The Pharmacology of Bile Acids and Their Receptors
The Pharmacology of Bile Acids and Their Receptors
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DOI：
10.1007/164_2019_238
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发表时间：
2019-01-01
期刊：
影响因子：
--
通讯作者：
Distrutti, Eleonora
中科院分区：
文献类型：
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作者：
Fiorucci, Stefano;Distrutti, Eleonora
本文综述了胆汁酸及其受体作为治疗靶点的历史观点。胆汁酸是由肝脏从胆固醇产生的非典型类固醇，并且已经被用于治疗肝脏和胆道疾病几乎半个世纪。自上个世纪的20世纪70年代初以来，鹅去氧胆酸（CDCA）（一种初级胆汁酸）和熊去氧胆酸（UDCA）（一种二级胆汁酸和CDCA的7 β差向异构体）已被证明可有效促进胆固醇结石的溶解。然而，CDCA缺乏活性和副作用，沿着腹腔镜胆囊切除术的出现，大大降低了该应用的临床相关性。然而，在世纪之交，发现胆汁酸激活特异性受体，沿着发现这些受体位于宿主和肠道微生物群的界面，调节生理相关的肠肝和肠胰腺轴，导致了“胆汁酸复兴”。与其他类固醇类似，胆汁酸结合并激活细胞表面和核受体，包括胆汁酸传感器法尼醇X受体（FXR）和G蛋白偶联胆汁酸受体，称为GPBAR 1（TGR 5）。这两种受体已被证明是可药用的，并且在过去的二十年中已经发现了两种受体的几种高效的、选择性的和非选择性的配体。目前，除了奥贝胆酸之外，已经开发了CDCA的半合成衍生物和第一种批准用于临床使用的FXR配体，选择性或双重FXR和GPBAR 1配体，其中一些正在进行批准前试验。本文综述了FXR和GPBAR 1配体在不同治疗领域的作用。
This review provides a historical perspective of bile acids and their receptors as therapeutic targets. Bile acids are atypical steroids generated by the liver from cholesterol and have been used for almost half a century for treating liver and biliary disorders. Since the early 1970s of the last century, chenodeoxycholic acid (CDCA), a primary bile acid, and ursodeoxycholic acid (UDCA), a secondary bile acid and the 7 beta epimer of CDCA, have been shown effective in promoting the dissolution of cholesterol gallstones. However, lack of activity and side effects associated with the use of CDCA, along with the advent of laparoscopic cholecystectomy, have greatly reduced the clinical relevance of this application. At the turn of the century, however, the discovery that bile acids activate specific receptors, along with the discovery that those receptors are placed at the interface of the host and intestinal microbiota regulating physiologically relevant enterohepatic and entero-pancreatic axes, has led to a "bile acid renaissance." Similarly to other steroids, bile acids bind and activate both cell surface and nuclear receptors, including the bile acid sensor farnesoid X receptor (FXR) and a G-protein-coupled bile acid receptor, known as GPBAR1 (TGR5). Both receptors have been proved druggable, and several highly potent, selective, and nonselective ligands for the two receptors have been discovered in the last two decades. Currently, in addition to obeticholic acid, a semisynthetic derivative of CDCA and the first in class of FXR ligands approved for clinical use, either selective or dual FXR and GPBAR1 ligands, have been developed, and some of them are undergoing pre-approval trials. The effects of FXR and GPBAR1 ligands in different therapeutic area are reviewed.