奥贝胆酸是一种法尼醇 X 受体激动剂，通过两种不同的途径改善肝硬化大鼠的门静脉高压,Hepatology

当前位置： X-MOL 学术 › Hepatology › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

奥贝胆酸是一种法尼醇 X 受体激动剂，通过两种不同的途径改善肝硬化大鼠的门静脉高压
Hepatology ( IF 12.9 ) Pub Date : 2014-04-14 , DOI: 10.1002/hep.26939
Len Verbeke ₁ , Ricard Farre _{2,

3} , Jonel Trebicka ₄ , Mina Komuta ₅ , Tania Roskams ₅ , Sabine Klein ₄ , Ingrid Vander Elst ₁ , Petra Windmolders ₁ , Tim Vanuytsel ₂ , Frederik Nevens ₁ , Wim Laleman ₁

Affiliation

法尼醇 X 受体 (FXR) 是一种核胆汁酸受体，参与胆汁酸稳态、肝脏和肠道炎症、肝纤维化和心血管疾病。我们研究了奥贝胆酸 (INT-747)（一种有效的选择性 FXR 激动剂）短期治疗对不同肝硬化门静脉高压 (PHT) 大鼠模型肝内血流动力学功能障碍和信号通路的影响。为此，硫代乙酰胺（TAA）中毒和胆管结扎（BDL）大鼠被用作模型。在 24 小时内灌胃两剂 30 mg/kg 的 INT-747 或赋形剂后，评估了体内血流动力学。此外，我们通过原位肝灌注系统评估了 INT-747 对肝内总血管阻力 (IHVR) 和肝内血管张力（内皮功能障碍和对甲氧胺的高反应性）的直接影响，以及对体外肝星状细胞收缩的影响。通过免疫组织化学、逆转录酶聚合酶链反应或蛋白质印迹分析 FXR 表达和涉及的肝内血管活性途径（例如，内皮一氧化氮合酶 [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。在 TAA 和 BDL 中用 INT-747 治疗重新激活了 FXR 下游信号通路，并通过降低总 IHVR 降低门静脉压力而没有有害的全身性低血压。在灌注的 TAA 和 BDL 肝硬化肝脏中，INT-747 改善内皮血管舒张能力，但不改善高反应性。在两组中，这都与 eNOS 活性增加有关，在 TAA 中，这与 Rho 激酶的下调有关，而在 BDL 中与 DDAH-2 的上调有关。结论：FXR 激动剂 INT-747 通过降低 IHVR 来改善两种不同肝硬化大鼠模型的 PHT。这种血液动力学效应与肝内 eNOS 活性增加有关，途径因肝硬化的病因而异。（肝病学 2014；59：2286–2298）FXR 激动剂 INT-747 通过降低 IHVR 来改善两种不同肝硬化大鼠模型的 PHT。这种血液动力学效应与肝内 eNOS 活性增加有关，途径因肝硬化的病因而异。（肝病学 2014；59：2286–2298）FXR 激动剂 INT-747 通过降低 IHVR 来改善两种不同肝硬化大鼠模型的 PHT。这种血液动力学效应与肝内 eNOS 活性增加有关，途径因肝硬化的病因而异。（肝病学 2014；59：2286–2298）

"点击查看英文标题和摘要"

Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats

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. Conclusion: 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. (Hepatology 2014;59:2286–2298)

更新日期：2014-04-14

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南