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Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR.

Abstract
Phytosterols, components of soy-derived lipids, are among the proposed exacerbants of parenteral nutrition-associated cholestasis (PNAC). We investigated whether phytosterols contribute to bile acid (BA)-induced hepatocyte damage by antagonizing a nuclear receptor (NR) critically involved in hepatoprotection from cholestasis, FXR (farnesoid X receptor, NR1H4). In HepG2 cells, stigmasterol acetate (StigAc), a water-soluble Stig derivative, suppressed ligand-activated expression of FXR target genes involved in adaptation to cholestasis (i.e. BSEP, FGF-19, OSTalpha/beta). Furthermore, StigAc antagonized BA-activated, FXR target genes SHP and BSEP in FXR+/+, but not in FXR-/- mouse hepatocytes. Both Stig and StigAc inhibited BA-activated, FXR-dependent reporter gene expression in transfected HepG2 cells, whereas the most prevalent phytosterol in lipids, beta-sitosterol, had no inhibitory effect. Finally, among six ligand-activated NR-ligand binding domains (LBDs) tested, antagonism by StigAc was specific to only two (FXR and PXR, pregnane X receptor, NR1I2). We demonstrate that Stig, a phytosterol prevalent in soy-derived PN lipid solutions, is a potent in vitro antagonist of the NR for bile acids FXR.
AuthorsBeth A Carter, Olga A Taylor, Daniel R Prendergast, Tracy L Zimmerman, Richard Von Furstenberg, David D Moore, Saul J Karpen
JournalPediatric research (Pediatr Res) Vol. 62 Issue 3 Pg. 301-6 (Sep 2007) ISSN: 0031-3998 [Print] United States
PMID17622954 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Bile Acids and Salts
  • DNA-Binding Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • farnesoid X-activated receptor
  • Stigmasterol
Topics
  • Animals
  • Bile Acids and Salts (metabolism)
  • Cell Line
  • DNA-Binding Proteins (antagonists & inhibitors, genetics, metabolism)
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mice, Knockout
  • Molecular Structure
  • Receptors, Cytoplasmic and Nuclear (antagonists & inhibitors, genetics, metabolism)
  • Soybeans (chemistry)
  • Stigmasterol (chemistry, metabolism)
  • Transcription Factors (antagonists & inhibitors, genetics, metabolism)

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