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Metabolic activation of tachysterol3 to biologically active hydroxyderivatives that act on VDR, AhR, LXRs, and PPARγ receptors

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cris.lastimport.scopus2024-02-12T19:59:55Z
dc.abstract.enCYP11A1 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 ligan-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
dc.affiliationUniwersytet Warszawski
dc.contributor.authorTang, Edith K.Y.
dc.contributor.authorRaman, Chander
dc.contributor.authorSong, Yuwei
dc.contributor.authorFabisiak, Adrian
dc.contributor.authorBrzemiński, Paweł
dc.contributor.authorSłomiński, Radomir M.
dc.contributor.authorKim, Tae-Kang
dc.contributor.authorSłomiński, Andrzej T.
dc.contributor.authorSong, Yuhua
dc.contributor.authorReddy, Sivani B.
dc.contributor.authorPodgórska, Ewa
dc.contributor.authorJanjetovic, Zorica
dc.date.accessioned2024-01-25T11:27:33Z
dc.date.available2024-01-25T11:27:33Z
dc.date.issued2022
dc.description.financePublikacja bezkosztowa
dc.description.number8
dc.description.sdgGoodHealthAndWellBeing
dc.description.volume36
dc.identifier.doi10.1096/FJ.202200578R
dc.identifier.issn0892-6638
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/112306
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofFASEB Journal
dc.relation.pagese22451
dc.rightsClosedAccess
dc.sciencecloudnosend
dc.subject.enCYP11A1
dc.subject.enkeratinocytes
dc.subject.enreceptors
dc.subject.enskin
dc.subject.entachysterol
dc.subject.entachysterol hydroxymetabolites
dc.subject.enultraviolet B
dc.subject.envitamin D3
dc.titleMetabolic activation of tachysterol3 to biologically active hydroxyderivatives that act on VDR, AhR, LXRs, and PPARγ receptors
dc.typeJournalArticle
dspace.entity.typePublication