ABSTRACT
CYP11A1 and CYP27A1 hydroxylate tachysterol3, a photoproduct of previtamin D3, producing 20S-hydroxytachysterol3 [20S(OH)T3] and 25(OH)T3, respectively. Both metabolites were detected in the human epidermis and serum. Tachysterol3 was also detected in human serum at a concentration of 7.3 ± 2.5 ng/ml. 20S(OH)T3 and 25(OH)T3 inhibited the proliferation of epidermal keratinocytes and dermal fibroblasts and stimulated the expression of differentiation and anti-oxidative genes in keratinocytes in a similar manner to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. They acted on the vitamin D receptor (VDR) as demonstrated by image flow cytometry and the translocation of VDR coupled GFP from the cytoplasm to the nucleus of melanoma cells, as well as by the stimulation of CYP24A1 expression. Functional studies using a human aryl hydrocarbon receptor (AhR) reporter assay system revealed marked activation of AhR by 20S(OH)T3, a smaller effect by 25(OH)T3, and a minimal effect for their precursor, tachysterol3. Tachysterol3 hydroxyderivatives showed high-affinity binding to the ligand-binding domain (LBD) of the liver X receptor (LXR) α and β, and the peroxisome proliferator-activated receptor γ (PPARγ) in LanthaScreen TR-FRET coactivator assays. Molecular docking using crystal structures of the LBDs of VDR, AhR, LXRs, and PPARγ revealed high docking scores for 20S(OH)T3 and 25(OH)T3, comparable to their natural ligands. The scores for the non-genomic-binding site of the VDR were very low indicating a lack of interaction with tachysterol3 ligands. Our identification of endogenous production of 20S(OH)T3 and 25(OH)T3 that are biologically active and interact with VDR, AhR, LXRs, and PPARγ, provides a new understanding of the biological function of tachysterol3.
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Date of publication: 115 July 2022; The Federation of American Societies for Experimental Biology Journal
Andrzej T. Slominski (1), Tae-Kang Kim (1), Radomir M. Slominski (1,2,3), Yuwei Song (1,2,3), Zorica Janjetovic (1), Ewa Podgorska (1), Sivani B. Reddy (1), Yuhua Song (4), Chander Raman (1), Edith K. Y. Tang (5), Adrian Fabisiak (6), Pawel Brzeminski (6), Rafal R. Sicinski (6), Venkatram Atigadda (1), Anton M. Jetten (7), Michael F. Holick (8), Robert C. Tuckey (5)
(1) Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA
(2) Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA
(3) Informatics Institute, University of Alabama at Birmingham, Birmingham, Alabama, US
(4) Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, Alabama, USA
(5) School of Molecular Sciences, The University of Western Australia, Perth, Western Australia, Australia
(6) Department of Chemistry, University of Warsaw, Warsaw, Poland
(7) Cell Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
(8) Department of Medicine, Boston University, Boston, Massachusetts, USA