Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium.
Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
Lab Invest. 2018 Oct;98(10):1263-1275. doi: 10.1038/s41374-017-0018-z. Epub 2018 Jan 11.
Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease. The presence of portal hypertension has been demonstrated in NAFLD prior to development of inflammation or fibrosis, and is a result of extrahepatic and intrahepatic factors, principally driven by vascular dysfunction. An increased intrahepatic vascular resistance potentially contributes to progression of NAFLD via intralobular hypoxia. However, the exact mechanisms underlying vascular dysfunction in NAFLD remain unknown. This study investigates systemic hemodynamics and both aortic and intrahepatic vascular reactivity in a rat model of severe steatosis. Wistar rats were fed a methionine-choline-deficient diet, inducing steatosis, or control diet for 4 weeks. In vivo hemodynamic measurements, aortic contractility studies, and in situ liver perfusion experiments were performed. The mean arterial blood pressure was lower and portal blood pressure was higher in steatosis compared to controls. The maximal contraction force in aortic rings from steatotic rats was markedly reduced compared to controls. While blockade of nitric oxide (NO) production did not reveal any differences, cyclooxygenase (COX) blockade reduced aortic reactivity in both controls and steatosis, whereas effects were more pronounced in controls. Effects could be attributed to COX-2 iso-enzyme activity. In in situ liver perfusion experiments, exogenous NO donation or endogenous NO stimulation reduced the transhepatic pressure gradient (THPG), whereas NO synthase blockade increased the THPG only in steatosis, but not in controls. Alpha-1-adrenergic stimulation and endothelin-1 induced a significantly more pronounced increase in THPG in steatosis compared to controls. Our results demonstrate that severe steatosis, without inflammation or fibrosis, induces portal hypertension and signs of a hyperdynamic circulation, accompanied by extrahepatic arterial hyporeactivity and intrahepatic vascular hyperreactivity. The arterial hyporeactivity seems to be NO-independent, but appears to be mediated by specific COX-2-related mechanisms. Besides, the increased intrahepatic vascular resistance in steatosis appears not to be NO-related but rather to vasoconstrictor hyperreactivity.
非酒精性脂肪性肝病（NAFLD）已成为最常见的慢性肝病。在炎症或纤维化发生之前，NAFLD 就已经存在门静脉高压，这是肝外和肝内因素的结果，主要由血管功能障碍驱动。肝内血管阻力增加可能通过小叶间缺氧促进 NAFLD 的进展。然而，NAFLD 中血管功能障碍的确切机制尚不清楚。本研究在大鼠严重脂肪变性模型中研究了系统性血液动力学和主动脉及肝内血管反应性。Wistar 大鼠用蛋氨酸-胆碱缺乏饮食诱导脂肪变性或对照饮食喂养 4 周。进行了体内血液动力学测量、主动脉收缩性研究和原位肝灌注实验。与对照组相比，脂肪变性大鼠的平均动脉血压较低，门静脉压力较高。与对照组相比，脂肪变性大鼠主动脉环的最大收缩力明显降低。虽然阻断一氧化氮（NO）的产生没有显示出任何差异，但环氧化酶（COX）阻断减少了对照组和脂肪变性组的主动脉反应性，而在对照组中更为明显。这种作用可归因于 COX-2 同工酶的活性。在原位肝灌注实验中，外源性 NO 供体或内源性 NO 刺激降低了经肝压力梯度（THPG），而 NO 合酶阻断仅在脂肪变性组中增加 THPG，但在对照组中没有增加。α-1 肾上腺素能刺激和内皮素-1 引起的 THPG 增加在脂肪变性组比对照组更为显著。我们的结果表明，严重的脂肪变性，没有炎症或纤维化，会导致门静脉高压和高动力循环的迹象，同时伴有肝外动脉反应性降低和肝内血管反应性增加。动脉反应性似乎与 NO 无关，但似乎与特定的 COX-2 相关机制有关。此外，脂肪变性中增加的肝内血管阻力似乎与 NO 无关，而是与血管收缩剂的高反应性有关。
