Estrogen Increases 1,25-Dihydroxyvitamin D Receptors Expression and Bioresponse in the Rat Duodenal Mucosa

Abstract

Menopause and estrogen deficiency are associated with apparent intestinal resistance to vitamin D, which can be reversed by estrogen replacement. The in vivo influence of estrogens on duodenal vitamin D receptor (VDR) was studied in three groups of rats: ovariectomized (OVX), sham-operated, and ovariectomized rats treated daily with estrogen (40 g/kg BW) for 2 weeks (OVX ϩ E). Estrogen administration to OVX rats resulted in a 2-fold increase in VDR messenger RNA transcripts. 1,25(OH) 2 D 3 was shown to bind specifically to one class of receptors in duodenal mucosal extracts, with a dissociation constant of 0.03 nM. Binding was significantly increased in duodenal extracts from OVX ϩ E rats, compared with OVX rats (735 Ϯ 81 vs. 295 Ϯ 26 fmol/mg protein; P Ͻ 0.001); a comparable, 1.5-to 2-fold increase in VDR protein expression was observed in Western blot analyzes of the duodenal mucosa. Markers of VDR activity were increased in estrogen-exposed rats: calbindin-9k messenger RNA transcript content was 1.4-to 1.6-fold higher, and alkaline phosphatase activity was 1.4-to 3-fold higher in sham-operated and OVX ϩ E, respectively, compared with OVX. 25(OH)D, 1,25(OH) 2 D, or PTH levels were not altered by estrogen treatment. Cumulatively, these findings suggest that estrogen up-regulates VDR expression in the duodenal mucosa and concurrently increases the responsiveness to endogenous 1,25(OH) 2 D. Modulation of intestinal VDR activity by estrogen, and subsequent influence on intestinal calcium absorption, could be one of the major protective mechanisms of estrogen against osteoporosis. (Endocrinology 140: 280 -285, 1999) I NTESTINAL calcium absorption takes place via two main mechanisms: passive diffusion, which occurs when luminal calcium is high; and active absorption, a complex and not fully understood process mediated by 1,25(OH) 2 D 3 , which predominates when luminal calcium is low (1). Under physiological circumstances, 1,25(OH) 2 D 3 is primarily produced in the kidneys under the influence of PTH stimulation. PTH secretion, in turn, is dependent on extracellular free calcium concentration, as sensed by calcium-sensing-receptors located in parathyroid cells' membranes (2). Overall, the rate of active intestinal calcium absorption is determined by physiologic interactions between various components of the PTH-vitamin D-endocrine system organized in a multilevel negative feed-back loop structure.Intestinal calcium absorption declines with age, both in humans (3, 4) and in rats (5). A widely held hypothesis suggests that the decrease in intestinal calcium absorption results from a sequence of events initiated by low estrogen levels, causing increased bone resorption; released calcium increases extracellular space calcium concentration, which suppresses PTH secretion, followed by a subsequent decrease in 1,25(OH) 2 D 3 production and in 1,25(OH) 2 D 3 plasma concentration, and finally results in decreased intestinal calcium absorption (6).Nevertheless, there is evidence that estrogen may be more directly i...

Vitamin D receptor distribution in intestines of domesticated sheep Ovis ammon f. aries

“…This lack of age-dependent differences is in accordance with findings --gained with identical study design and methodology --in cattle and goat (Riner, 2006;Singer, 2006) and several other reports (Kinyamu et al, 1997;Wood et al, 1998;Lee et al, 2003;Pazianas et al, 2003;Yamagishi et al, 2006) and in contrast to data published elsewhere (Horst et al, 1990;Ebeling et al, 1992;Liang et al, 1994;Bischoff et al, 2001;Duque et al, 2002;Holick, 2003). Since an age and/or estrogen dependent impairment of calcium resorption was detectable in elder subjects in numerous studies, a resistance to vitamin D was postulated (Kinyamu et al, 1997;Wood et al, 1998) and furthermore vitamin D-dependent (Kinyamu et al, 1997;Liel et al, 1999;Schwartz et al, 2000;Leonard et al, 2001;Duque et al, 2002;Gilad et al, 2005) and independent effects of estrogens on calcium resorption were verified (Colin et al, 1999;Eisman, 2001;Van Cromphaut et al, 2003). Thus, in future studies hormone-and age-associated effects on calcium and vitamin D metabolism in sheep should be re-examined also in senescent dams with and without hormone substitution and evaluated separately.…”

“…Studies on vitamin D receptor expression in several species generally revealed that vitamin D receptor amounts within the gastrointestinal tract are highest in duodenum and decrease towards the large intestine (Feldman et al, 1979;Lointier et al, 1991;Kallay et al, 2005). Vitamin D receptors are supposed to be reduced with age (Horst et al, 1990;Duque et al, 2002) and decline during a decrease in blood estrogen concentrations (Liel et al, 1999;Schwartz et al, 2000;Duque et al, 2002). Vitamin D receptors are also more abundant deep in crypts than in villar cells (Clemens et al, 1988).…”

Regulation of vitamin D receptor expression via estrogen-induced activation of the ERK 1/2 signaling pathway in colon and breast cancer cells

“…Previously we demonstrated that E2 regulates the transcription and expression of VDR in rat colonocytes and duodenocytes in vivo (Liel et al 1999, Schwartz et al 2000. Here, we analyzed the effect of E2 on VDR mRNA and protein expression in HT29 and MCF-7 cells.…”

Energy Restriction Reduces Fractional Calcium Absorption in Mature Obese and Lean Rats

“…Serum PTH may rise with weight reduction (9), and the increased Ca-PTH axis activity may be driven by a decrease in Ca absorption due to EnR. In addition, intestinal Ca absorption is influenced by serum E 2 (12)(13)(14), and E 2 may decline with EnR (5,6), but the relationship between EnR, E 2 and Ca absorption is not known. Finally, there may also be an association between weight loss, increased glucocorticoids and decreased calcium absorption (15).…”