肝肠法尼酯X受体在代谢性疾病中的作用研究进展  

Research progress on the role of hepatoenteric farnesoid X receptor in metabolic diseases

作　　者：李云[1] 刘天宇[1] 张文军[1] Li Yun;Liu Tianyu;Zhang Wenjun(General Hospital,Tianjin Medical University,Tianjin 300052)

机构地区：[1]天津医科大学总医院,天津300052

出　　处：《天津药学》2023年第1期71-78,共8页Tianjin Pharmacy

基　　金：国家自然科学基金资助项目(No.82100574);天津市卫生健康科技项目(No.TJWJ2022QN010)。

摘　　要：法尼酯X受体(FXR)具有多种生物学功能,其在代谢性疾病中发挥的重要作用已引起研究者们的极大关注。FXR高表达于肝脏和肠道,越来越多的研究表明,肝肠FXR可以通过调控多种代谢通路影响机体糖脂、能量代谢发挥代谢改善作用,因此以肝肠FXR为靶点的激动剂及拮抗剂研究已成为探索代谢性疾病干预的有效手段。肝肠FXR的激活与抑制在防治代谢性疾病中的作用机制:肝脏FXR的激活多可通过肝脏小分子异源二聚体(SHP)依赖的方式加速下游脂肪酸氧化分解及糖代谢,抑制脂质合成改善代谢;而肠道FXR的抑制与激活则均可依赖于肠道纤维母细胞生长因子通过肠肝循环调节胆汁酸代谢产生机体代谢改善作用。与此同时,临床试验阶段的不同类型FXR激动剂与拮抗剂在改善代谢的同时不可避免地出现了不良反应,限制了其应用前景。基于肝肠FXR在代谢性疾病中相反的作用,以及肠道FXR调控糖脂代谢的复杂性,为此类药物的研发带来了新的挑战与思路。Farnesoid X receptor(FXR)possesses multi biological functions,and it has rightly attracted great attention of researchers on it due to its key role in metabolic diseases.Now,emerging evidences have suggested that FXR,highly expressed in the liver and intestine,played metabolic improvement effect via regulating multiple metabolic pathways,which could affect glucose,lipid and energy metabolism.Thus,the study of agonists and antagonists targeting hepatoenteric FXR has become an effective means to explore the intervention of metabolic diseases.The mechanism of the activation and inhibition of hepatoenteric FXR in the prevention and treatment of metabolic diseases:the activation of liver FXR can accelerate the oxidative decomposition of downstream fatty acids and glucose metabolism,inhibit lipid synthesis and improve metabolism through liver small heterodimer partner(SHP)-dependent manner;While,both the inhibition and activation of intestinal FXR can be dependent on the regulation of bile acid metabolism by intestinal fibroblastic growth factor through enterohepatic circulation to improve the body metabolism.At the same time,different types of FXR agonists and antagonists in clinical trials inevitably have adverse effects during the metabolic improvement,which limits their application prospects.Based on the opposite role of hepatointestinal FXR in metabolic diseases,and the complexity of intestinal FXR in regulating glucose and lipid metabolism,it brings new challenges and ideas for the research and development of such drugs.

关 键 词：肝肠法尼酯X受体 代谢性疾病 激动剂 拮抗剂 

分 类 号：R363[医药卫生—病理学]