Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR
Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR
复制标题
DOI：
10.1203/pdr.0b013e3181256492
复制
发表时间：
2007-09-01
影响因子：
3.6
通讯作者：
Karpen, Saul J.
中科院分区：
文献类型：
--
作者：
Carter, Beth A.;Taylor, Olga A.;Karpen, Saul J.
植物甾醇。大豆衍生的脂质成分，是肠外营养相关胆汁淤积（PNAC）的加重剂。我们研究了植物甾醇是否有助于胆汁酸（BA）诱导的肝细胞损伤，通过拮抗核受体（NR）的关键参与肝保护前线胆汁淤积。FXR（法尼醇X受体，NR 1H 4）。在HepG 2细胞中，豆甾醇乙酸酯（StigAc），一种水溶性Stig衍生物，抑制参与胆汁淤积适应的FXR靶基因（即BSEP，FGF-19，OST α/β）的配体激活表达。此外，StigAc拮抗BA激活。FXR靶向FXR+/+中的基因SHP和BSEP 9。但在FXR-/-小鼠肝细胞中没有。Stig和StigAc都抑制了转染的HepG 2细胞中BA激活的FXR依赖性报告基因的表达，而脂质中最常见的植物甾醇β-谷甾醇没有抑制作用。最后，在测试的六个配体激活的NR-配体结合结构域（LBD）中，StigAc的拮抗作用仅对两个（FXR和PXR，双氢吡喃X受体，NR 112）具有特异性。我们证明，Stig，一种普遍存在于大豆衍生的PN脂质溶液中的植物甾醇，是一种有效的胆汁酸FXR的NR体外拮抗剂。
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.