法尼醇X受体(FXR)在90年代后期被鉴定为类似于类固醇受体的孤儿核受体。FXR的激活是肝脏许多生理功能中的关键步骤。FXR的一个重要作用是影响肝细胞中胆汁酸的量,它通过减少胆汁酸合成来执行,刺激胆盐出口泵,抑制它的肝肠循环,从而保护肝细胞免受胆汁酸的毒性积累。此外,FXR介导肠道胆汁酸生物转化,肝再生,葡萄糖止血,和脂质代谢。在这次审查中,我们首先讨论FXR激动剂不同多效作用的机制。然后,我们深入研究奥贝胆酸(OCA)的药代动力学,一流的选择性,有效的FXR激动剂。我们还讨论了OCA在人类中的临床旅程,它目前在各种人类疾病中的证据,以及它在未来可能扮演的角色。
Farnesoid X receptor (FXR) was identified as an orphan nuclear receptor resembling the steroid receptor in the late \'90s. Activation of FXR is a crucial step in many physiological functions of the liver. A vital role of FXR is impacting the amount of bile acids in the hepatocytes, which it performs by reducing bile acid synthesis, stimulating the bile salt export pump, and inhibiting its enterohepatic circulation, thus protecting the hepatocytes against the toxic accumulation of bile acids. Furthermore, FXR mediates bile acid biotransformation in the intestine, liver regeneration, glucose hemostasis, and lipid metabolism. In this
review, we first discuss the mechanisms of the disparate pleiotropic actions of FXR agonists. We then delve into the pharmacokinetics of Obeticholic acid (OCA), the first-in-class selective, potent FXR agonist. We additionally discuss the clinical journey of OCA in humans, its current evidence in various human diseases, and its plausible roles in the future.