Protective functions of the bile acid phospholipid conjugate Ursodeoxycholyl Lysophosphatidylethanolamide (UDCA-LPE) during hepatofibrogenesis

胆汁酸磷脂结合物熊去氧胆酰溶血磷脂酰乙醇酰胺 (UDCA-LPE) 在肝纤维化过程中的保护功能

• 批准号: 236740732
• 负责人: Privatdozentin Dr. Anita Pathil-Warth
• 金额: --
• 依托单位: Klinik für Gastroenterologie, Infektionskrankheiten, Vergiftungen
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/236740732?language=en
• 关键词: Protective; functions; bile; acid; phospholipid

Liver fibrosis generally evolves from persisting inflammatory conditions of the liver. With increasing incidence of chronic inflammatory liver diseases such as non-alcoholic fatty disease (NAFLD), new therapeutic approaches to prevent fibrotic progression are urgently needed. As inflammation is the fuel perpetuating fibrogenesis, new anti-fibrogenic compounds capable of dampening inflammatory response within the liver in addition to the ability to inhibit ECM deposition would be desirable. Based upon the anti-inflammatory properties of certain phospholipids such as phosphatidylcholine the bile acid phospholipid conjugate Ursodeoxycholyl Lysophosphatidylethanolamide (UDCA-LPE) was designed in our group as a novel hepatoprotective agent. Our previous work revealed profound anti-apoptotic and anti-inflammatory properties of UDCA-LPE against TNF-induced cytotoxicity in vitro and further confirmed hepatoprotective functions in mouse models of endotoxin-mediated fulminant hepatitis and non-alcoholic fatty liver disease (NAFLD) in vivo. In this DFG application, we aim to characterize anti-fibrogenic functions of UDCA-LPE and its influence on pro-fibrogenic signalling pathways during hepatofibrogenesis. In our preliminary work we confirmed anti-fibrogenic functions of the conjugate in experimental models of stellate cell activation in LX2 cells, as well as in a mouse model of advanced non-alcoholic steatohepatitis with fibrosis due to long-term MCD diet. Thus, we now pursue to verify our results in primary human hepatic stellate cells and we aim to study the mechanisms contributing to an inhibition of TGF-mediated signal transduction especially regarding the suppressed phosphorylation of Smad3 and Smad2 due to UDCA-LPE. Moreover, besides the influence of the conjugate on hepatic stellate cells the effect of UDCA-LPE on TGF-mediated epithelial-to-mesenchymal transition (EMT) will be analyzed in primary mouse hepatocytes. Our preliminary data showed profound anti-inflammatory properties of UDCA-LPE due to the ability of the compound to inhibit the secretion of pro-inflammatory cyto- and chemokines by macrophages. Thus, we aim to study the suppression of inflammatory mediators by UDCA-LPE with respect to its impact on signalling pathways like e.g. the Interleukin-6/pStat3 pathway, which is supposed to play an important role during hepatofibrogenesis. Furthermore, protective functions of UDCA-LPE will be analyzed in a mouse model of NASH-induced fibrosis and hepatocarcinogenesis in vivo. The results will help to define a precise anti-fibrogenic profile of UDCA-LPE with respect to potential therapeutic applications of the conjugate for the prevention of fibrogenic progression of chronic liver disease.

肝纤维化通常由肝脏持续的炎症状况演变而来。随着非酒精性脂肪病（NAFLD）等慢性炎症性肝病发病率的增加，迫切需要新的治疗方法来预防纤维化进展。由于炎症是纤维化持续存在的动力，因此除了能够抑制 ECM 沉积之外，还需要能够抑制肝脏内炎症反应的新型抗纤维化化合物。基于某些磷脂（例如磷脂酰胆碱）的抗炎特性，我们小组设计了胆汁酸磷脂结合物熊去氧胆酰溶血磷脂酰乙醇酰胺（UDCA-LPE）作为一种新型保肝剂。我们之前的工作揭示了 UDCA-LPE 在体外对 TNF 诱导的细胞毒性具有深远的抗凋亡和抗炎特性，并进一步证实了内毒素介导的暴发性肝炎和非酒精性脂肪肝（NAFLD）小鼠体内模型的保肝功能。在此 DFG 应用中，我们旨在表征 UDCA-LPE 的抗纤维化功能及其对肝纤维化过程中促纤维化信号通路的影响。在我们的初步工作中，我们在 LX2 细胞星状细胞活化的实验模型以及因长期 MCD 饮食而导致纤维化的晚期非酒精性脂肪性肝炎小鼠模型中证实了该缀合物的抗纤维化功能。因此，我们现在试图在原代人肝星状细胞中验证我们的结果，我们的目标是研究抑制 TGF 介导的信号转导的机制，特别是 UDCA-LPE 抑制 Smad3 和 Smad2 磷酸化的机制。此外，除了缀合物对肝星状细胞的影响外，还将在原代小鼠肝细胞中分析UDCA-LPE对TGF介导的上皮间质转化（EMT）的影响。我们的初步数据显示 UDCA-LPE 具有深远的抗炎特性，因为该化合物能够抑制巨噬细胞分泌促炎细胞因子和趋化因子。因此，我们的目标是研究 UDCA-LPE 对炎症介质的抑制及其对信号通路的影响，例如信号通路。 Interleukin-6/pStat3 通路被认为在肝纤维化过程中发挥重要作用。此外，还将在 NASH 诱导的体内纤维化和肝癌发生的小鼠模型中分析 UDCA-LPE 的保护功能。这些结果将有助于确定 UDCA-LPE 的精确抗纤维化特性，并了解该缀合物预防慢性肝病纤维化进展的潜在治疗应用。