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首页> 外文期刊>American Journal of Physiology >Adaptive regulation of intestinal thiamin uptake: molecular mechanism using wild-type and transgenic mice carrying hTHTR-1 and -2 promoters.
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Adaptive regulation of intestinal thiamin uptake: molecular mechanism using wild-type and transgenic mice carrying hTHTR-1 and -2 promoters.

机译：肠道硫胺素的适应性调节：使用携带hTHTR-1和-2启动子的野生型和转基因小鼠的分子机制。

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摘要

Thiamin participates in metabolic pathways contributing to normal cellular functions, growth, and development. The molecular mechanism of the human intestinal thiamin absorption process involves the thiamin transporters-1 (hTHTR-1) and -2 (hTHTR-2), products of the SLC19A2 and SLC19A3 genes. Little is known about adaptive regulation of the intestinal thiamin uptake process or the molecular mechanism(s) involved during thiamin deficiency. In these studies, we addressed these issues using wild-type mice and transgenic animals carrying the promoters of the hTHTR-1 and -2. We show that, in thiamin deficiency, a significant and specific upregulation in intestinal carrier-mediated thiamin uptake occurs and that this increase is associated with an induction in protein and mRNA levels of mTHTR-2 but not mTHTR-1; in addition, an increase in the activity of the SLC19A3, but not the SLC19A2, promoter was observed in the intestine of transgenic mice. Similar findings were detected in the kidney; however, expression of both thiamin transporters and activity of both human promoters were upregulated in this organ in thiamin deficiency. We also examined the effect of thiamin deficiency on the level of expression of mTHTR-1 and mTHTR-2 messages and activity of the human promoters in the heart and brain of transgenic mice and found an increase in mTHTR-1 mRNA and a rise in activity of the SLC19A2 promoter in thiamin-deficient mice. These results show that the intestinal and renal thiamin uptake processes are adaptively upregulated during dietary thiamin deficiency, that expression of mTHTR-1 and mTHTR-2 is regulated in a tissue-specific manner, and that this upregulation is mediated via transcriptional regulatory mechanism(s).
机译：硫胺素参与有助于正常细胞功能，生长和发育的代谢途径。人类肠道硫胺素吸收过程的分子机制涉及硫胺素转运蛋白-1（hTHTR-1）和-2（hTHTR-2），它们是SLC19A2和SLC19A3基因的产物。关于肠硫胺摄取过程的自适应调节或硫胺缺乏过程中涉及的分子机制的知之甚少。在这些研究中，我们使用野生型小鼠和携带hTHTR-1和-2启动子的转基因动物解决了这些问题。我们表明，在硫胺素缺乏症中，肠道载体介导的硫胺素摄取会发生明显的特异性上调，并且这种增加与mTHTR-2而不是mTHTR-1的蛋白质和mRNA水平的诱导有关。另外，在转基因小鼠的肠中观察到SLC19A3启动子的活性增加，但SLC19A2启动子的活性没有增加。在肾脏中发现了类似的发现。然而，硫胺素缺乏时，该器官中硫胺素转运蛋白的表达和两种人类启动子的活性均被上调。我们还检查了硫胺素缺乏对转基因小鼠心脏和大脑中mTHTR-1和mTHTR-2信息表达水平以及人类启动子活性的影响，发现mTHTR-1 mRNA的增加和活性的增加缺乏硫胺素的小鼠中SLC19A2启动子的表达。这些结果表明，在饮食中缺乏硫胺素期间，肠和肾硫胺素的摄取过程被自适应地上调，mTHTR-1和mTHTR-2的表达以组织特异性方式被调节，并且这种上调是通过转录调节机制介导的。 ）。

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