A bile acid derivative with PPARγ-mediated anti-inflammatory activity

Steroids. 2018 Sep:137:40-46. doi: 10.1016/j.steroids.2018.07.011. Epub 2018 Aug 4.

Abstract

During our search for bioactive secondary metabolites in the jellyfish-derived fungus Penicillium chrysogenum J08NF-4, several bile acid derivatives (2-6) were isolated along with a new steroidal artifact (1). An in vitro anti-inflammatory assay showed that pretreatment with 1 suppressed NO production and the gene expressions of the pro-inflammatory mediators iNOS and TNF-α in LPS-induced RAW 264.7 macrophages. Docking analysis of 1 revealed that it might bind to the ligand binding domain (LBD) of PPARγ in a manner similar to that of the synthetic steroid mifepristone (7), which is used clinically to treat hypercortisolism and was recently reported to be a PPARγ agonist. Compound 1 activated PPARγ in murine Ac2F liver cells and suppressed the LPS-induced phosphorylation of the NF-κB p65 subunit leading to downregulation of pro-inflammatory mediators. Our findings suggest that 1 acts as a steroidal PPARγ activator that downregulates the expressions of pro-inflammatory mediators by suppressing the NF-κB signaling pathway.

Keywords: Anti-inflammatory activity; Bile acid derivatives; NF-κB; PPARγ agonist.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Bile Acids and Salts / chemistry*
  • Bile Acids and Salts / pharmacology*
  • Gene Expression Regulation / drug effects
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mifepristone / chemistry
  • Mifepristone / metabolism
  • Mifepristone / pharmacology
  • Molecular Docking Simulation
  • NF-kappa B / metabolism
  • PPAR gamma / chemistry
  • PPAR gamma / metabolism*
  • Protein Domains
  • RAW 264.7 Cells
  • Signal Transduction / drug effects

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Bile Acids and Salts
  • NF-kappa B
  • PPAR gamma
  • Mifepristone