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1 Department of Medical Research, VA Medical Center, Long Beach, CA, USA; Departments of Medicine and Physiology, University of California College of Medicine, Irvine, CA, USA
* To whom correspondence should be addressed. E-mail: hmsaid{at}uci.edu.
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 transporter-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 human thiamin transporter-1 and -2. We show that in thiamin deficiency, a significant and specific up-regulation in intestinal carrier-mediated thiamin uptake occur 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 up-regulated 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 up-regulated during dietary thiamin deficiency, that expression of mTHTR-1 and mTHTR-2 is regulated in a tissue-specific manner, and that this up-regulation is mediated via transcriptional regulatory mechanism(s).
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