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Abstract
The interactions of derivatives of lumisterol (L3) and vitamin D3 (D3) with liver X receptors (LXRs) were investigated. Molecular docking using crystal structures of the ligand binding domains (LBDs) of LXRα and β revealed high docking scores for L3 and D3 hydroxymetabolites, similar to those of the natural ligands, predicting good binding to the receptor. RNA sequencing of murine dermal fibroblasts stimulated with D3-hydroxyderivatives revealed LXR as the second nuclear receptor pathway for several D3-hydroxyderivatives, including 1,25(OH)2D3. This was validated by their induction of genes downstream of LXR. L3 and D3-derivatives activated an LXR-response element (LXRE)-driven reporter in CHO cells and human keratinocytes, and by enhanced expression of LXR target genes. L3 and D3 derivatives showed high affinity binding to the LBD of the LXRα and β in LanthaScreen TR-FRET LXRα and β coactivator assays. The majority of metabolites functioned as LXRα/β agonists; however, 1,20,25(OH)3D3, 1,25(OH)2D3, 1,20(OH)2D3 and 25(OH)D3 acted as inverse agonists of LXRα, but as agonists of LXRβ. Molecular dynamics simulations for the selected compounds, including 1,25(OH)2D3, 1,20(OH)2D3, 25(OH)D3, 20(OH)D3, 20(OH)L3 and 20,22(OH)2L3, showed different but overlapping interactions with LXRs. Identification of D3 and L3 derivatives as ligands for LXRs suggests a new mechanism of action for these compounds.
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1 University of Alabama at Birmingham, Department of Dermatology, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000000106344187); University of Alabama at Birmingham, Comprehensive Cancer Center, Cancer Chemoprevention Program, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000000106344187); VA Medical Center, Pathology and Laboratory Medicine Service, Birmingham, USA (GRID:grid.280808.a) (ISNI:0000 0004 0419 1326)
2 University of Alabama at Birmingham, Department of Dermatology, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000000106344187)
3 University of Alabama at Birmingham, Department of Dermatology, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000000106344187); Nicolaus Copernicus University Medical College, Department of Oncology, Bydgoszcz, Poland (GRID:grid.5374.5) (ISNI:0000 0001 0943 6490)
4 University of Alabama at Birmingham, Department of Dermatology, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000000106344187); University of Alabama at Birmingham, Department of Chemistry, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000000106344187)
5 University of Alabama at Birmingham, Department of Genetics, Genomics Core Facility, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000000106344187)
6 OTAVA LTD, Vaughan, Canada (GRID:grid.265892.2)
7 The University of Western Australia, School of Molecular Sciences, Perth, Australia (GRID:grid.1012.2) (ISNI:0000 0004 1936 7910)
8 University of Alabama at Birmingham, Informatics Institute, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000000106344187)
9 National Institute of Environmental Health Sciences, National Institutes of Health, Cell Biology Section, Research Triangle Park, USA (GRID:grid.280664.e) (ISNI:0000 0001 2110 5790)
10 University of Alabama at Birmingham, Department of Biomedical Engineering, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000000106344187)