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. 2009 Dec;297(6):G1193-7.
doi: 10.1152/ajpgi.00237.2009. Epub 2009 Sep 24.

Human duodenum responses to vitamin D metabolites of TRPV6 and other genes involved in calcium absorption

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Human duodenum responses to vitamin D metabolites of TRPV6 and other genes involved in calcium absorption

Sara Balesaria et al. Am J Physiol Gastrointest Liver Physiol. 2009 Dec.

Abstract

Calcium absorption by the intestine is necessary for bone mineralization. Much has been learned about this process and the role of vitamin D metabolites in gene transcription from animal studies, but the molecular mechanisms in humans are less well understood. We have used samples of normal human duodenal mucosa, obtained at endoscopy, to investigate the effects of the vitamin D metabolites, 1alpha-dihydroxycholecalciferol [1,25(OH)(2)D(3)] and 25-hydroxycholecalciferol (25OHD), on transcripts on genes involved in calcium absorption and vitamin D metabolism. TRPV6 transcripts were significantly higher after incubation for 6 h with 1,25(OH)(2)D(3) (10(-9) mol/l) than after control incubations (median difference 3.1-fold, P < 0.001). Unexpectedly, TRPV6 expression was also higher (2.4-fold, P < 0.02) after incubation with 25OHD (10(-7) mol/l). Transcripts for the calcium-ATPase, PMCA1, were significantly higher with 1,25(OH)(2)D(3); CYP24 transcripts were reliably detected after incubation with either metabolite, but calbindin-D9k transcripts were unaffected. The response of TRPV6 to 25OHD and the expression of transcripts for CYP27B1, the 25OHD-1alpha-hydroxylase, were significantly correlated (r = 0.82, P < 0.02). Basal duodenal expression of TRPV6 and CYP27B1 were significantly associated (r = 0.72, P < 0.001) in a separate previously reported series of subjects. Multiple regression analysis of the associations with basal duodenal TRPV6 expression identified CYP27B1 expression and serum 1,25(OH)(2)D as major factors. Expression of the CYP27B1 protein was demonstrated immunohistochemically in duodenal mucosa. This study has shown that human duodenal TRPV6, PMCA1, and CYP24 transcripts respond rapidly to 1,25(OH)(2)D(3) and provides evidence suggesting that local duodenal production of 1,25(OH)(2)D(3) by 25OHD-1alpha-hydroxylase may have a role in human calcium absorption.

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Figures

Fig. 1.
Fig. 1.
Expression ratios of transcripts of genes expressed in human duodenal mucosa after 6-h incubation with either the addition of 1α-dihydroxycholecalciferol [1,25(OH)2D3] at 10−9 mol/l or 0.1% ethanol control. Median and quartiles are shown for the change in expression induced by 1,25(OH)2D3. All expression values were normalized to GAPDH. A twofold change indicates that the expression value with 1,25(OH)2D3 was twice that seen with the ethanol control. The number (n) of subjects studied were as follows: TRPV6, 26; calbindin-D9k (Calb), 24; PMCA1, 25; the vitamin D receptor (VDR), 25-hydroxycholecalciferol 1α-hydroxylase (25OHD-1αOHase) (CYP27B1), and sucrase, all 24. P values were determined by nonparametric Wilcoxon signed-rank tests.
Fig. 2.
Fig. 2.
Expression ratios for transcripts of genes expressed in duodenum, as described in Fig. 1, showing the change in expression induced by the addition of 25OHD at 10−7 mol/l. Six subjects were studied so that only medians, and not quartiles, are shown.
Fig. 3.
Fig. 3.
Relationship of the baseline, unstimulated expression of TRPV6 and CYP27B1 (1αOHase) transcripts, expressed relative to GAPDH in arbitrary units (AU), in duodenal mucosal biopsies from 33 healthy subjects. The linear regression line is shown together with the correlation coefficient and significance.
Fig. 4.
Fig. 4.
Representative histology of human duodenum after immunochemical staining with an antibody to 25OHD-1αOHase (30). The solid arrow shows strong staining of the crypt, and the open arrow indicates the villi. B shows the Brunner's glands. Magnification ×100.

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