从SIRT1-内质网应激调节途径探讨紫檀芪缓解IUGR断奶仔猪肝脏损伤的机理

Intra-uterine growth retardation (IUGR) seriously impairs the growth performance and health status of piglets and it is a key factor that limits the production efficiency of swine industry in China. Liver injury is one of the main causes that results in the poor growth, weakened disease resistance, and metabolic disorders of IUGR piglets. However, the underlying mechanism of liver injury in the IUGR piglets is unclear, and the effective interventions are still scarce. We previously found that prolonged endoplasmic reticulum stress is an important factor contributing to the liver injury of IUGR weanling piglets. SIRT1 has the capacity to improve endoplasmic reticulum function and cellular homeostasis. It may be a target for alleviating the hepatic damage of IUGR piglets. Therefore, this project will employ the route of “activating SIRT1, regulating endoplasmic reticulum stress, and repairing liver injury”. At first, we will adopt the strategy of gain-and loss-of-function, investigating the protective effect of SIRT1 on the hepatocytes of IUGR piglets under endoplasmic reticulum stress. Then, we will take the pterostilbene (a plant extract) as regulation substance, to explore the underlying mechanism of SIRT1-endoplasmic reticulum stress regulation in protecting the liver function of IUGR weanling piglets and to reveal the hepatoprotective effect of pterostilbene from the tissular, cellular, subcellular, and molecular levels, with the aid of the comprehensive profiling of protein acetylation. The results will provide new targets and approaches for improving the growth and health of the IUGR piglets.

宫内发育迟缓（IUGR）严重影响仔猪的生长发育与健康状况，是制约我国养猪生产效率的一个重要因素。肝脏损伤是导致IUGR仔猪生长性能下降、抗病能力降低、代谢功能紊乱的主要原因之一，但损伤机制尚未阐明，有效的干预措施也十分缺乏。前期研究发现，持续、剧烈的内质网应激是造成IUGR断奶仔猪肝脏损伤的重要机制。SIRT1具有改善内质网功能与细胞稳态等作用，有望成为缓解IUGR仔猪肝脏损伤的干预靶点。因此，本研究基于“SIRT1激活—内质网应激调节—肝脏损伤修复”这一思路，首先采用功能获得和缺失策略，阐明SIRT1对IUGR仔猪肝细胞内质网应激的调节作用；随后，以植物提取物紫檀芪为调控物质，从组织、细胞、亚细胞器及分子水平，并借助蛋白质乙酰化修饰谱，深入解析SIRT1-内质网应激调节途径在改善IUGR断奶仔猪肝脏功能中的潜在机制及紫檀芪的肝脏保护作用，为改善IUGR仔猪的生长和健康提供新靶点和新思路。

宫内发育迟缓（IUGR）是制约我国仔猪养殖效率的一个瓶颈问题。近来发现，以肝脏为典型的器官损伤是导致IUGR仔猪生长性能下降、抗病能力降低、代谢功能紊乱的主要原因，但其损伤机制尚未阐明，有效的干预手段也十分缺乏。前期研究发现，持续、剧烈的内质网应激是造成IUGR仔猪肝脏损伤的重要机制。SIRT1具有调节未折叠蛋白反应、改善内质网稳态等积极作用。因此，基于“SIRT1激活—内质网功能重塑—肝脏损伤修复”这一思路，本研究以紫檀芪（白藜芦醇甲基化衍生物）为调控物质，系统阐述了其对IUGR断奶仔猪肝脏内质网功能的修复作用及保肝效果。结果表明：1）SIRT1是调节细胞内质网应激的重要因子，沉默SIRT1会加剧内质网应激状态下肝细胞损伤程度，过表达SIRT1可缓解细胞损伤与内质网应激现象。2）与芪类化合物白藜芦醇、虎杖苷及白皮杉醇相比，紫檀芪具有更高的SIRT1激活效果；紫檀芪可有效缓解内质网应激肝细胞损伤程度，敲减或抑制SIRT1均会削弱紫檀芪的保护效果。3）紫檀芪在断奶仔猪日粮中的最适添加量为250 mg/kg，该剂量可有效缓解IUGR导致的断奶仔猪早期肝损伤和内质网应激，效果明显优于其母体化合物。4）紫檀芪主要通过去乙酰化作用激活PPAR信号、GSH代谢及脂肪酸代谢等重要途径，以缓解肝脏内质网应激；多组学结果揭示了EHHADH、IDH1、HMGCL、PRDX1、PRDX3及PPARα等一系列关键靶点，其共同参与紫檀芪保护肝脏的过程。本研究成果可为改善IUGR仔猪的生长性能和健康水平提供新靶点和新思路。