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The primary role of 1,25(OH)₂D and the vitamin D receptor (VDR) during growth is to mediate intestinal calcium (Ca) absorption by regulating the expression of genes (e.g., Trpv6, S100g) that control Ca fluxes through enterocyte. In contrast to the well-defined role during rapid growth, the understanding of 1,25(OH)₂D signaling in post-growth, mature adult or the elderly is poor. Some observational studies suggest intestinal 1,25(OH)₂D signaling is not important to Ca absorption and bone for mature adult. In the elderly, intestine develops resistance to 1,25(OH)₂D action which might be due to age-related reductions in intestinal VDR level. In addition, there is lack of evidence that directly tests the role of 1,25(OH)₂D action in the distal intestine post-growth. My dissertation research focuses on discovering the importance of 1,25(OH)₂D signaling from both the temporal and spatial perspectives. By using 4-month old, whole intestine or large intestine VDR knockout mice, we found that for mature mice, 1,25(OH)₂D signaling plays a minimal role in regulating Ca absorption and protecting bone mass when dietary Ca intake is adequate. In contrast, 1,25(OH)₂D signaling in the whole intestine, and to a lesser extent the proximal colon, is critical to upregulate Ca absorption and protect bone when dietary Ca intake is low. Next, we proved that the Ca absorptive machinery in the proximal colon can be locally stimulated to enhance the expression of Trpv6 by 1,25(OH)₂D released from glycoside and glucuronide forms of calcitriol. Furthermore, our transcriptomic analysis on 1,25(OH)₂D-regulated genes in the duodenum of mature (4-month old), middle-aged (11.5-month old), and old (20.5-month old) mice suggest although aging did reduce the induction of some genes by 1,25(OH)₂D, this effect is not universally present across the genome and it is not related to intestinal Vdr expression. The findings from my dissertation research serve as a foundation for future research to identify a) the potential of specifically targeting proximal colon to increase intestinal Ca absorption and protect bone in adult; b) the molecular mechanisms that contribute to the aging-associated, non-universal resistance to 1,25(OH)₂D action.

The purpose of this study was to analyze the effect of fatty acid chain length and quantity on the bioavailability of calcium. Thirteen healthy subjects were randomly assigned to a series of 5 test meals containing varying types and levels of fat and calciumconsumed over a three week time period. The test meals included 10 grams MCT oil (MCT 10), 20 grams MCT oil (MCT 20), 10 grams beef fat (BT 10), 20 grams beef fat (BT 20), and calcium only (Ca). Calcium absorption was assessed using timed urine collections following a specified calcium load. Three day food records were obtained to assess typical nutrient intakes of the subjects coming into and during the study. MCT oil provided better absorption of the calcium supplement than did the beef tallow. A difference was also noted in the absorption of calcium based on the amount of fat consumed. A higher intake of MCT oil (10 g vs. 20 g) appeared to favor the absorption of calcium. Urine calcium excretion was significantly greater (p < .009) during the MCT oil treatments (MCT 10, MCT 20) compared to the beef fat treatments (BT 10, BT 20), suggesting reduced calcium absorption during the beef fat treatments. There were no differences in mean calcium excretion based on quantity of fat consumed ( 10 g vs. 20 g), nor any interaction between type of fat and amount. Tests for detecting differences between individual treatments indicated a significance difference (p < .05) in calcium excretion between MCT 20 and BT 10 treatments. Urine calcium excretion was corrected for body size using urine calcium/creatinine ratio (Ca/Cr). There was a significant time effect between the 0 - 2, 2 - 4 hour time periods (p < .005) and the various treatments for Ca/Cr. Though not significant, mean Ca/Cr was highest for the calcium treatment (0.42), compared to the MCT oil treatments (36, z of MCT 10 & MCT 20), and beef fat treatments (28, x of BT 10 & BT 20). The beef fat treatments significantly decreased the absorption of calcium compared to the MCT oil treatments. It appears that beef fat, when compared to the calcium only treatment, decreased calcium absorption. / Department of Home Economics