靶向FXR治疗胆汁淤积性肝病的研究进展

Recent advances in the treatment targeting FXR for cholestatic liver disease

胆汁淤积性肝病是指肝内外各种原因造成的胆汁形成、分泌和排泄障碍,严重危害着人类的身体健康,目前尚无根治性的治疗手段。20世纪末的研究发现胆汁酸是法尼酯衍生物X受体(FXR)的天然内源性配体,通过激动FXR引起的负反馈调节自身的合成与排泄。自此,靶向FXR成为治疗胆汁淤积性肝病的新热点,相关候选药物不断涌现。本文细述了FXR的结构与功能,及其在胆汁酸代谢、脂代谢等过程中的重要调节作用,介绍了靶向FXR的药物(FXR激动剂)在胆汁淤积性肝病(原发性胆汁性肝硬化、原发性硬化性胆管炎和非酒精性脂肪性肝病)治疗中的临床应用进展。此外,进一步拓展了近年来比较新颖的在研FXR激动剂对胆汁淤积性肝病及其他疾病(骨病和心肌梗死)的基础研究新进展。

Cholestatic liver disease refers to a series disturbances involved in the synthesis,secretion and excretion of bile. It is a serious hazard to human health and still under no effective treatment. It has been found that bile acid moderating its own synthesis and secretion by negative feedback mechanism induced by binding itself to Farnesoid X receptor as a signal molecular at the end of 20 th century. Since then,targeting FXR( FXR agonist)plays an important role in the strategy of treating cholestasis and results in an emergence of a series new candidate drugs. In this review,we discussed the current knowledge about the roles of FXR in the synthesis,secretion and excretion of bile,and the clinical progress of relative drugs in the treatment of cholestatic liver disease such as primary biliary cirrhosis,primary sclerosing cholangitis,and nonalcoholic fatty liver diseases. In addition,recent advances in the basic research of cholestasis and other diseases( bone disease and myocardial infarction) based on novel FXR agonists were also introduced.