Tachysterol - a UVB secosteroid in foods: implications for calcium and bone metabolism

• Applicant: Professorin Dr. Gabriele Stangl
• Subject Area: Nutritional Sciences
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 524746341

The conversion of provitamin D to vitamin D after absorption of ultraviolet B (UVB) energy represents the most fundamental reaction in photobiology, and ensures the vitamin D supply in humans. Due to the high prevalence of vitamin D insufficiency, a relatively old idea for improving vitamin D supply has recently been revisited, namely UVB exposure of food. However, this procedure is accompanied by the formation of photoproducts, such as tachysterol. We have already shown that orally ingested tachysterol can be absorbed, accumulates in tissues, reduces the level of active vitamin D hormone (calcitriol), and increases the synthesis of the phosphaturic hormone fibroblast-growth factor 23 in bone via inducing the transcriptional activity of the vitamin D receptor (VDR). The proposed project addresses the hypothesis that oral tachysterol has calcitriol-like functions and in turn can modulate the calcium and bone metabolism. Own preliminary analysis found a higher expression of the calcitriol-regulated calcium transporters in intestinal cells treated with tachysterol, indicating putative effects of tachysterol on calcium balance. In the first part of our proposal, we will address the question, of whether tachysterol may modulate mineral and bone metabolism. Therefore, we will conduct a study feeding Cyp27b1 knockout mice characterized by a calcitriol deficiency, hypocalcemia and a rachitic/osteomalacic bone morphology, with tachysterol. To evaluate the capability of tachysterol to normalize hypocalcemia and the bone disorder, plasma minerals, hormones involved in calcium homeostasis, the expression of intestinal calcium transporters, as well as comprehensive histomorphometric, microstructural, biomechanical and molecular properties of bones will be analyzed. Second and third parts of the project aim to identify the molecular mode of action and effect size of tachysterol in comparison to vitamin D. For this purpose, intestinal and osteoblast-like cell lines will be used. We hypothesize that hydroxy-tachysterol may modulate calcium and bone metabolism via interaction with VDR, and VDR-regulated genes, and will test the hypothesis by using VDR-specific siRNA to knockdown the VDR. Additionally, we will identify the hydroxylases necessary for the synthesis of active hydroxy-tachysterol, as well as enzymes involved in the activation and degradation of secosteroids and xenobiotics that are modulated by tachysterol. Our results will contribute to evaluate the safety of tachysterol formed in UVB-exposed foods, to understand the implications and molecular mechanisms of photoproducts on calcitriol-regulated processes, to identify enzymes which are influenced by tachysterol and involved in tachysterol activation, and to explore the potential of tachysterol to be used as a calcitriol-analogue.

• DFG Programme: Research Grants