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

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 front 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, OST alpha/beta). Furthermore, StigAc antagonized BA-activated. FXR tar et genes SHP and BSEP 9 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, NR112). 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.