Barcelona Hepatic Hemodynamic Laboratory, Hospital Clínic, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), 08036 Barcelona, Spain.
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
Nutrients. 2021 Oct 21;13(11):3700. doi: 10.3390/nu13113700.
Chronic liver diseases are multifactorial and the need to develop effective therapies is high. Recent studies have shown the potential of ameliorating liver disease progression through protection of the liver endothelium. Polyamine spermidine (SPD) is a caloric restriction mimetic with autophagy-enhancing properties capable of prolonging lifespan and with a proven beneficial effect in cardiovascular disease in mice and humans. We evaluated the use of dietary supplementation with SPD in two models of liver disease (CCl and CDAAH diet). We analyzed the effect of SPD on endothelial dysfunction in vitro and in vivo. C57BL/6J mice were supplemented with SPD in the drinking water prior and concomitantly with CCl and CDAAH treatments. Endothelial autophagy deficient (Atg7endo) mice were also evaluated. Liver tissue was used to evaluate the impact of SPD prophylaxis on liver damage, endothelial dysfunction, oxidative stress, mitochondrial status, inflammation and liver fibrosis. SPD improved the endothelial response to oxidative injury in vitro and improved the liver endothelial phenotype and protected against liver injury in vivo. SPD reduced the overall liver oxidative stress and improved mitochondrial fitness. The absence of benefits in the Atg7endo mice suggests an autophagy-dependent effect of SPD. This study suggests SPD diet supplementation in early phases of disease protects the liver endothelium from oxidative stress and may be an attractive approach to modify the chronic liver disease course and halt fibrosis progression.
慢性肝脏疾病是多因素的，因此需要开发有效的治疗方法。最近的研究表明，通过保护肝脏内皮细胞，有可能改善肝脏疾病的进展。多胺亚精胺（SPD）是一种热量限制模拟物，具有增强自噬的特性，能够延长寿命，并已被证明对小鼠和人类的心血管疾病有益。我们评估了在两种肝脏疾病模型（CCl 和 CDAAH 饮食）中使用 SPD 饮食补充的效果。我们分析了 SPD 对体外和体内内皮功能障碍的影响。C57BL/6J 小鼠在饮用 SPD 的同时接受 CCl 和 CDAAH 处理。还评估了内皮自噬缺陷（Atg7endo）小鼠。使用肝组织评估 SPD 预防对肝损伤、内皮功能障碍、氧化应激、线粒体状态、炎症和肝纤维化的影响。SPD 改善了体外氧化损伤的内皮反应，改善了肝内皮表型，并在体内保护了肝脏免受损伤。SPD 降低了整体肝氧化应激，改善了线粒体适应性。Atg7endo 小鼠中没有获益表明 SPD 具有自噬依赖性作用。这项研究表明，在疾病的早期阶段补充 SPD 饮食可以保护肝脏内皮免受氧化应激的影响，这可能是一种有吸引力的方法，可以改变慢性肝脏疾病的进程并阻止纤维化的进展。
