Developmental reprogramming of rat GLUT5 requires glucocorticoid receptor translocation to the nucleus
Developmental reprogramming of rat GLUT5 requires glucocorticoid receptor translocation to the nucleus
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DOI：
10.1113/jphysiol.2008.155226
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发表时间：
2008-08-01
影响因子：
5.5
通讯作者：
Ferraris, Ronaldo P.
中科院分区：
文献类型：
--
作者：
Douard, Veronique;Choi, Hye-In;Ferraris, Ronaldo P.
果糖消耗量急剧增加，但对体内肠道果糖转运蛋白GLUT 5的调节机制知之甚少。在新生大鼠中，GLUT 5只能由鲁米那果糖诱导，并且只能在14天后才能诱导，除非在果糖灌注前用地塞米松预处理肠道。为了阐明地塞米松调节GLUT 5发育的机制，我们首先确定了介导其作用的受体，然后确定这些作用是否是基因组的。糖皮质激素受体（GR）拮抗剂RU 486剂量依赖性地阻止地塞米松介导的对体重、肠转移酶2（一种已知的GR调节基因）和GLUT 5的影响。相反，盐皮质激素受体拮抗剂以及孕酮（PR）和孕烷-X（PXR）受体激动剂不阻断地塞米松的作用。这些受体拮抗剂和激动剂对肠道葡萄糖转运蛋白SGLT 1无影响。转运到肠上皮细胞核的GR只发生在地塞米松注射的幼仔灌注果糖，伴随着刷状缘GLUT 5丰度显着增加，并被RU 486阻断。类似于24小时的引发持续时间对于诱导是最佳的，但是在地塞米松引发之前注射放线菌素D防止地塞米松允许鲁米那果糖诱导GLUT 5。放线菌素D对地塞米松非依赖性果糖诱导的葡萄糖-6-磷酸酶mRNA丰度的增加没有影响，这表明它不能阻止果糖诱导的GLUT 5，而是阻止地塞米松诱导的果糖调节GLUT 5所需的中间体的合成。在< 14日龄的乳鼠中，转运蛋白的发育调节可能涉及调节肠道成熟的激素信号和调节特定转运蛋白的营养信号之间的串扰。
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 similar to 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.