2 Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, and 1 Graduate School of the Biomedical Sciences, Newark, New Jersey 07103-2714
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ABSTRACT |
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Fructose transporter (GLUT-5) expression is low in mid-weaning rat small intestine, increases normally after weaning is completed, and can be precociously induced by premature consumption of a high-fructose (HF) diet. In this study, an in vivo perfusion model was used to determine the mechanisms regulating this substrate-induced reprogramming of GLUT-5 development. HF (100 mM) but not high-glucose (HG) perfusion increased GLUT-5 activity and mRNA abundance. In contrast, HF and HG perfusion had no effect on Na+-dependent glucose transporter (SGLT-1) expression but increased c-fos and c-jun expression. Intraperitoneal injection of actinomycin D before intestinal perfusion blocked the HF-induced increase in fructose uptake rate and GLUT-5 mRNA abundance. Actinomycin D also prevented the perfusion-induced increase in c-fos and c-jun mRNA abundance but did not affect glucose uptake rate and SGLT-1 mRNA abundance. Cycloheximide blocked the HF-induced increase in fructose uptake rate but not the increase in GLUT-5 mRNA abundance and had no effect on glucose uptake rate and SGLT-1 mRNA abundance. In neonatal rats, the substrate-induced reprogramming of intestinal fructose transport is likely to involve transcription and translation of the GLUT-5 gene.
membranes; mucosa; nutrient transport; sodium ion-dependent glucose transporter; sugars
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INTRODUCTION |
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AT BIRTH, THE MAMMALIAN small intestine undergoes an abrupt transition from being an nonutilized organ to one with a vital new function: the absorption of digested nutrients from milk. At weaning, it undergoes a second transition, acquiring the ability to synthesize different types or different numbers of nutrient transporters to match expected changes in intestinal luminal substrate concentrations. All cells differentiate, proliferate, or undergo apoptosis during development, depending on signals received from neighboring cells. Unlike most cells, intestinal epithelial cells are also directly exposed to environmental cues via luminal contents. An unsolved problem in developmental biology is how intestinal cells interpret these two types of signals and how these signals alter the expression of brush-border enzymes and transporters. Weaning-related increases in sucrase activity have been shown to rely more on endogenous signals than on luminal cues and to be primarily regulated at the mRNA level (18). In contrast, little is known about molecular regulation of nutrient transporters during development, particularly in rats, which like humans are omnivores and for which much is known about other aspects of gut development. In sheep, ruminant herbivores, regulation of the Na+-dependent glucose transporter SGLT-1 during development is dependent almost entirely on luminal signals and on translational or posttranslational processes (21).
The brush-border fructose transporter GLUT-5 (4) is normally expressed at significant levels in rat and rabbit intestines only after completion of weaning (6, 19, 22, 25). In rats, the expression of GLUT-5, which appears only after 28 days of age, is considerably delayed compared with that of SGLT-1 and many intestinal amino acid transporters, all of which are active well before birth (2). Postponing the completion of weaning does not postpone the appearance of GLUT-5 (25), suggesting that the program regulating its postweaning appearance is "hardwired." Our laboratory (11, 22) has demonstrated that this developmentally regulated time course of GLUT-5 expression can be reprogrammed so that marked increases in GLUT-5 activity and mRNA abundance can be observed in 18- to 26-day-old pups, several days ahead of the natural schedule. Although the signal required for reprogramming normal neonatal GLUT-5 development is now known to be primarily luminal fructose (23), the molecular mechanisms underlying substrate modulation are not known.
We therefore tested the hypothesis that the precocious enhancement of intestinal fructose transport by luminal fructose is regulated mainly at the level of transcription. We first had to establish an in vivo perfusion model that could mimic the precocious enhancement of fructose absorption by dietary (pelletized) fructose in free-living weaning rats, because preliminary work showed that free-living weaning rats injected with transcription inhibitors consume less food than vehicle-injected rats. Using the perfusion model, we could control perfusion duration and nutrient concentrations in the perfusate. We injected weaning rats with the transcription inhibitor actinomycin D or the translation inhibitor cycloheximide, perfused the intestines in vivo, and then assayed the intestines for transporter activity and mRNA concentration.
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MATERIALS AND METHODS |
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Animals
Adult male and female Sprague-Dawley rats weighing ~200 g were purchased from Taconic and bred. Rats were allowed free access to water and chow (Purina Mills). During the mating and pregnancy period, the rat diet was supplemented with cheese (2 g · dayTo estimate luminal fructose concentrations, luminal contents were collected following the method of Ferraris et al. (13) from intestines of weaning rats (21 to 22 day old) fed 65% (wt/wt) fructose (n = 3) or 65% glucose pellets (n = 3) (for composition, see Ref. 22). Soluble fructose concentrations were determined spectrophotometrically at 340 nm (16).
Perfusion Model
Rat pups (21 to 22 day old, not starved) were anesthetized by intraperitoneal injection (20% ketamine and 12.5% xylazine in 0.9% NaCl, 2.5 ml/kg body wt). The abdominal cavity was opened, and the small intestine with intact blood vessels and nerve connections was exposed. About 10 cm distal to the stomach, a small incision was made, and a catheter was inserted into the lumen and then secured with surgical thread. A plastic tube (Tygon, 0.8-mm ID) was catheterized into the ileum 10 cm from the ileocecal valve. After the contents were flushed, the small intestine (100 mM fructose or glucose in Ringer, 37°C) was continuously perfused with sugar solution at a rate of 60 ml/h at 37°C using a peristaltic pump. The composition of the perfusion solution was as follows (in mM): 78 NaCl, 4.7 KCl, CaCl2 · 2.5H2O, 1.2 MgSO4, 19 NaHCO3, 2.2 KH2CO3, and 100 fructose or glucose. Rat pups were kept under continuous anesthesia by adding ketamine cocktail into the abdominal cavity every 30 min. Body and perfusion solution temperatures were maintained at 37°C by heating pads and water baths, respectively.To determine the effect of perfusion on intestinal morphology, the intestines from pups perfused for 8 h with 100 mM fructose [high fructose (HF); n = 2], pups perfused with 100 mM glucose [high glucose (HG); n = 2], or littermates with access to mother's milk and chow (MMC; n = 2) were collected and then fixed in formaldehyde, paraffinized, and cut into thin sections for light microscopy.
A second series of pups was divided into three groups, and the
intestines were perfused for 1, 4, or 8 h. Each group was further divided into two subgroups (n = 7-8
rats/subgroup), one of which was perfused with HF and the other with HG
(control). At the end of each perfusion, the small intestine was gently
isolated and flushed with ice-cold Krebs-Ringer- bicarbonate solution.
Representative tissues (~10 cm from the stomach) were isolated and
everted for sugar uptake determinations (n = 2 per
sugar per rat). The tissue 15-20 cm from the stomach was frozen in
liquid nitrogen and stored at 80°C for later Northern blot
analysis. Fructose and glucose absorption rates as well as GLUT-5 and
SGLT-1 mRNA abundance were measured. Results were then compared with
those from the classic feeding model used in previous work (22,
23).
Effect of Actinomycin D on Luminal Fructose-Induced Increase in Fructose Absorption
Pups were injected with actinomycin D (2.4 mg/kg body wt ip) or vehicle (10% ethanol in PBS) 12 h before intestinal perfusion. One group of pups was perfused with sugar solutions for 1 h and another group for 4 h. Each group was further divided into six subgroups (n = 5-6 pups/subgroup), as follows. Pups were 1) injected with vehicle and perfused with HF, 2) injected with actinomycin D and perfused with HF, 3) injected with vehicle and perfused with HG, 4) injected with actinomycin D and perfused with HG, 5) injected with vehicle but not operated or perfused and instead remained with the dam (MMC), and 6) injected with actinomycin D but not perfused and remained with the dam. After each perfusion, fructose and glucose absorption rates as well as GLUT-5 and SGLT-1 mRNA abundance were determined. The mRNA abundance of the immediate-early genes known to be enhanced during perfusion, c-fos and c-jun, was also measured to ensure that transcription of inducible genes other than GLUT-5 was inhibited by actinomycin D.Effect of Cycloheximide on Luminal Fructose-Induced Increase in Fructose Absorption
Mid-weaning rats were injected (2.5 mg/kg body wt ip) with cycloheximide or vehicle (0.6% ethanol in PBS) 1 h before intestinal perfusion for 4 h, because previous studies (see Fig. 1) indicated that this duration was sufficient for fructose-enhanced GLUT-5 expression. Rats were divided into the following four groups (n = 5-6 pups). Rats were 1) injected with vehicle and perfused with HF, 2) injected with cycloheximide and perfused with HF, 3) injected with vehicle and perfused with HG, and 4) injected with cycloheximide and perfused with HG. After perfusion, sugar absorption rates and transporter mRNA abundance were determined.
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Northern Blot Analysis
Total RNA isolation, Northern blot analysis, and hybridization methods were as described previously (22). Briefly, cDNA probes were each labeled with [32P]dCTP using a random primer labeling kit (RTS RadPrime, GIBCO BRL). After air drying, the membrane was exposed to an X-ray film for ~4-48 h depending on blot density. To remain within the linear part of the sensitivity of the film to radioactivity in the membrane, each X-ray film was checked for saturation. Quantification was performed using the IS-1000 digital imaging system (Alpha Innotech).Rat 18S and GLUT-5 cDNA were gifts from Drs. M. Lee and C. Burant, respectively. The SGLT-1 probe was generated by PCR. Total RNA isolated from rat small intestine was first used as a template in a reverse transcription reaction to generate cDNA. A pair of primers (5) was used to amplify the reverse-transcribed product. A 908-bp expected product was generated and used as the SGLT-1 probe. Mouse c-fos and c-jun cDNA probes were purchased from the American Type Culture Collection.
Sugar Uptake Measurements
Glucose and fructose uptake rates were determined by following the technique of Karasov and Diamond (15). Briefly, a 1-cm segment was everted and mounted on a grooved steel rod (3-mm diameter) and preincubated at 37°C for 5 min in Ringer solution bubbled with 95% O2-5% CO2. The sleeves were then incubated at 37°C in an oxygenated solution containing either D-[14C]glucose for 1 min or D-[14C]fructose for 2 min. L-[3H]glucose was used to correct for adherent fluid and passive diffusion of glucose or fructose. All radioisotopes were purchased from NEN (Boston, MA). Results were expressed as nanomoles per milligram wet weight of intestine. Because uptake rates of glucose or fructose were measured twice in each rat, the average was used to represent glucose or fructose absorption in that rat. Sugar uptakes were determined at 50 mM, which yields near maximum velocity (Vmax) values, so that any change in uptake rate will be due mainly to a change in Vmax (15, 24).Statistical Analysis
A two-way ANOVA was first used to determine the significance of the difference of relative absorption rates and mRNA abundance among groups with different treatments. If there was a significant difference, a one-way ANOVA or unpaired t-test was used to determine the particular effect that caused that difference. P ![]() |
RESULTS |
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Luminal Fructose Concentrations
The mean luminal fructose concentration in weaning rats fed 65% fructose pellets, a diet known to enhance GLUT-5 expression (23), was 26 ± 5 mM. In littermates fed 65% glucose pellets, fructose concentration was not detectable. In a previous study (13), adult rats fed 65% glucose pellets had mean luminal glucose concentrations that ranged from 10 ± 6 mM at 4 PM to 100 ± 35 mM at 8 PM in the proximal intestine. We therefore used 100 mM as the concentration of sugars in the perfusate.Animal Survival and Villus Morphology
All animals survived after 1-, 4-, and 8-h perfusion of their intestines in vivo. The perfused small intestine had a good blood supply throughout the experiment, as indicated by its healthy pink color and the pulse of the mesentery arteries. The diameter of the intestinal lumen and the height of villi were similar (not shown) among MMC rats and littermates perfused with HF or HG. There was no perfusion-related difference (not shown) in enterocyte dimensions. However, there tended to be more mucus in the intestinal lumen of perfused pups.Effect of Perfusion on mRNA Abundance and Uptake Rates
After 1 h of perfusion, there was a 50% increase (P = 0.036) in GLUT-5 mRNA abundance in HF- vs. HG-perfused intestines (Fig. 1). After 4 and 8 h, GLUT-5 mRNA abundance increased markedly (P < 0.0001) in HF-perfused intestines to levels three times higher than in HG-perfused intestines (Fig. 1). In a previous study (23), same-age pups refed 65% fructose pellets after a 12-h fast also markedly increased their intestinal GLUT-5 mRNA 4 and 8 h after refeeding. The time course of GLUT-5 mRNA increase was similar between pellet-fed and perfused pups (Fig. 1B). There was no statistical difference (P = 0.3~0.9) in SGLT-1 mRNA abundance between HF- and HG-perfused intestines after 1-, 4-, and 8-h perfusion (not shown).There were marked effects of perfusion solution (P = 0.0006)
and perfusion duration (P = 0.02) on fructose uptake rate
(Fig. 2). Initially, there was no
significant difference in fructose uptake rate between HF- and
HG-perfused intestines after 1 h (P = 0.41). However,
after 4- and 8-h perfusion, fructose uptake rates increased by 50%
(P = 0.014) and 200% (P = 0.017), respectively. Hence, the longer the duration of HF perfusion, the greater the increase in fructose uptake. Similar results were obtained in same-age
pups refed 65% fructose pellets after a 12-h fast (23). As in perfused rats, fructose uptake rates increased markedly 4 and
8 h after refeeding (Fig. 2). There was no significant effect of
perfusion solution and perfusion duration (P = 0.99 and
0.08, respectively) on glucose uptake rate (not shown). Our initial studies clearly indicated that intestinal perfusion of fructose in vivo
mimics the intestinal response of weaning pups to precocious consumption of fructose pellets.
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Effect of Actinomycin D
GLUT-5 and SGLT-1
mRNA.
When comparing HF, HG, and MMC vehicle-injected pups after 1 h of
perfusion, there was a marked effect of perfusion solution (P = 0.0042 by one-way ANOVA) on GLUT-5 mRNA
abundance that was greatest in HF pups (Fig.
3A). Although actinomycin D
modestly inhibited GLUT-5 mRNA abundance in HG (P = 0.014) and MMC (P = 0.09) pups, it markedly
inhibited the fructose-induced increase in GLUT-5 mRNA abundance in
HF-perfused pups (P < 0.0001). GLUT-5 mRNA levels were
similar (P = 0.6) among actinomycin D-injected pups.
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c-fos and c-jun mRNA.
After 1 and 4 h, HG and HF perfusion (P 0.03 by
one-way ANOVA) each increased c-fos mRNA abundance in the
absence of actinomycin D (Fig.
4A). There was an effect of
actinomycin D on c-fos expression in perfused (P
0.004) but not in nonperfused (P
0.5) MMC animals. Hence, actinomycin D blocked the perfusion-induced increase in c-fos mRNA expression.
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Fructose and glucose uptake.
After 1 h, there was no effect of perfusion solution (P
= 0.54) on fructose uptake in both actinomycin D- and
vehicle-injected pups (Fig.
5A). Actinomycin D had no
effect (P = 0.11) on fructose uptake in HF, HG, and MMC
pups. After 4 h, however, there was a marked increase (P
= 0.018) in fructose uptake rates in HF compared with HG and MMC
pups in the vehicle-injected group. The inhibitory effect of
actinomycin D was significant only in HF-perfused intestines (P
= 0.02). There were no actinomycin D effects in the HG and MMC
pups (P = 0.82 and 0.20, respectively). In the 1- and 4-h groups, there was no effect of perfusion solution (P 0.23) and actinomycin D (P
0.59) on glucose uptake rates
(Fig. 5B).
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Low dosage of actinomycin D. Because of reports (e.g., Ref. 17) suggesting that actinomycin D had no effect on diet-induced changes in gene transcription, the effects of a lower dosage of actinomycin D on GLUT-5 expression were examined. Rat pups were injected with actinomycin D (0.24 mg/kg body wt, as described in Ref. 17) 12 h before perfusion with either HF or HG. In animals injected with vehicle (P = 0.015) or with actinomycin D (P = 0.005), HF perfusion significantly enhanced GLUT-5 mRNA abundance (not shown) and fructose uptake rates (not shown) relative to those in HG perfusion. This suggested that a 10× lower actinomycin D dose did not block the effect of fructose perfusion on GLUT-5 expression.
As previously observed, in pups injected with vehicle (P = 0.88) or with low dose of actinomycin D (P = 0.75), there is no significant difference in glucose uptake rate and SGLT-1 mRNA abundance among pups perfused with different sugar solutions (not shown).Effect of Cycloheximide
GLUT-5 and SGLT-1 mRNA.
GLUT-5 mRNA abundance varied with perfusion solution (P =
0.0002) but was independent of cycloheximide treatment (P =
0.614, Fig. 6A). In
cycloheximide-treated and untreated pups, GLUT-5 mRNA abundance in
intestines perfused with HF increased 2-21/2 times over those
perfused with HG (P 0.0017). In contrast, SGLT-1 mRNA
abundance was independent (Fig. 6B) of perfusion solution (P = 0.88) and cycloheximide (P = 0.75).
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Fructose and glucose uptake.
Fructose uptake rate varied with perfusion solution (P = 0.04) and cycloheximide (P = 0.0074). In pups injected
with vehicle, HF perfusion enhanced fructose uptake rates by 50%
(P = 0.0035) compared with littermates also perfused with HF
but injected with cycloheximide (Fig.
7A). Perfusion solution
(P = 0.97) and cycloheximide (P=0.77) had no
effect on glucose uptake rate (Fig. 7B).
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DISCUSSION |
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In Vivo Perfusion Model Mimics the Feeding Model
In the precocious feeding model, only fructose, but not glucose or other sugars except sucrose, can enhance GLUT-5 expression (11, 22). In neonatal (23) and adult (3) rats subjected to Thiry-Vella surgery, dietary fructose enhanced GLUT-5 mRNA abundance and fructose uptake rate only in intestinal segments through which the food passed, further confirming that luminal fructose was required for the enhancement of GLUT-5. In the perfusion model, we confirm not only the specificity of luminal fructose as the signal for GLUT-5 enhancement during development [because HG (see Figs. 1 and 3) and mannitol (unpublished observations) perfusion has no effect on GLUT-5] but also the time course of enhancement of fructose transport. In both models, fructose uptake rate and GLUT-5 mRNA abundance are each markedly enhanced by luminal fructose after 4 h.In the feeding (22, 23) and perfusion models, the expression of SGLT-1 is not affected by its substrate glucose and other monosaccharides. We have therefore confirmed, using two independent methods, that SGLT-1 expression cannot be modulated and is instead programmed to run at full capacity during the early developmental stages of the rat. GLUT2, the basolateral glucose and fructose transporter (7), is also not regulated by diet in weaning rats (22). This is in stark contrast to sheep and adult rodents, in which SGLT-1 and GLUT2 are upregulated by luminal glucose, dietary carbohydrate, or intestinal hormones (8, 9, 12, 21). Modulation of SGLT-1 may be unnecessary during early development because milk is the main nutrient source and yields only glucose and galactose, substrates of SGLT-1. Through evolution, this source of nutrition was consistently and constantly available during the suckling and weaning stages, and perhaps there was no need to develop regulatory mechanisms to modulate SGLT-1 expression. In contrast, modulation of GLUT-5 is permitted if pups must be weaned early (e.g., death of dam) and would need to subsist on a diet that varies in nutrient composition.
Precocious Enhancement Requires De Novo mRNA Synthesis
Because actinomycin D blocks the fructose-induced increase in fructose uptake rate and GLUT-5 mRNA abundance without affecting glucose uptake rate and SGLT-1 mRNA abundance in fructose-perfused intestines, the inhibitory effect of actinomycin D is clearly specific to transcriptional events regulating the fructose transporter. This specific effect is dose dependent, because a concentration of actinomycin D that is 10 times lower has no effect. It is not caused by nonspecific effects on nutrient transporters, because SGLT-1 mRNA abundance is not affected. The parallel, tightly linked changes in GLUT-5 mRNA abundance and fructose uptake rates in actinomycin D- and vehicle-injected pups indicate that enhanced transcription of GLUT-5 mRNA is needed for the fructose-induced increase in fructose uptake rate in mid-weaning rats that otherwise would normally have a low fructose uptake rate. In neonatal rats, there is also a very low turnover rate of enterocytes (1), probably allowing these regulatory transcriptional events to occur in the same enterocytes that received the luminal fructose signal.If we compare the effects of HF and HG perfusion after 1 h, HF can enhance GLUT-5 mRNA abundance (Figs. 1B and 3A) but not fructose uptake rate (Figs. 2 and 5A). Fructose uptake increases only after 4 h of HF perfusion. The time-dependent, sequential increase in GLUT-5 activity after an increase in GLUT-5 mRNA abundance is also supportive of transcriptionally regulated GLUT-5 induction by luminal fructose. It is interesting to note that, in the 1-h perfusion group, actinomycin D reduced the already low level of GLUT-5 mRNA in the MMC and HG groups. This may indicate that GLUT-5 is actively transcribed at a very low rate under normal conditions and that this low level of GLUT-5 mRNA is responsible for the baseline level of fructose uptake exhibited by the small intestine at this age. The absence of an actinomycin D effect on SGLT-1 mRNA abundance and glucose uptake rate suggests that, in developing rats, SGLT-1 mRNA may be very stable and SGLT-1 protein turns over slowly.
Because c-fos and c-jun expression is very low in MMC animals and perfusion per se (mannitol perfusion increases c-fos and c-jun mRNA; unpublished observations) enhances their mRNA abundance, c-fos and c-jun are very good markers to determine the effectiveness of actinomycin D in suppressing induced expression of genes. Indeed, actinomycin D blocked the perfusion-induced increase in c-fos and c-jun mRNA abundance, suggesting that it blocked the transcription of inducible genes other than GLUT-5. This control is needed to distinguish between two alternative interpretations of a negative finding (absence of an actinomycin D effect): 1) actinomycin D did not block the upregulation of a gene of interest or 2) actinomycin D was ineffective at blocking transcription at a certain dose.
Precocious Enhancement Requires De Novo Protein Synthesis
The fructose-induced increase in fructose uptake requires de novo protein synthesis, probably of GLUT-5 protein, and this in turn requires upregulated transcription of the GLUT-5 gene. Cycloheximide blocks the increase in GLUT-5 protein abundance after gavage feeding of adult rats with 5 mM fructose solutions for 4 h (10). Thus the inhibition of fructose-induced increases in fructose uptake rate by cycloheximide is likely due to inhibited synthesis of GLUT-5 proteins. This inhibition cannot be due to the nonspecific toxic effects of cycloheximide, because glucose uptake rate is not affected in fructose- or glucose-perfused intestines of cycloheximide-treated rats and cycloheximide has no effect on fructose-enhanced increases in GLUT-5 mRNA abundance and on steady-state levels of SGLT-1 mRNA. These results also indicate that the upregulation of GLUT-5 mRNA abundance does not need de novo protein synthesis of transcriptional factors to turn on its transcription. Increased concentrations of intracellular fructose or of its metabolites apparently can activate existing transcriptional factors required for GLUT-5 transcription.Cycloheximide may also increase mRNA abundance by enhancing mRNA stability through inhibition of the synthesis of enzymes for mRNA degradation in intestinal cells. This effect does not seem likely, because there should also be an increase in GLUT-5 mRNA abundance in vehicle-injected pups perfused with HG compared with cycloheximide-injected pups perfused with HG.
The expression of sugar transporters in adult intestine may have a distinct circadian rhythm (6, 10, 20). Superimposed on this diurnal regulation is a dietary effect, and either diurnal or dietary regulation can sometimes be blocked by cycloheximide. In contrast, GLUT-5 mRNA expression and transporter activity in weaning rats did not follow a circadian rhythm (22). This might be caused by differences in feeding habits between adult and weaning rats, because the typical diurnal rhythm of food intake of adult rats begins only when postweaning pups reach 29 days of age (14).
The precocious enhancement of intestinal fructose transport by dietary fructose probably requires de novo mRNA and protein synthesis. Direct measurements of transcription and translation rates are needed to confirm these findings.
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ACKNOWLEDGEMENTS |
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We thank Drs. C. Burant and M. Lee for the cDNA probes and Dr. M. Dudley for reviewing the manuscript.
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FOOTNOTES |
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This work was supported by National Science Foundation Grant IBN-9985808, National Institute on Aging Grant AG-11403, and United States Department of Agriculture and Northeastern Regional Aquaculture Center Grant 94-38500-0044.
This work was submitted by L. Jiang in partial fulfillment of requirements for a doctorate in biomedical sciences.
Address for reprint requests and other correspondence: R.P. Ferraris, Dept. of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 S. Orange Ave., Newark, NJ 07103-2714 (E-mail: ferraris{at}umdnj.edu).
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.
Received 11 July 2000; accepted in final form 22 August 2000.
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