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.