Review
Recent advances in our understanding of 1,25-dihydroxyvitamin D3 regulation of intestinal calcium absorption

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Abstract

Calcium is required for many cellular processes including muscle contraction, nerve pulse transmission, stimulus secretion coupling and bone formation. The principal source of new calcium to meet these essential functions is from the diet. Intestinal absorption of calcium occurs by an active transcellular path and by a non-saturable paracellular path. The major factor influencing intestinal calcium absorption is vitamin D and more specifically the hormonally active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). This article emphasizes studies that have provided new insight related to the mechanisms involved in the intestinal actions of 1,25(OH)2D3. The following are discussed: recent studies, including those using knock out mice, that suggest that 1,25(OH)2D3 mediated calcium absorption is more complex than the traditional transcellular model; evidence for 1,25(OH)2D3 mediated active transport of calcium by distal as well as proximal segments of the intestine; 1,25(OH)2D3 regulation of paracellular calcium transport and the role of 1,25(OH)2D3 in protection against mucosal injury.

Highlights

► A major function of 1,25(OH)2D3 is intestinal calcium transport. ► The proximal and distal intestine contribute to the calcium absorptive process. ► TRPV6 and calbindin-D9k may act together in the calcium absorptive process. ► Active calcium absorption independent of TRPV6 or calbindin-D9k can occur. ► Evidence suggests that 1,25(OH)2D3 can also regulate paracellular calcium transport.

Introduction

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3)1, the hormonally active form of vitamin D, is the most significant factor controlling intestinal calcium absorption [1], [2]. Two modes of intestinal calcium absorption have been proposed: one is a saturable, active, transcellular process and the other mode is non-saturable, paracellular, occurs at luminal concentrations of calcium >2–6 mmol/l and is driven, at least in part, by the integrity of tight junctions [3], [4]. Calcium absorption occurs in each segment of the small intestine and is determined by the rate of absorption and the transit time through each segment. In mammals most of the ingested calcium is absorbed in the lower segments of the small intestine (mostly in the ileum) where the transit time is longer compared to more proximal segments. Only about 8–10% of calcium absorption takes place in the mammalian duodenum although its capacity to absorb calcium is more rapid than any other segment [3], [4], [5], [6], [7]. As the body’s demand for calcium increases as a result of a diet deficient in calcium or due to growth, pregnancy or lactation, synthesis of 1,25(OH)2D3 is increased resulting in the stimulation of active calcium transport [1], [2]. Although the duodenum has been a focus of research related to 1,25(OH)2D3 mediated active calcium absorption, 1,25(OH)2D3 regulation of calcium absorption in the ileum, cecum and colon has also been reported [8], [9], [10], [11], [12], [13], [14]. The vitamin D receptor (VDR) is expressed in all segments of the small and large intestine [15], [16], [17] and two targets of vitamin D (the calcium binding protein calbindin-D9k and the epithelial calcium channel TRPV6) are present in all segments of mouse and rat intestine [18], [19]. Thus, although calcium is absorbed most rapidly in the duodenum compared to other segments, 1,25(OH)2D3 action in the distal segments of the intestine also contributes to the calcium absorptive process.

Section snippets

1,25(OH)2D3 regulated transcellular intestinal calcium absorption

Transcellular calcium transport is believed to be comprised of three 1,25(OH)2D3 regulated steps: (1) the entry of calcium from the intestinal lumen across the brush border membrane; (2) the transcellular movement of calcium through the cytosol of the enterocyte; and (3) the energy requiring extrusion of calcium against a concentration gradient at the basolateral membrane [3], [4]. It has been reported that only 2–4 h after 1,25(OH)2D3 treatment to vitamin D deficient or normal animals is

Effect of other hormones (estrogen, prolactin, glucocorticoids) and the effect of aging on active intestinal calcium transport

During pregnancy and lactation active intestinal calcium transport is increased [42], [43], [44]. It has been reported that estrogens and prolactin, independent of vitamin D, stimulate active intestinal calcium transport [45], [46]. Mechanisms include induction of TRPV6 by estrogen via estrogen receptor α and induction of TRPV6 by prolactin [45], [47]. Prolactin also has cooperative effects with 1,25(OH)2D3 in induction of intestinal calcium transport genes and intestinal calcium transport [47]

Paracellular intestinal calcium absorption

In addition to transcellular transport of calcium, calcium is also absorbed by the paracellular pathway that occurs through tight junctions and structures present within the intercellular spaces. The paracellular pathway functions throughout the length of the intestine but predominates in the more distal regions when dietary calcium is adequate or high [4]. Paracellular intestinal transport and its regulation by vitamin D, which has been a matter of debate [4], [58], remain much less defined

Role of 1,25(OH)2D3 in protecting against mucosal injury

In addition to intestinal calcium absorption, it has been suggested that 1,25(OH)2D3 maintains the integrity of the intestinal barrier, protecting against mucosal injury. Evidence was obtained in studies showing that VDR KO mice are more susceptible to dextran sulfate sodium induced mucosal injury than WT mice [69]. Also, using Caco-2 monolayers, 1,25(OH)2D3 was found to induce tight junction proteins ZO-1, claudin-1 and claudin-2 and the adherin junction protein E-cadherin and to preserve the

1,25(OH)2D3 and intestinal phosphate absorption

Although intestinal calcium absorption is the major biological function of vitamin D, 1,25(OH)2D3 can also enhance intestinal absorption of dietary phosphate. In rats and humans phosphate absorption is highest in the jejunum (greater than the duodenum and greater than the ileum) [70], [71]. In mice the highest efficiency of phosphate absorption is in the ileum [72], [73]. It has been suggested that 1,25(OH)2D3 acts by affecting sodium dependent phosphate influx into the brush border membrane by

In summary

1,25(OH)2D3 mediated calcium absorption is more complex than the traditional three step model of transcellular calcium transport. Experimental evidence supports 1,25(OH)2D3 regulation of both transcellular active transport and paracellular absorption of calcium. In order to determine new approaches to sustain calcium balance, further studies are needed. Future directions include: (1) identification of novel 1,25(OH)2D3 regulated proteins in different regions of the intestine; (2) examination of

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