Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre University of Amsterdam, Amsterdam, The Netherlands.
Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
J Hepatol. 2015 Apr;62(1 Suppl):S25-37. doi: 10.1016/j.jhep.2015.02.023.
Cholestasis is an impairment of bile formation/flow at the level of the hepatocyte and/or cholangiocyte. The first, and for the moment, most established medical treatment is the natural bile acid (BA) ursodeoxycholic acid (UDCA). This secretagogue improves, e.g. in intrahepatic cholestasis of pregnancy or early stage primary biliary cirrhosis, impaired hepatocellular and cholangiocellular bile formation mainly by complex post-transcriptional mechanisms. The limited efficacy of UDCA in various cholestatic conditions urges for development of novel therapeutic approaches. These include nuclear and membrane receptor agonists and BA derivatives. The nuclear receptors farnesoid X receptor (FXR), retinoid X receptor (RXR), peroxisome proliferator-activated receptor α (PPARα), and pregnane X receptor (PXR) are transcriptional modifiers of bile formation and at present are under investigation as promising targets for therapeutic interventions in cholestatic disorders. The membrane receptors fibroblast growth factor receptor 4 (FGFR4) and apical sodium BA transporter (ASBT) deserve attention as additional therapeutic targets, as does the potential therapeutic agent norUDCA, a 23-C homologue of UDCA. Here, we provide an overview on established and future promising therapeutic agents and their potential molecular mechanisms and sites of action in cholestatic diseases.
胆汁淤积是指在肝细胞和/或胆管细胞水平胆汁形成/流动受损。目前，第一种也是最成熟的医学治疗方法是天然胆汁酸（BA）熊去氧胆酸（UDCA）。这种分泌促进剂可改善例如妊娠肝内胆汁淤积症或原发性胆汁性肝硬化的早期阶段，主要通过复杂的转录后机制来改善肝细胞和胆管细胞的胆汁形成。UDCA 在各种胆汁淤积症中的疗效有限，促使人们开发新的治疗方法。这些方法包括核受体和膜受体激动剂以及 BA 衍生物。核受体法尼醇 X 受体（FXR）、视黄醇 X 受体（RXR）、过氧化物酶体增殖物激活受体α（PPARα）和妊娠相关 X 受体（PXR）是胆汁形成的转录调节剂，目前正在作为治疗胆汁淤积症的有前途的靶点进行研究。膜受体成纤维细胞生长因子受体 4（FGFR4）和顶端钠 BA 转运体（ASBT）作为额外的治疗靶点值得关注，UDCA 的 23-C 同系物 norUDCA 也是如此。在这里，我们概述了在胆汁淤积性疾病中已建立的和有前途的治疗剂及其潜在的分子机制和作用部位。
