrated using appropriate dilutions of pooled human serum, Precinorm L (Boehringer Mannheim). Plasma glucose concentration was also determined enzymatically using a GOD-PAP method (Boehringer Mannheim). Plasma insulin was measured by RIA (kit ref. Insulin CT, ORIS, Gif sur Yvette, France).
Lipoproteins were separated into d < 1.006, d = 1.006–1.019 and d = 1.019–1.063 kg/L fractions by sequential isopycnic ultracentrifugation using KBr to adjust densities. Pooled plasma samples (equal aliquots of plasma from each group of mice) were used. Each centrifugation was carried out for 2 or 2.5 h at 435,000 x g at 15°C in a fixed-angle rotor as described (20
). Plasma lipoprotein distribution was also assayed using a fast protein liquid chromatography system (FPLC; Pharmacia, Sweden) with one Superose 6 and one Superose 12 HR column (Pharmacia, Sweden). The columns were equilibrated with PBS-EDTA buffer containing 1.5 mmol/L NaN3. The absorbance of the eluate was monitored at 280 nm. In each analysis, 200 µL of pooled mice plasma was injected and eluted at a constant flow rate of 12 mL/h. Fractions of 0.5 mL were collected in which we determined the distribution of the human apolipoproteins after quantification with the same methods used for whole-plasma samples. These experiments were carried out 4 mo after the beginning of the treatment.
Statistical analysis was done using the StatView program (Berkeley, CA). Data were expressed as means ± SD. Two-way ANOVA was used to test the significant genetic effects, fructose effects and their interaction on plasma lipids, glucose concentration, final weight and final insulin concentration. Fisher’s protected least significant difference was used as a post-hoc test. One-way ANOVA was applied to analyze differences in human apolipoprotein concentration and in human apolipoprotein mRNA levels. All analyzed variables except triglycerides were normally distributed as assessed by the Kolmogorov-Smirnov test. Triglyceride concentrations were logarithmically transformed to achieve an approximately normal distribution, and ANOVA was then applied to the transformed values. Differences were considered significant at P < 0.05. Values are means ± SD.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). Plasma glucose and insulin concentrations were not affected by fructose or genetic group (Table 1)
. Plasma cholesterol and triglyceride concentrations were significantly higher in Tg than in control mice and an increase due to fructose treatment was observed only in Tg mice (Table 1)
.
|
). In control mice, only cholesterol concentration was also enhanced in the d = 1.019–1.063 kg/L fraction, corresponding to LDL (Table 2)
. In Tg mice, fructose augmented the apo B48 concentration in the three lipoprotein fractions analyzed, whereas in control mice, fructose increased apo B48 particles mainly in the d = 1.019–1.063 kg/L fraction. In Tg mice, fructose augmented the apo B100 particles in the three lipoprotein fractions, whereas in control mice consuming fructose, apo B100 particles were also increased, but principally in the d = 1.019–1.063 kg/L fraction (Table 2)
. In conclusion, fructose ingestion in apo AI-CIII-AIV Tg mice increased cholesterol and triglyceride levels mainly in VLDL particles containing apo B48 and apo B100, and increased LDL cholesterol in control mice.
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). Hepatic human apo AIV mRNA abundance was enhanced 320% by fructose, whereas the levels of intestinal human apo AIV mRNA were 63% lower. The abundance of human hepatic apo AI and apo CIII mRNA was not affected by fructose (Table 3)
. The plasma concentration of the three human apolipoproteins was greater in fructose-fed Tg mice than in untreated mice (Fig. 1
). The greatest increase (threefold) was in the human apo AIV plasma concentration, consistent with the threefold augmentation of the corresponding apolipoprotein mRNA concentration in liver.
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). Results confirmed the increased concentrations of the three apolipoproteins found in plasma due to fructose treatment. In mice fed both diets, apo A-I was present principally in HDL, but also in small lipid-poor particles; interestingly apo A-IV and apo C-III were also present in this size range. Apo C-III levels were not enhanced in VLDL particles of Tg mice that drank the fructose solution.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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) demonstrated that a fructose diet increases triglycerides in men. They also observed a transient increase in LDL cholesterol that did not persist. However, they could not exclude the possibility that fructose has adverse effects on fasting plasma cholesterol, effects that their study did not have the power to detect. Because their analysis was performed in healthy subjects, the results observed in the apo AI-CIII-AIV Tg mice in the present study suggest that the effect of fructose on hyperlipidemic subjects may be more dramatic. Hyperlipidemia in humans has been related to genetic variations in the apo AI-CIII-AIV gene cluster (22
,23
) and to mutations in the apo CIII gene (24
). Therefore, it would be interesting to study the effect of fructose in these groups.
The mechanism by which fructose increases triglycerides may be due to the stimulation of triacylglycerol synthesis, as had been previously described in rats (4
,25
). This is consistent with the fact that we observed an increase in apo B48 and apo B100 levels due to fructose. The apo AI-CIII-AIV Tg mice are characterized by an increase of d < 1.006 kg/L apo B48-rich particles when fed in a standard diet (19
). However, after fructose treatment, the accumulation of particles in this fraction also rich in apo B100 indicate that they have a possible hepatic origin. We hypothesize that the apo B48 increase observed is related to the fact that in mice, a high percentage of apo B mRNA from liver is subject to splicing (26
). In control mice, the particles accumulated are rich in apo B100 and have a d = 1.019–1.063 kg/L, corresponding to LDL. Thus, the differences between Tg and control mice can be due to the higher expression of apo CIII in the Tg mice, which inhibits triglyceride hydrolysis mediated by lipoprotein lipase, resulting in a greater accumulation of triglyceride-rich lipoproteins.
We did not observe any difference in final weight due to the fructose treatment between the control and the Tg mice. However, at the end of the study, the fructose-treated Tg mice had a large fat accumulation in the sternum that was not observed in Tg mice that consumed water (data not shown). The plasma glucose concentration was unaffected in Tg and control mice throughout the study period and we did not observe any difference in insulin levels among the different groups of mice at the end of the study. These results suggest that, in contrast to those described in rats (5
,6
), fructose does not induce IR in mice. In a unique murine model previously subjected to a fructose-rich diet, Merat et al. (7
) obtained similar results, i.e., a fructose diet did not enhance IR in LDLR-/- mice. However, after consuming a Western-type diet, these mice develop IR. Interestingly, mice fed this diet gained much more weight than those fed a fructose-rich diet. In the same study, the authors analyzed the extent of atherosclerosis in mice fed both diets and observed that the fructose-fed group had a significantly greater extent of atherosclerosis than the Western-diet group (7
). We have also analyzed atherosclerotic formation in our model, but we did not find any lesions in either Tg or control mice that consumed fructose, suggesting that the cholesterol increase observed due to this diet is not sufficient to produce lesions in mice with a C57Bl/6 genetic background.
We have also examined the regulation of the human apo AI-CIII-AIV gene cluster expression in response to fructose. The Tg mouse model used was generated using a 33-kb human genomic fragment containing the entire cluster and its 5' and 3' flanking regions. These mice provide an interesting model for studies of the regulation of the three genes in combination. We observed a threefold increase in hepatic human apo AIV mRNA abundance after the fructose treatment; in contrast, the levels of intestinal human apo AIV mRNA decreased 63%. In addition, we did not find a difference in human apo AI and apo CIII mRNA levels in liver. In the intestine, no expression of the two human genes was observed. However, the concentration of the three human apolipoproteins in total plasma as well as in the subfractions isolated by FPLC, were greater in fructose-treated Tg mice than in untreated Tg mice. The main increases were observed for apo AIV. Interestingly, FPLC analysis did not show major changes in the distribution of human apolipoproteins in Tg mice consuming fructose. Several studies in animals have demonstrated differential expression of the apo AI and apo AIV genes in response to dietary perturbations. Apo AIV, but not apo AI mRNA abundance in enterocytes of rats increased after a fat bolus (27
). Interestingly, we have recently demonstrated that after a cholesterol-rich diet, apo AI-CIII-AIV Tg mice had increased intestinal human apo AI, apo CIII and apo AIV mRNAs. This was accompanied by an augmentation in the concentration of the corresponding proteins in plasma, but particularly in that of apo AIV (28
). These results were consistent with previous observations that apo AIV plasma concentration in rats and in humans were enhanced after a fat- or cholesterol-rich diet (29
,30
). We have no experimental explanation to account for the decreased human apo AIV mRNA level in the intestine after the fructose treatment. We hypothesize that the addition of fructose to the drinking water induces a satiety effect that could reduce food consumption (hence lipid intake), without modifying total energy intake.
In this report, we demonstrated that fructose increases principally human apo AIV gene expression in liver at the transcriptional level. Because fructose increases hepatic triglyceride synthesis and secretion, our study suggests an association between apo AIV gene transcription and hepatic lipogenesis. Although the function of apo AIV in the context of cellular lipoprotein assembly and secretion is unknown, several lines of evidence have already suggested a strong association between apo AIV gene expression and triglyceride synthesis and secretion (31
–35
). Similarly, the hepatic apo AIV and triglyceride increase have been observed in rats fed a sucrose-rich diet (36
). Because sucrose is composed of glucose and fructose, the latter observation can be explained by the presence of fructose in the diet.
In conclusion, the present study demonstrates that fructose administered as a 250 g/L drinking solution increases triglyceride and cholesterol concentrations in apo AI-CIII-AIV Tg mice. This is associated with an increased abundance of human hepatic apo AIV mRNA and of the plasma apo AIV concentration. To test the atherogenic effect of fructose, further experiments must be performed using the apo AI-CIII-AIV Tg mice but in an apo E-deficient background.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: apo, apolipoprotein; FPLC, fast protein liquid chromatography; IR, insulin-resistance; LDL-/-, LDL receptor deficient; Tg, transgenic.
Manuscript received 19 October 2001. Initial review completed 15 November 2001. Revision accepted 11 February 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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