Department of Internal Medicine IV, University of Heidelberg, 69120 Heidelberg, Germany.
J Hepatol. 2011 Apr;54(4):674-84. doi: 10.1016/j.jhep.2010.07.028. Epub 2010 Sep 27.
BACKGROUND & AIMS: Excessive apoptosis and leukocyte-dependent inflammation mediated by pro-inflammatory cytokines, such as TNFα, are cardinal features of acute liver injury. This study evaluated the ability of the newly designed bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) to protect from hepatocellular injury in comparison to the known hepatoprotectant ursodeoxycholic acid (UDCA) and phosphatidylcholine (PC).
Anti-apoptotic and anti-inflammatory properties of UDCA-LPE were evaluated after TNFα treatment of embryonic human hepatocyte cell line CL48 as well as of primary human hepatocytes. Acute liver injury was induced in C57BL/6 mice with d-galactosamine/lipopolysaccharide (GalN/LPS) in order to determine in vivo efficacy of the conjugate.
UDCA-LPE inhibited TNFα-induced apoptosis and inflammation in hepatocytes in vitro and markedly ameliorated GalN/LPS-mediated fulminant hepatitis in mice, whereas UDCA or PC failed to show protection. The conjugate was able to decrease injury-induced elevation of phospholipase A(2) activity as well as its product lysophosphatidylcholine. Analysis of hepatic gene expression showed that UDCA-LPE treatment led to favourable inhibitory effects on expression profiles of key pro-inflammatory cytokines and chemokines, which are crucial for leukocyte recruitment and activation thereby inhibiting chemokine-mediated aggravation of parenchymal damage.
Thus, UDCA-LPE as a synthetic bile acid-phospholipid conjugate may represent a potent anti-inflammatory agent that is more effective than UDCA and PC for treatment of liver diseases.
过度的细胞凋亡和由促炎细胞因子（如 TNFα）介导的白细胞依赖性炎症是急性肝损伤的主要特征。本研究评估了新设计的胆汁酸-磷脂缀合物熊去氧胆酸赖氨酸磷脂酰乙醇胺（UDCA-LPE）与已知的肝保护剂熊去氧胆酸（UDCA）和磷脂酰胆碱（PC）相比，保护肝细胞免受损伤的能力。
在 TNFα处理胚胎人肝细胞系 CL48 以及原代人肝细胞后，评估 UDCA-LPE 的抗凋亡和抗炎特性。用半乳糖胺/脂多糖（GalN/LPS）诱导 C57BL/6 小鼠急性肝损伤，以确定该缀合物的体内疗效。
UDCA-LPE 在体外抑制 TNFα诱导的肝细胞凋亡和炎症，并显著改善 GalN/LPS 介导的小鼠暴发性肝炎，而 UDCA 或 PC 则未能显示保护作用。该缀合物能够降低损伤诱导的磷脂酶 A2 活性及其产物溶血磷脂酰胆碱的升高。肝基因表达分析表明，UDCA-LPE 治疗导致关键促炎细胞因子和趋化因子的表达谱出现有利的抑制作用，这些因子对于白细胞募集和激活至关重要，从而抑制趋化因子介导的实质损伤加重。
因此，作为一种合成的胆汁酸-磷脂缀合物，UDCA-LPE 可能代表一种有效的抗炎剂，比 UDCA 和 PC 更有效地治疗肝脏疾病。
