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 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.
Carter
Beth A
BA
Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Texas Children's Liver Center, Baylor College of Medicine, Houston 77030, USA.
Taylor
Olga A
OA
Prendergast
Daniel R
DR
Zimmerman
Tracy L
TL
Von Furstenberg
Richard
R
Moore
David D
DD
Karpen
Saul J
SJ
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013025:Glycine max / Q000737:chemistry*; D013265:Stigmasterol / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D013265:Stigmasterol; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated