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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-20360

Eloranta, J J; Hiller, C; Hausler, S; Stieger, B; Kullak-Ublick, G A (2009). Vitamin D3 and its Nuclear Receptor Increase the Expression and Activity of the Human Proton-Coupled Folate Transporter. Molecular Pharmacology:Epub ahead of print.

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Abstract

Folates are essential for nucleic acid synthesis and required particularly in rapidly proliferating tissues, such as intestinal epithelium and hemopoietic cells. Availability of dietary folates is determined by their absorption across the intestinal epithelium, mediated by the proton-coupled folate transporter (PCFT) at the apical enterocyte membranes. Whereas transport properties of PCFT are well characterized, regulation of PCFT gene expression remains less elucidated. We have studied the mechanisms that regulate PCFT promoter activity and expression in intestine-derived cells. PCFT mRNA levels are increased in Caco-2 cells treated with 1,25-dihydroxyvitamin D3 (vitamin D3) in a dose-dependent fashion, and the duodenal rat Pcft mRNA expression is induced by vitamin D3 ex vivo. The PCFT promoter region is transactivated by the vitamin D receptor (VDR) and its heterodimeric partner retinoid X receptor-alpha (RXRalpha) in the presence of vitamin D3. In silico analyses predicted a VDR response element (VDRE) in the PCFT promoter region -1694/-1680. DNA-binding assays showed direct and specific binding of the VDR:RXRalpha heterodimer to the PCFT(-1694/-1680), and chromatin immunoprecipitations verified that this interaction occurs within living cells. Mutational promoter analyses confirmed that the PCFT(-1694/-1680) motif mediates a transcriptional response to vitamin D3. In functional support of this regulatory mechanism, treatment with vitamin D3 significantly increased the uptake of [(3)H]-folic acid into Caco-2 cells at pH5.5. In conclusion, vitamin D3 and VDR increase intestinal PCFT expression, resulting in enhanced cellular folate uptake. Pharmacological treatment of patients with vitamin D3 may have the added therapeutic benefit of enhancing the intestinal absorption of folates.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
04 Faculty of Medicine > Center for Integrative Human Physiology
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:7 August 2009
Deposited On:25 Aug 2009 12:03
Last Modified:30 Nov 2013 13:27
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN:0026-895X
Additional Information:Free full text at http://molpharm.aspetjournals.org/cgi/reprint/mol.109.055392v1
Publisher DOI:10.1124/mol.109.055392
PubMed ID:19666701
Citations:Web of Science®. Times Cited: 17
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Scopus®. Citation Count: 17

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