Department of Liver and Biliopancreatic Disorders, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium.
Hepatology. 2014 Jun;59(6):2286-98. doi: 10.1002/hep.26939. Epub 2014 Apr 14.
The farnesoid X receptor (FXR) is a nuclear bile acid receptor involved in bile acid homeostasis, hepatic and intestinal inflammation, liver fibrosis, and cardiovascular disease. We studied the effect of short-term treatment with obeticholic acid (INT-747), a potent selective FXR agonist, on intrahepatic hemodynamic dysfunction and signaling pathways in different rat models of cirrhotic portal hypertension (PHT). For this, thioacetamide (TAA)-intoxicated and bile-duct-ligated (BDL) rats were used as models. After gavage of two doses of 30 mg/kg of INT-747 or vehicle within 24 hours, in vivo hemodynamics were assessed. Additionally, we evaluated the direct effect of INT-747 on total intrahepatic vascular resistance (IHVR) and intrahepatic vascular tone (endothelial dysfunction and hyperresponsiveness to methoxamine) by means of an in situ liver perfusion system and on hepatic stellate cell contraction in vitro. FXR expression and involved intrahepatic vasoactive pathways (e.g., endothelial nitric oxide synthase [eNOS], Rho-kinase, and dimethylarginine dimethylaminohydrolase [DDAH]) were analyzed by immunohistochemistry, reverse-transcriptase polymerase chain reaction, or western blotting. In both cirrhotic models, FXR expression was decreased. Treatment with INT-747 in TAA and BDL reactivated the FXR downstream signaling pathway and decreased portal pressure by lowering total IHVR without deleterious systemic hypotension. In the perfused TAA and BDL cirrhotic liver, INT-747 improved endothelial vasorelaxation capacity, but not hyperresponsiveness. In both groups, this was associated with an increased eNOS activity, which, in TAA, related to down-regulation of Rho-kinase and in BDL to up-regulation of DDAH-2.
FXR agonist INT-747 improves PHT in two different rat models of cirrhosis by decreasing IHVR. This hemodynamic effect relates to increased intrahepatic eNOS activity by pathways that differ depending on the etiology of cirrhosis.
研究核胆汁酸受体法尼醇 X 受体（FXR）激动剂奥贝胆酸（INT-747）短期治疗对不同肝硬化门脉高压（PHT）大鼠模型肝内血流动力学障碍及信号通路的影响。
采用四氯化碳（TAA）诱导和胆管结扎（BDL）大鼠模型。在 24 小时内给予 30mg/kg 的 INT-747 或载体两次灌胃，评估体内血流动力学。此外，通过原位肝灌注系统评估 INT-747 对总肝内血管阻力（IHVR）和肝内血管张力（内皮功能障碍和对甲氧胺的高反应性）的直接作用，并在体外评估肝星状细胞收缩。通过免疫组织化学、逆转录聚合酶链反应或 Western blot 分析 FXR 表达及涉及的肝内血管活性途径（如内皮型一氧化氮合酶[eNOS]、Rho-激酶和二甲基精氨酸二甲氨基水解酶[DDAH]）。
在两种肝硬化模型中，FXR 表达均降低。INT-747 治疗可在 TAA 和 BDL 中重新激活 FXR 下游信号通路，通过降低总 IHVR 降低门静脉压力，而不会导致有害的全身低血压。在灌注的 TAA 和 BDL 肝硬化肝脏中，INT-747 改善了内皮血管舒张能力，但不能改善高反应性。在这两组中，这与 eNOS 活性增加有关，在 TAA 中与 Rho-激酶下调有关，在 BDL 中与 DDAH-2 上调有关。
FXR 激动剂 INT-747 通过降低 IHVR 改善了两种不同的肝硬化大鼠模型中的 PHT。这种血流动力学效应与不同病因肝硬化中不同的肝内 eNOS 活性增加途径有关。
