Developmental reprogramming of rat GLUT5 requires glucocorticoid receptor translocation to the nucleus

Abstract

Fructose consumption has increased dramatically but little is known about mechanisms regulating the intestinal fructose transporter GLUT5 in vivo. In neonatal rats, GLUT5 can be induced only by luminal fructose and only after 14 days of age, unless the gut is primed with dexamethasone prior to fructose perfusion. To elucidate the mechanisms underlying dexamethasone modulation of GLUT5 development, we first identified the receptor mediating its effects then determined whether those effects were genomic. The glucocorticoid receptor (GR) antagonist RU486 dose-dependently prevented the dexamethasone-mediated effects on body weight, intestinal arginase2 (a known GR-regulated gene) and GLUT5. In contrast, an antagonist of the mineralocorticoid receptor as well as agonists of progesterone (PR) and pregnane-X (PXR) receptors did not block the effects of dexamethasone. These receptor antagonists and agonists had no effect on the intestinal glucose transporter SGLT1. Translocation of the GR into the enterocyte nucleus occurred only in dexamethasone-injected pups perfused with fructose, was accompanied by marked increases in brush border GLUT5 abundance, and was blocked by RU486. A priming duration of ∼24 h is optimal for induction but actinomycin D injection before dexamethasone priming prevented dexamethasone from allowing luminal fructose to induce GLUT5. Actinomycin D had no effect on dexamethasone-independent fructose-induced increases in glucose-6-phosphatase mRNA abundance, suggesting that it did not prevent fructose-induction of GLUT5, but instead prevented dexamethasone-induced synthesis of an intermediate required by fructose for GLUT5 regulation. In suckling rats < 14 days old, developmental regulation of transporters may involve cross-talk between hormonal signals modulating intestinal maturation and nutrient signals regulating specific transporters.

Acute interactions between intestinal sugar and calcium transport in vitro

“…Fructose transport occurs mainly in the proximal regions of rat and mouse intestines (13,61), paralleling the regional distribution of GLUT5 (22) and KHK expression, which is modestly reduced in the distal intestine. Many studies have already shown ATP concentrations to decrease markedly in enterocytes and hepatocytes exposed to fructose (33,38,45,49,54).…”

“…Two centimeters of mouse duodenum were excised and immediately fixed in fresh 10% paraformaldehyde in PBS (pH ϭ 7.35) overnight at room temperature (25°C). After fixation, tissue samples were embedded in paraffin, then sectioned (ϳ5 m), deparaffinized, and rehydrated as previously described (22). Antigen unmasking was processed in 10 mM sodium citrate buffer (pH 6.0) solution in heat-induced antigen retrieval programmed pressure cooker (2100-Retriever; ProteoGenix, Schiltigheim, France Ϫ/Ϫ mice, respectively.…”

The Western-style diet: a major risk factor for impaired kidney function and chronic kidney disease

“…In rats, Glut5 expression is induced by fructose but only after weaning begins at 14 days of age (40). Fig.…”

Intestinal fructose transport and malabsorption in humans

“…The capacity for fructose uptake in neonatal rats was paralleled by GLUT5 expression, with GLUT5 expressed at a low level through the suckling (0 -14 days of age) and weaning (14 -28 days) stages, but increasing dramatically after 28 days (57). Expression and activity of GLUT5 was enhanced, from 14 days of age at the earliest, by the introduction of fructose into the diet (16,35,58). An increase in GLUT5 mRNA abundance has been shown to occur within a few hours of fructose consumption in differentiated cells lining the intestinal villi of 20-day-old rat pups (35).…”

“…An increase in GLUT5 mRNA abundance has been shown to occur within a few hours of fructose consumption in differentiated cells lining the intestinal villi of 20-day-old rat pups (35). This upregulation of GLUT5 mRNA may involve cross talk between nutrient signals from dietary fructose and hormonal signals involved in intestinal maturation, such as from glucocorticoids (16). Developmental regulation of GLUT5 has been established in these animal models, but this is yet to be definitively confirmed in humans.…”