Vitamin D and lumisterol derivatives can act on liver X receptors (LXRs)

Sci Rep. 2021 Apr 13;11(1):8002. doi: 10.1038/s41598-021-87061-w.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter 1 / genetics
  • ATP Binding Cassette Transporter 1 / metabolism
  • Animals
  • Animals, Newborn
  • CHO Cells
  • Calcitriol
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cholesterol Side-Chain Cleavage Enzyme / metabolism
  • Computational Biology
  • Cricetulus
  • Dermis / cytology
  • Ergosterol / pharmacology*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Hydrogen Bonding
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Ligands
  • Liver X Receptors / chemistry
  • Liver X Receptors / genetics
  • Liver X Receptors / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Protein Structure, Secondary
  • Protein Transport / drug effects
  • RNA-Seq
  • Static Electricity
  • Thermodynamics
  • Vitamin D / pharmacology*


  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • Ligands
  • Liver X Receptors
  • Vitamin D
  • Cholesterol Side-Chain Cleavage Enzyme
  • Calcitriol
  • Ergosterol