Bioavailability, seasonal variability, and metabolization of vitamin D-photosiomers in humans
Final Report Abstract
The photoisomers lumisterol3 (L3) and tachysterol3 (T 3) are naturally formed in the skin exposed to UVB-light and can be released into the circulation. Similarly, lumisterol2 (L2) and tachysterol2 (T 2) are found in foods such as mushrooms or yeast that have been treated with UVB-light to increase their vitamin D2 content. Those irradiated foods are approved as novel foods in the EU. Own research in mice has shown that food-derived photoproducts are bioavailable. Once metabolized to bioactive hydroxy derivatives, they interact with nuclear transcription factors such as vitamin D receptor (VDR) or liver X receptor regulating biological processes. These findings imply the efficient metabolism and potential hormonal activity for photoisomers. However, little is known about the oral uptake, metabolism, and function of food-derived photoisomers in humans, or how their skin production varies seasonally, as seen with vitamin D3. The current project aimed to fill this knowledge gap. This data is essential for assessing the safety of consuming UVB-irradiated foods and understanding the relationships between photoisomer intake, seasonal UVB exposure, and other endogenous hydroxy secosteroid metabolite levels. To address this, we used blood samples from a randomized double-blind intervention study with 35 participants of both sexes in February 2023. The participants were divided into two groups: one received a standardized meal made from UVB-treated mushrooms, and the control group received the same meal made from nonirradiated mushrooms for seven days. Blood samples were collected before consumption, 3 hours, and 6 hours post-prandial, after seven days, and again 3 months later in summer. During the research stay, we were able to process the 166 samples with an adapted protocol to extract the sterol fractions for qTOF-LC/MS analysis. Starting with measurements of L 3 and its hydroxyderivatives, qTOF-LC/MS analysis successfully detected L 3 and its hydroxyderivatives, 25(OH)L 3 and 25(R)-27(OH)L3, in the human blood samples examined. A collaboration with Robert C. Tuckey was established for the purification and biochemical synthesis of necessary standards for (hydroxy-)L2, allowing further analysis of absorbed and metabolized L2 from UVB-treated mushrooms. It was also shown for the first time that human skin cells express and secrete the hormone fibroblast growth factor 23 (FGF23), which is regulated by 1,25(OH) 2D3 and its VDR. In addition, novel targets of FGF23 in the skin were described based on the observed FGF23-mediated stimulation of gene expression of the sterol metabolizing enzymes CYP11A1 and CYP27A1. Other findings indicate that CYP11A1- derived hydroxyvitamin D3 compounds can regulate osteoblast gene expression, and that 1αhydroxylation plays a key role in their biological effects. Finally, further experiments provided the opportunity to analyze the role of (hydroxy-) D3 and L3 in regulating gene expression in primary skin cell lines from mice deficient in RAR-related orphan receptor alpha or gamma to determine their role in D3 and L3 function. These existing and pending results advance our understanding of the bioavailability, metabolism, and potential hormonal activities of photoisomers and other D3 compounds.
Publications
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The vitamin D3 hormone, 1,25(OH)2D3, regulates fibroblast growth factor 23 (FGF23) production in human skin cells. American Journal of Physiology-Cell Physiology, 328(4), C1177-C1192.
Ewendt, Franz; Janjetovic, Zorica; Kim, Tae-Kang; Mobley, Alisa A.; Brożyna, Anna A.; Ravichandran, Senthilkumar; Fabisiak, Adrian; Brzeminski, Pawel; Sicinski, Rafal R.; Stangl, Gabriele I.; Tuckey, Robert C. & Slominski, Andrzej T.
