Developmental reprogramming of rat GLUT5 requires glucocorticoid receptor translocation to the nucleus.
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 approximately 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.
Department of Pharmacology and Physiology, NJ Medical School, 185 S. Orange Avenue, Newark, NJ 07101, USA.
Véronique
V
Douard
Hye-In
HI
Choi
Summer
S
Elshenawy
David
D
Lagunoff
Ronaldo P
RP
Ferraris
D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D000375:Aging; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D005632:Fructose / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051296:Glucose Transporter Type 5 / Q000235:genetics* / Q000378:metabolism*; D015735:Mifepristone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism*
D051296:Glucose Transporter Type 5; D011965:Receptors, Glucocorticoid; C495727:Slc2a5 protein, rat; D005632:Fructose; D015735:Mifepristone; D003907:Dexamethasone