Discovery that theonellasterol a marine sponge sterol is a highly selective FXR antagonist that protects against liver injury in cholestasis.
Discovery that theonellasterol a marine sponge sterol is a highly selective FXR antagonist that protects against liver injury in cholestasis.
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DOI：
10.1371/journal.pone.0030443
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Fiorucci S
中科院分区：
文献类型：
--
作者：
Renga B;Mencarelli A;D'Amore C;Cipriani S;D'Auria MV;Sepe V;Chini MG;Monti MC;Bifulco G;Zampella A;Fiorucci S
法尼醇-x受体(FXR)是一种胆汁酸感受器，表达于肝脏和胃肠道。尽管FXR配体正在接受治疗胆汁淤积的研究，胆汁淤积是一种发生在许多肝病中的生化状况，现有的治疗方法效果不佳，但在胆汁淤积的啮齿动物模型中，携带FXR基因中断的小鼠可以保护自己免受胆汁酸过载引起的肝脏损伤。Theonellasterol是从海洋海绵Theonella swinhoei中分离得到的一种4-亚甲基-24-乙基类固醇。在这里，我们表征了茶烯雌醇在FXR调节的基因和生物学功能上的活性。对人肝细胞系HepG2细胞的基因芯片分析和反式激活分析表明，茶烯雌醇是一种选择性的FXR拮抗剂，对包括维生素D受体、PPARs、PXR、LXRs、孕激素、雌激素、糖皮质激素和甲状腺等在内的多种核受体没有任何激动剂或拮抗剂活性。将细胞暴露于茶烯雌醇可拮抗天然和合成的FXR激动剂对FXR调节基因的影响，包括SHP、OSTα、BSEP和MRP4。一项旨在研究FXR拮抗剂是否能挽救梗阻性胆汁淤积症模型胆总管结扎造成的肝损伤的概念验证研究表明，茶酮类固醇可以减轻胆管结扎造成的损伤，这是通过在组织病理学上评估血清丙氨酸转氨酶水平和肝坏死程度来衡量的。对肝细胞胆汁酸摄取和排泄相关基因的分析表明，茶酮类固醇增加了肝脏MRP4的表达，MRP4是一种受FXR负调控的基侧转运体。用FXR激动剂给胆管结扎的小鼠注射FXR激动剂未能从肝损伤中拯救出来，并下调MRP4的表达。体内FXR拮抗剂可正向调节肝脏MRP4的表达，是治疗梗阻性胆汁淤积症的可行策略。
The farnesoid-x-receptor (FXR) is a bile acid sensor expressed in the liver and gastrointestinal tract. Despite FXR ligands are under investigation for treatment of cholestasis, a biochemical condition occurring in a number of liver diseases for which available therapies are poorly effective, mice harboring a disrupted FXR are protected against liver injury caused by bile acid overload in rodent models of cholestasis. Theonellasterol is a 4-methylene-24-ethylsteroid isolated from the marine sponge Theonella swinhoei. Here, we have characterized the activity of this theonellasterol on FXR-regulated genes and biological functions. Interrogation of HepG2 cells, a human hepatocyte cell line, by microarray analysis and transactivation assay shows that theonellasterol is a selective FXR antagonist, devoid of any agonistic or antagonistic activity on a number of human nuclear receptors including the vitamin D receptor, PPARs, PXR, LXRs, progesterone, estrogen, glucorticoid and thyroid receptors, among others. Exposure of HepG2 cells to theonellasterol antagonizes the effect of natural and synthetic FXR agonists on FXR-regulated genes, including SHP, OSTα, BSEP and MRP4. A proof-of-concept study carried out to investigate whether FXR antagonism rescues mice from liver injury caused by the ligation of the common bile duct, a model of obstructive cholestasis, demonstrated that theonellasterol attenuates injury caused by bile duct ligation as measured by assessing serum alanine aminostrasferase levels and extent of liver necrosis at histopathology. Analysis of genes involved in bile acid uptake and excretion by hepatocytes revealed that theonellasterol increases the liver expression of MRP4, a basolateral transporter that is negatively regulated by FXR. Administering bile duct ligated mice with an FXR agonist failed to rescue from liver injury and downregulated the expression of MRP4. FXR antagonism in vivo results in a positive modulation of MRP4 expression in the liver and is a feasible strategy to target obstructive cholestasis.
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