It was believed that these various, sometime contradictory, activities were mainly mediated by 1,25(OH) 2D3/2, a product of the sequential hydroxylation of vitamin D3, through interaction with the nuclear vitamin D receptor (VDR) 7, 11, 12, 13, 14. It also regulates endocrine and central nervous systems and plays an important role in development, and regulates various skin functions in a heterogeneous manner 2, 3, 9, 10.

It has pleotropic activities that, in addition to regulation of body calcium homeostasis and musculoskeletal system, include a vast spectrum of actions including stimulation of differentiation and inhibition of proliferation of cells of different lineages, anti-cancerogenic effects and stimulation of innate and inhibition of adaptive immunity and inflammation, and photoprotection 2, 5, 6, 7, 8. Vitamin D3 is a product of ultraviolet B (UVB)-induced photochemical transformation of 7-dehydrocholestrol (7DHC), of which the intermediate, pre-vitamin D3, can also isomerize to lumisterol and tachysterol 1, 2, 3, 4. Identification of D3 and 元 derivatives as ligands for LXRs suggests a new mechanism of action for these compounds. Molecular dynamics simulations for the selected compounds, including 1,25(OH) 2D3, 1,20(OH) 2D3, 25(OH)D3, 20(OH)D3, 20(OH)元 and 20,22(OH) 2元, showed different but overlapping interactions with LXRs. 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. 元 and D3 derivatives showed high affinity binding to the LBD of the LXRα and β in LanthaScreen TR-FRET LXRα and β coactivator assays. 元 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. This was validated by their induction of genes downstream of LXR. 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. Molecular docking using crystal structures of the ligand binding domains (LBDs) of LXRα and β revealed high docking scores for 元 and D3 hydroxymetabolites, similar to those of the natural ligands, predicting good binding to the receptor. The interactions of derivatives of lumisterol (元) and vitamin D3 (D3) with liver X receptors (LXRs) were investigated.

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