肠源性成纤维细胞生长因子15在胰高血糖素样肽-2改善肠外营养相关性肝损害中的调控作用

Abnormalities of bile acids metabolism, which are regulated by enterogenous fibroblast growth factor 15 (FGF15), may play important roles in the pathogenesis of parenteral nutrition associated liver disease (PNALD). Previous researches had proved that glucagon-like peptide 2 (GLP-2) could improve cholestasis in PNALD. However, GLP-2 receptor (GLP-2R) is not expressed on hepatocytes or nonparenchymal cells in the liver and its mechanism remains to be further investigated. Thus, we propose the hypothesis that disorder of enterogenous FGF15 may make a significant contribution to the PNALD. GLP-2 maybe improve liver damage in PNALD by regulating the expression of FGF15. In order to verify this hypothesis, through the model mice with PNALD, we will explore the important relations among enterogenous FGF15, GLP-2 and PNALD and clarify the role of abnormal expression of enterogenous FGF15 in the pathogenesis of PNALD and the regulating mechanism of GLP-2 at different levels, such as molecular, cell, tissue and individual levels, using real-time PCR, Western blot, HE staining, immunohistochemistry, gene knock-out and other means. Our aim is to investigate intestinal endocrine dysfunction in the pathogenesis of PNALD from a new point of view, and provide new ideas for preventing and treating PNALD.

胆汁酸异常代谢是肠外营养相关肝损害（PNALD）重要发病机制之一，肠道成纤维细胞生长因子15（FGF15）在胆汁酸代谢中起重要调节作用。研究证实外源性胰高血糖素样肽-2（GLP-2）可减轻PNALD动物肝损害，但GLP-2受体在肝脏并无表达，其作用机制有待进一步探讨。为此，我们提出假说：肠源性FGF15分泌障碍可能是PNALD发生的重要原因，GLP-2可能通过调节肠道FGF15的表达，进而减轻及预防PNALD。为验证这一假说，本研究通过PNALD小鼠模型，采用Western blot、HE染色、免疫组化、基因敲除等技术，从分子、细胞、组织及动物整体水平等层次探讨肠源性FGF15、GLP-2与PNALD的重要关系，明确肠源性FGF15异常表达在PNALD发病中的作用及GLP-2的调控机制。本研究将从肠内分泌功能障碍这个新视点为揭示PNALD发生机制奠定基础，为PNALD的防治提供新思路。

肠外营养（PN）的出现解决了肠功能障碍时无合适途径提供营养的难题，但随之而来的肝胆系统病变也成为临床工作中常见而棘手的并发症。胆汁酸异常代谢是肠外营养相关肝损害（PNALD）重要发病机制之一，肠道成纤维细胞生长因子15（FGF15）在胆汁酸代谢中起重要调节作用。越来越多的研究证实，肠内分泌功能障碍与PNALD的发生有着密切联系。本项目主要研究目的是探讨PNALD的相关发病机制和早期预防及治疗措施。.本研究通过建立的PNALD大鼠模型，采用Western blot、HE染色、PCR等技术，探讨了肠源性FGF15异常表达在PNALD发病中的作用及胰高血糖素样肽-2（GLP-2）和ω-3多不饱和脂肪酸（ω-3PUFAs）的调控机制。研究结果表明， GLP-2可以改善PNALD大鼠肝功能相关生化指标及肝脏脂肪变性，减轻肝损害程度，参与对PNALD的保护作用。肠源性FGF15蛋白分泌减少是 PNALD 发生的重要原因，GLP-2可通过上调肠道FXR、FGF15的表达，以抑制肝脏CYP7A1的表达，进而减少胆汁酸的合成，从而达到治疗及预防PNALD的目的。此外，FXR-FGF15信号通路也在ω-3PUFAs减轻PNALD大鼠肝损伤的过程中发挥了重要作用。本研究主要从肠内分泌功能障碍这个新视点为揭示PNALD发生机制奠定了基础，为临床PNALD的防治提供新思路，为相关药物的临床应用奠定了理论基础。