Calcium Channel TRPV6 Expression in Human Duodenum: Different Relationships to the Vitamin D System and Aging in Men and Women

Abstract

Intestinal absorption of calcium affects bone mineralization and varies greatly. In human duodenum, expression of the calcium channel TRPV6 was directly related to blood 1,25-dihydroxyvitamin D in men, but effects of age with lower median vitamin D receptor levels were more significant in women.Introduction: The TRPV6 calcium channel/transporter is implicated in animal studies of intestinal calcium absorption, but in humans, its role and relationship to differences in mineral metabolism is unclear. We aimed to characterize TRPV6 expression in human intestine including defining relationships to the vitamin D endocrine system. Materials and Methods: TRPV6 transcript expression was determined in endoscopic mucosal biopsies obtained from normal duodenum. Expression was compared with that in ileum and with in situ hybridization in archival tissues and related to sequence variants in genomic DNA. TRPV6 expression was related in 33 subjects to other transcripts involved in calcium absorption including the vitamin D receptor (VDR) and to blood vitamin D metabolites including 1,25-dihydroxyvitamin D [1,25(OH) 2 D]. Results: TRPV6 transcripts were readily detected in duodenum but not in ileum. Expression was highest in villous epithelial cells. Sequence variants in the coding and upstream regions of the gene did not affect TRPV6 expression. The relationship between duodenal TRPV6 expression and 1,25(OH) 2 D differed in men and women. In men, linear regression showed a strong association with 1,25(OH) 2 D (r ‫ס‬ 0.87, p < 0.01), which was unaffected by age. In women, there was no significant overall relationship with 1,25(OH) 2 D, but there was a significant decrease with age (r ‫ס‬ −0.69, p < 0.001). Individual expression of TRPV6 and VDR was significantly correlated. The group of older women (>50) had lower median levels of both TRPV6 and VDR transcripts than younger women (p < 0.001 and 0.02, respectively). Conclusions: Duodenal TRPV6 expression is vitamin D dependent in men, but not in older women, where expression of TRPV6 and VDR are both reduced. These findings can explain, at least in part, the lower fractional calcium absorption seen in older postmenopausal women.

Calcium and vitamin D: Skeletal and extraskeletal health

“…This channel facilitates calcium entry into the enterocytes. TRPV6 is highly regulated by 1,25(OH) 2 D and is most highly expressed in the duodenum compared to the jejunum and ileum [4]. In women, TRPV6 levels decline with aging, which partially explains the age-associated decline in calcium absorption [5].…”

Non-Bone Effects of Vitamin D in Children, Adolescents, and Young Adults

“…Changes in the expression of VDR leading to vitamin D resistance with aging have also been elaborated in recent literature. Several studies have reported association of aging with decrease in the expression of VDR in bone, intestine, and muscle tissues [38][39][40]. Various factors that decrease with aging have been identified to influence VDR such as estrogen, growth hormones, and vitamin D itself [11,41].…”

Minireview on Regulation of Intestinal Calcium Absorption

“…Walters et al [22] characterized TRPV6 transcript expression in normal human intestinal biopsies. TRPV6 transcripts were detected in the duodenum but not in the ileum.…”

“…This decrease occurs, at least in part, because of a declination in the serum calcitriol levels, but in addition, a resistance to the actions of calcitriol in the intestine has been reported [22]. Although the mechanisms are poorly known, in women the lack of estrogen during menopause could partially explain this age-associated intestinal resistance to calcitriol.…”

“…Although the mechanisms are poorly known, in women the lack of estrogen during menopause could partially explain this age-associated intestinal resistance to calcitriol. It has also been reported that duodenal TRPV6 expression is not vitamin D-dependent in postmenopausal women [22]. Recent data have shown that in mice, heterozygotes for the VDR gene KO, low levels of VDR produce resistance to intestinal Ca 2+ absorption of 1,25(OH) 2 D 3 .…”