Skip to main content
Top
Published in: European Journal of Nutrition 4/2014

01-06-2014 | Original Contribution

Vitamin D is not linked to folate status and mRNA expression of intestinal proton-coupled folate transporter

Authors: C. Brandsch, J. Zibolka, M. Frommhagen, U. Lehmann, J. Dierkes, H. Kühne, F. Hirche, G. I. Stangl

Published in: European Journal of Nutrition | Issue 4/2014

Login to get access

Abstract

Purpose

In vitro studies discovered intestinal proton-coupled folate transporter (PCFT) as a vitamin D hormone-responsive gene. In vivo effects of vitamin D on PCFT and folate status are currently not available.

Methods

Three experiments were conducted. At first, vitamin D receptor knockout (VDR−/−) mice and corresponding wild-type (WT) mice were compared for their plasma and hepatic folate concentration and PCFT mRNA expression in intestinal mucosa. In a second experiment with rats, we analyzed the folate status of offspring in response to a maternal vitamin D-adequate (1,000 IU/kg) or vitamin D-deficient (0 IU/kg) diet that was fed for 11 weeks. Finally, the plasma folate concentration of healthy individuals was studied at baseline (in winter) and in response to an oral treatment for 8 weeks with 2,000 IU vitamin D3 per day or a placebo, respectively.

Results

Here, we show that folate status and intestinal PCFT mRNA abundance did not differ between the VDR−/− and the WT mice. No effect of vitamin D on folate status was also found in rat dams and their offspring, and plasma folate levels of individuals did not change in response to vitamin D.

Conclusions

Current data from studies with model animals and humans provide no indication for a vitamin D effect on intestinal uptake and status of folate.
Literature
1.
go back to reference Holick MF, Chen TC (2008) Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr 87:1080S–1086S Holick MF, Chen TC (2008) Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr 87:1080S–1086S
2.
go back to reference Genuis SJ, Schwalfenberg GK, Hiltz MN, Vaselenak SA (2009) Vitamin D status of clinical practice populations at higher latitudes: analysis and applications. Int J Environ Res Public Health 6:151–173CrossRef Genuis SJ, Schwalfenberg GK, Hiltz MN, Vaselenak SA (2009) Vitamin D status of clinical practice populations at higher latitudes: analysis and applications. Int J Environ Res Public Health 6:151–173CrossRef
3.
go back to reference Holick MF (2006) High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 81:353–373CrossRef Holick MF (2006) High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 81:353–373CrossRef
4.
go back to reference Pike JW, Zella LA, Meyer MB, Fretz JA, Kim S (2007) Molecular actions of 1,25-dihydroxyvitamin D3 on genes involved in calcium homeostasis. J Bone Miner Res 22(Suppl 2):V16–V19CrossRef Pike JW, Zella LA, Meyer MB, Fretz JA, Kim S (2007) Molecular actions of 1,25-dihydroxyvitamin D3 on genes involved in calcium homeostasis. J Bone Miner Res 22(Suppl 2):V16–V19CrossRef
5.
go back to reference Christakos S (2012) Mechanism of action of 1,25-dihydroxyvitamin D3 on intestinal calcium absorption. Rev Endocr Metab Disord 13:39–44CrossRef Christakos S (2012) Mechanism of action of 1,25-dihydroxyvitamin D3 on intestinal calcium absorption. Rev Endocr Metab Disord 13:39–44CrossRef
6.
go back to reference Nagpal S, Na S, Rathnachalam R (2005) Noncalcemic actions of vitamin D receptor ligands. Endocr Rev 26:662–687CrossRef Nagpal S, Na S, Rathnachalam R (2005) Noncalcemic actions of vitamin D receptor ligands. Endocr Rev 26:662–687CrossRef
7.
go back to reference Penna G, Roncari A, Amuchastegui S, Daniel KC, Berti E, Colonna M, Adorini L (2005) Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4 + Foxp3 + regulatory T cells by 1,25-dihydroxyvitamin D3. Blood 106:3490–3497CrossRef Penna G, Roncari A, Amuchastegui S, Daniel KC, Berti E, Colonna M, Adorini L (2005) Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4 + Foxp3 + regulatory T cells by 1,25-dihydroxyvitamin D3. Blood 106:3490–3497CrossRef
8.
go back to reference Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, Tavera-Mendoza L, Lin R, Hanrahan JW, Mader S, White JH (2004) Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 173:2909–2912CrossRef Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, Tavera-Mendoza L, Lin R, Hanrahan JW, Mader S, White JH (2004) Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 173:2909–2912CrossRef
9.
go back to reference Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW (2008) Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol 181:7090–7099CrossRef Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW (2008) Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol 181:7090–7099CrossRef
10.
go back to reference McCarthy TC, Li X, Sinal CJ (2005) Vitamin D receptor-dependent regulation of colon multidrug resistance-associated protein 3 gene expression by bile acids. J Biol Chem 280:23232–23242CrossRef McCarthy TC, Li X, Sinal CJ (2005) Vitamin D receptor-dependent regulation of colon multidrug resistance-associated protein 3 gene expression by bile acids. J Biol Chem 280:23232–23242CrossRef
11.
go back to reference Eloranta JJ, Zaïr ZM, Hiller C, Häusler S, Stieger B, Kullak-Ublick GA (2009) Vitamin D3 and its nuclear receptor increase the expression and activity of the human proton-coupled folate transporter. Mol Pharmacol 76:1062–1071CrossRef Eloranta JJ, Zaïr ZM, Hiller C, Häusler S, Stieger B, Kullak-Ublick GA (2009) Vitamin D3 and its nuclear receptor increase the expression and activity of the human proton-coupled folate transporter. Mol Pharmacol 76:1062–1071CrossRef
12.
go back to reference Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, Sandoval C, Zhao R, Akabas MH, Goldman ID (2006) Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127:917–928CrossRef Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, Sandoval C, Zhao R, Akabas MH, Goldman ID (2006) Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127:917–928CrossRef
13.
go back to reference Subramanian VS, Marchant JS, Said HM (2008) Apical membrane targeting and trafficking of the human proton-coupled transporter in polarized epithelia. Am J Physiol Cell Physiol 294:C233–C240CrossRef Subramanian VS, Marchant JS, Said HM (2008) Apical membrane targeting and trafficking of the human proton-coupled transporter in polarized epithelia. Am J Physiol Cell Physiol 294:C233–C240CrossRef
14.
go back to reference Zhao R, Gao F, Hanscom M, Goldman ID (2004) A prominent low-pH methotrexate transport activity in human solid tumors: contribution to the preservation of methotrexate pharmacologic activity in HeLa cells lacking the reduced folate carrier. Clin Cancer Res 10:718–727CrossRef Zhao R, Gao F, Hanscom M, Goldman ID (2004) A prominent low-pH methotrexate transport activity in human solid tumors: contribution to the preservation of methotrexate pharmacologic activity in HeLa cells lacking the reduced folate carrier. Clin Cancer Res 10:718–727CrossRef
15.
go back to reference Wang Y, Rajgopal A, Goldman ID, Zhao R (2005) Preservation of folate transport activity with a low-pH optimum in rat IEC-6 intestinal epithelial cell lines that lack reduced folate carrier function. Am J Physiol Cell Physiol 288:C65–C71CrossRef Wang Y, Rajgopal A, Goldman ID, Zhao R (2005) Preservation of folate transport activity with a low-pH optimum in rat IEC-6 intestinal epithelial cell lines that lack reduced folate carrier function. Am J Physiol Cell Physiol 288:C65–C71CrossRef
16.
go back to reference Max D, Brandsch C, Schumann S, Kühne H, Frommhagen F, Schutkowski A, Hirche F, Staege MS, Stangl GI (2013) Maternal vitamin D deficiency causes smaller muscle fibers and altered transcript levels of genes involved in protein degradation, myogenesis, and cytoskeleton organization in the newborn rat. Mol Nutr Food Res. doi:10.1002/mnfr.201300360 Max D, Brandsch C, Schumann S, Kühne H, Frommhagen F, Schutkowski A, Hirche F, Staege MS, Stangl GI (2013) Maternal vitamin D deficiency causes smaller muscle fibers and altered transcript levels of genes involved in protein degradation, myogenesis, and cytoskeleton organization in the newborn rat. Mol Nutr Food Res. doi:10.​1002/​mnfr.​201300360
17.
go back to reference Lehmann U, Hirche F, Stangl GI, Hinz K, Westphal S, Dierkes J (2013) Bioavailability of vitamin D2 and D3 in healthy volunteers, a randomised placebo-controlled trial. J Clin Endocrinol Metab. doi:10.1210/jc.2012-4287 Lehmann U, Hirche F, Stangl GI, Hinz K, Westphal S, Dierkes J (2013) Bioavailability of vitamin D2 and D3 in healthy volunteers, a randomised placebo-controlled trial. J Clin Endocrinol Metab. doi:10.​1210/​jc.​2012-4287
18.
go back to reference National Research Council (NRC), Committee on Animal Nutrition (1995) Nutrient Requirements of Laboratory Animals. National Academy Press, Washington, DC National Research Council (NRC), Committee on Animal Nutrition (1995) Nutrient Requirements of Laboratory Animals. National Academy Press, Washington, DC
19.
go back to reference Reeves PG, Nielsen FH, Fahey GC Jr (1993) AIN-93 purified diets for laboratory rodents: final report of the American institute of nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 123:1939–1951 Reeves PG, Nielsen FH, Fahey GC Jr (1993) AIN-93 purified diets for laboratory rodents: final report of the American institute of nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 123:1939–1951
20.
go back to reference Schmidt N, Brandsch C, Kühne H, Thiele A, Hirche F, Stangl GI (2012) Vitamin D receptor deficiency and low vitamin D diet stimulate aortic calcification and osteogenic key factor expression in mice. PLoS ONE 7:e35316CrossRef Schmidt N, Brandsch C, Kühne H, Thiele A, Hirche F, Stangl GI (2012) Vitamin D receptor deficiency and low vitamin D diet stimulate aortic calcification and osteogenic key factor expression in mice. PLoS ONE 7:e35316CrossRef
21.
go back to reference Untersuchung von Lebensmitteln: Bestimmung von Vitamin D (Cholecalciferol (D3) und Ergocalciferol (D2)) in Lebensmitteln mittels HPLC. L 00.00-61, Juli 2001, in: Amtliche Sammlung von Untersuchungsverfahren nach §35 LMBG, Bundesgesundheitsamt (ed), Beuth, Berlin, Köln, (according to DIN EN12821) Untersuchung von Lebensmitteln: Bestimmung von Vitamin D (Cholecalciferol (D3) und Ergocalciferol (D2)) in Lebensmitteln mittels HPLC. L 00.00-61, Juli 2001, in: Amtliche Sammlung von Untersuchungsverfahren nach §35 LMBG, Bundesgesundheitsamt (ed), Beuth, Berlin, Köln, (according to DIN EN12821)
22.
go back to reference Mattila PH, Piironen VI, Uusi-Rauva EJ, Koivistoinen PE (1995) Contents of cholecalciferol, ergocalciferol, and their 25-hydroxylated metabolites in milk products and raw meat and liver as determined by HPLC. J Agric Food Chem 43:2394–2399CrossRef Mattila PH, Piironen VI, Uusi-Rauva EJ, Koivistoinen PE (1995) Contents of cholecalciferol, ergocalciferol, and their 25-hydroxylated metabolites in milk products and raw meat and liver as determined by HPLC. J Agric Food Chem 43:2394–2399CrossRef
23.
go back to reference Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45CrossRef Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45CrossRef
24.
go back to reference Kondo A, Kamihira O, Ozawa H (2009) Neural tube defects: prevalence, etiology and prevention. Int J Urol 16:49–57CrossRef Kondo A, Kamihira O, Ozawa H (2009) Neural tube defects: prevalence, etiology and prevention. Int J Urol 16:49–57CrossRef
25.
go back to reference Flood VM, Smith WT, Webb KL, Rochtchina E, Anderson VE, Mitchell P (2006) Prevalence of low serum folate and vitamin B12 in an older Australian population. Aust NZ J Public Health 30:38–41CrossRef Flood VM, Smith WT, Webb KL, Rochtchina E, Anderson VE, Mitchell P (2006) Prevalence of low serum folate and vitamin B12 in an older Australian population. Aust NZ J Public Health 30:38–41CrossRef
26.
go back to reference Qiu A, Min SH, Jansen M, Malhotra U, Tsai E, Cabelof DC, Matherly LH, Zhao R, Akabas MH, Goldman ID (2007) Rodent intestinal folate transporters (SLC46A1): secondary structure, functional properties, and response to dietary folate restriction. Am J Physiol Cell Physiol 293:C1669–C1678CrossRef Qiu A, Min SH, Jansen M, Malhotra U, Tsai E, Cabelof DC, Matherly LH, Zhao R, Akabas MH, Goldman ID (2007) Rodent intestinal folate transporters (SLC46A1): secondary structure, functional properties, and response to dietary folate restriction. Am J Physiol Cell Physiol 293:C1669–C1678CrossRef
27.
go back to reference Zhao R, Qiu A, Tsai E, Jansen M, Akabas MH, Goldman ID (2008) The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier. Mol Pharmacol 74:854–862CrossRef Zhao R, Qiu A, Tsai E, Jansen M, Akabas MH, Goldman ID (2008) The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier. Mol Pharmacol 74:854–862CrossRef
28.
go back to reference Lips P (2007) Relative value of 25(OH)D and 1,25(OH)2D measurements. J Bone Miner Res 22:1668–1671CrossRef Lips P (2007) Relative value of 25(OH)D and 1,25(OH)2D measurements. J Bone Miner Res 22:1668–1671CrossRef
29.
go back to reference Gonen N, Assaraf YG (2010) The obligatory intestinal folate transporter PCFT (SLC46A1) is regulated by nuclear respiratory factor 1. J Biol Chem 285:33602–33613CrossRef Gonen N, Assaraf YG (2010) The obligatory intestinal folate transporter PCFT (SLC46A1) is regulated by nuclear respiratory factor 1. J Biol Chem 285:33602–33613CrossRef
30.
go back to reference Gonen N, Bram EE, Assaraf YG (2008) PCFT/SLC46A1 promoter methylation and restoration of gene expression in human leukemia cells. Biochem Biophys Res Commun 376:787–792CrossRef Gonen N, Bram EE, Assaraf YG (2008) PCFT/SLC46A1 promoter methylation and restoration of gene expression in human leukemia cells. Biochem Biophys Res Commun 376:787–792CrossRef
31.
go back to reference Wasson GR, McGlynn AP, McNulty H, O’Reilly SL, McKelvey-Martin VJ, McKerr G, Strain JJ, Scott J, Downes CS (2006) Global DNA and p53 region-specific hypomethylation in human colonic cells is induced by folate depletion and reversed by folate supplementation. J Nutr 136:2748–2753 Wasson GR, McGlynn AP, McNulty H, O’Reilly SL, McKelvey-Martin VJ, McKerr G, Strain JJ, Scott J, Downes CS (2006) Global DNA and p53 region-specific hypomethylation in human colonic cells is induced by folate depletion and reversed by folate supplementation. J Nutr 136:2748–2753
32.
go back to reference Zhao R, Diop-Bove N, Visentin M, Goldman ID (2011) Mechanisms of membrane transport of folates into cells and across epithelia. Annu Rev Nutr 31:177–201CrossRef Zhao R, Diop-Bove N, Visentin M, Goldman ID (2011) Mechanisms of membrane transport of folates into cells and across epithelia. Annu Rev Nutr 31:177–201CrossRef
33.
go back to reference Borradale DC, Kimlin MG (2012) Folate degradation due to ultraviolet radiation: possible implications for human health and nutrition. Nutr Rev 70:414–422CrossRef Borradale DC, Kimlin MG (2012) Folate degradation due to ultraviolet radiation: possible implications for human health and nutrition. Nutr Rev 70:414–422CrossRef
34.
go back to reference Cicarma E, Mørk C, Porojnicu AC, Juzeniene A, Tam TT, Dahlback A, Moan J (2010) Influence of narrowband UVB phototherapy on vitamin D and folate status. Exp Dermatol 19:e67–e72CrossRef Cicarma E, Mørk C, Porojnicu AC, Juzeniene A, Tam TT, Dahlback A, Moan J (2010) Influence of narrowband UVB phototherapy on vitamin D and folate status. Exp Dermatol 19:e67–e72CrossRef
35.
go back to reference Juzeniene A, Stokke KT, Thune P, Moan J (2010) Pilot study of folate status in healthy volunteers and in patients with psoriasis before and after UV exposure. J Photochem Photobiol B 101:111–116CrossRef Juzeniene A, Stokke KT, Thune P, Moan J (2010) Pilot study of folate status in healthy volunteers and in patients with psoriasis before and after UV exposure. J Photochem Photobiol B 101:111–116CrossRef
Metadata
Title
Vitamin D is not linked to folate status and mRNA expression of intestinal proton-coupled folate transporter
Authors
C. Brandsch
J. Zibolka
M. Frommhagen
U. Lehmann
J. Dierkes
H. Kühne
F. Hirche
G. I. Stangl
Publication date
01-06-2014
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Nutrition / Issue 4/2014
Print ISSN: 1436-6207
Electronic ISSN: 1436-6215
DOI
https://doi.org/10.1007/s00394-013-0614-7

Other articles of this Issue 4/2014

European Journal of Nutrition 4/2014 Go to the issue