The farnesoid-X-receptor (FXR) is validated target in the cholestatic disorders treatment. Obeticholic acid (OCA), the first in class of FXR agonist approved for clinical use, causes side effects including acute liver decompensation when administered to cirrhotic patients with primary biliary cholangitis at higher than recommended doses. The V-Maf avian-musculoaponeurotic-fibrosarcoma-oncogene-homolog-G (Mafg) and nuclear factor-erythroid-2-related-factor-2 (Nrf2) mediates some of the downstream effects of FXR. In the present study we have investigated the role of FXR/MafG/NRF2 pathway in the development of liver toxicity caused by OCA in rodent models of cholestasis. Cholestasis was induced by bile duct ligation (BDL) or administration of α-naphtyl-isothiocyanate (ANIT) to male Wistar rats and FXR-/- and FXR+/+ mice. Treating BDL and ANIT rats with OCA exacerbated the severity of cholestasis, hepatocytes injury and severely downregulated the expression of basolateral transporters. In mice, genetic ablation FXR or its pharmacological inhibition by 3-(naphthalen-2-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole rescued from negative regulation of MRP4 and protected against liver injury caused by ANIT. By RNAseq analysis we found that FXR antagonism effectively reversed the transcription of over 2100 genes modulated by OCA/ANIT treatment, including Mafg and Nrf2 and their target genes Cyp7a1, Cyp8b1, Mat1a, Mat2a, Gss. Genetic and pharmacological Mafg inhibition by liver delivery of siRNA antisense or S-adenosylmethionine effectively rescued from damage caused by ANIT/OCA. In contrast, Nrf2 induction by sulforaphane was protective. CONCLUSIONS: Liver injury caused by FXR agonism in cholestasis is FXR-dependent and is reversed by FXR and Mafg antagonism or Nrf2 induction.

中文翻译：

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FXR激动剂奥贝胆酸对Mafg和Nrf2的相反作用介导在胆汁淤积的啮齿动物模型中急性肝损伤的发展。

法尼醇X受体（FXR）是胆汁淤积性疾病治疗的有效靶点。批准用于临床的第一类FXR激动剂奥贝胆酸（OCA），当以高于推荐剂量的剂量给予肝硬化原发性胆管性胆管炎患者时，会引起副作用，包括急性肝失代偿。V-Maf禽肌腱膜纤维瘤肉瘤癌基因-同源物G（Mafg）和核因子-类胡萝卜素2相关因子2（Nrf2）介导FXR的一些下游作用。在本研究中，我们研究了在胆汁淤积的啮齿动物模型中，FXR / MafG / NRF2途径在OCA引起的肝毒性发展中的作用。胆汁结扎是通过胆管结扎（BDL）或对雄性Wistar大鼠以及FXR-/-和FXR + / +小鼠施用α-萘基异硫氰酸酯（ANIT）引起的。用OCA处理BDL和ANIT大鼠会加剧胆汁淤积的严重程度，肝细胞损伤并严重下调基底外侧转运蛋白的表达。在小鼠中，从MRP4的负调控中拯救了基因消融FXR或其3-（萘-2-基）-5-（哌啶丁基4-基）-1,2,4-恶二唑的药理抑制作用，从而避免了MRP4的负调控并防止肝损伤由ANIT。通过RNAseq分析，我们发现FXR拮抗作用有效逆转了由OCA / ANIT处理调制的2100多个基因的转录，包括Mafg和Nrf2及其靶基因Cyp7a1，Cyp8b1，Mat1a，Mat2a，Gss。肝脏递送siRNA反义或S-腺苷甲硫氨酸的遗传和药理学Mafg抑制作用有效地挽救了ANIT / OCA造成的损害。相反，萝卜硫烷对Nrf2的诱导是保护性的。结论：