The glucocorticoid mometasone furoate is a novel FXR ligand that decreases inflammatory but not metabolic gene expression

Sci Rep. 2015 Sep 15;5:14086. doi: 10.1038/srep14086.

Abstract

The Farnesoid X receptor (FXR) regulates bile salt, glucose and cholesterol homeostasis by binding to DNA response elements, thereby activating gene expression (direct transactivation). FXR also inhibits the immune response via tethering to NF-κB (tethering transrepression). FXR activation therefore has therapeutic potential for liver and intestinal inflammatory diseases. We aim to identify and develop gene-selective FXR modulators, which repress inflammation, but do not interfere with its metabolic capacity. In a high-throughput reporter-based screen, mometasone furoate (MF) was identified as a compound that reduced NF-κB reporter activity in an FXR-dependent manner. MF reduced mRNA expression of pro-inflammatory cytokines, and induction of direct FXR target genes in HepG2-GFP-FXR cells and intestinal organoids was minor. Computational studies disclosed three putative binding modes of the compound within the ligand binding domain of the receptor. Interestingly, mutation of W469A residue within the FXR ligand binding domain abrogated the decrease in NF-κB activity. Finally, we show that MF-bound FXR inhibits NF-κB subunit p65 recruitment to the DNA of pro-inflammatory genes CXCL2 and IL8. Although MF is not suitable as selective anti-inflammatory FXR ligand due to nanomolar affinity for the glucocorticoid receptor, we show that separation between metabolic and anti-inflammatory functions of FXR can be achieved.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / metabolism
  • Anti-Inflammatory Agents / pharmacology
  • Gene Expression
  • Gene Expression Regulation* / drug effects
  • Genes, Reporter
  • Hep G2 Cells
  • Humans
  • Inflammation / genetics*
  • Inflammation / metabolism*
  • Ligands
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Molecular Docking Simulation
  • Mometasone Furoate / chemistry
  • Mometasone Furoate / metabolism*
  • Mometasone Furoate / pharmacology
  • NF-kappa B / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Transcription Factor RelA / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Anti-Inflammatory Agents
  • Ligands
  • NF-kappa B
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Mometasone Furoate
  • farnesoid X-activated receptor