Koelfat Kiran V K, Visschers Ruben G J, Hodin Caroline M J M, de Waart D Rudi, van Gemert Wim G, Cleutjens Jack P M, Gijbels Marion J, Shiri-Sverdlov Ronit, Mookerjee Rajeshwar P, Lenaerts Kaatje, Schaap Frank G, Steven W M Olde Damink
Department of Surgery, Maastricht University Medical Center, Maastricht University, NUTRIM School of Nutrition and Translational Research in Me-tabolism, Maastricht, the Netherlands.
Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, the Netherlands.
J Clin Transl Res. 2017 Oct 15;3(3):318-327. eCollection 2018 Jan 15.
Intestinal failure-associated liver disease (IFALD) is a clinical challenge. The pathophysiol-ogy is multifactorial and remains poorly understood. Disturbed recirculation of bile salts, due to loss of bile via an enterocutaneous fistula, is considered a major contributing factor. We hypothesize that impaired signaling via the bile salt receptor FXR underlies the development of IFALD. The aim of this study was to investigate whether activation of FXR improves liver homeostasis during chronic loss of bile in rats.
To study consequences of chronic loss of bile, rats underwent external biliary drainage (EBD) or sham surgery for seven days, and the prophylactic potential of the FXR agonist INT-747 was assessed.
EBD for 7 days resulted in liver test abnormalities and histological liver damage. Expression of the intestinal FXR target gene was undetectable after EBD, and this was accompanied by an anticipated increase in hepatic expression, indicating increased bile salt synthesis. Treatment with INT-747 improved serum biochemistry, reduced loss of bile fluid in drained rats and prevented development of drainage-associated histological liver injury.
EBD results in extensive hepatobiliary injury and cholestasis. These data suggest that FXR activation might be a novel therapy in preventing liver dysfunction in patients with intestinal failure.
This study demonstrates that chronic loss of bile causes liver injury in rats. Abro-gated recycling of bile salts impairing of enterohepatic bile salt/FXR signaling underlies these pathological changes, as administration of FXR agonist INT747 prevents biliary drainage-induced liver damage. Phar-macological activation of FXR might be a therapeutic strategy to treat disorders accompanied by a per-turbed enterohepatic circulation such as intestinal failure-associated liver disease.
肠衰竭相关肝病（IFALD）是一项临床挑战。其病理生理学是多因素的，仍未被充分理解。由于胆汁经肠皮肤瘘流失导致胆汁盐再循环紊乱，被认为是一个主要促成因素。我们假设通过胆汁盐受体FXR的信号传导受损是IFALD发生发展的基础。本研究的目的是调查激活FXR是否能改善大鼠慢性胆汁流失期间的肝脏内环境稳定。
为研究慢性胆汁流失的后果，对大鼠进行了为期7天的外引流胆汁（EBD）或假手术，并评估了FXR激动剂INT-747的预防潜力。
EBD 7天导致肝功能检查异常和肝脏组织学损伤。EBD后未检测到肠道FXR靶基因的表达，同时肝脏表达如预期增加，表明胆汁盐合成增加。INT-747治疗改善了血清生化指标，减少了引流大鼠的胆汁液流失，并预防了与引流相关的肝脏组织学损伤的发生。
EBD导致广泛的肝胆损伤和胆汁淤积。这些数据表明，FXR激活可能是预防肠衰竭患者肝功能障碍的一种新疗法。
本研究表明，慢性胆汁流失会导致大鼠肝脏损伤。胆汁盐肠肝循环受损，导致肠肝胆汁盐/FXR信号传导受损是这些病理变化的基础，因为给予FXR激动剂INT747可预防胆汁引流引起的肝损伤。FXR的药理学激活可能是一种治疗策略，用于治疗伴有肠肝循环紊乱的疾病，如肠衰竭相关肝病。
