Department of Gastrointestinal Surgery & Solid Organ Transplant, Amrita Institute of Medical Sciences & Research Centre, Amrita University, Kochi 682041, Kerala, India.
Department of Gastroenterology & Hepatology, Amrita Institute of Medical Sciences & Research Centre, Amrita University, Kochi 682041, Kerala, India.
Curr Rev Clin Exp Pharmacol. 2024;19(3):225-233. doi: 10.2174/0127724328239536230919070001.
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.
法尼醇 X 受体 (FXR) 在 90 年代后期被鉴定为一种类似于甾体受体的孤儿核受体。FXR 的激活是肝脏许多生理功能的关键步骤。FXR 的一个重要作用是影响肝细胞中的胆汁酸含量,它通过减少胆汁酸合成、刺激胆汁盐输出泵和抑制其肠肝循环来实现,从而保护肝细胞免受胆汁酸的毒性积累。此外,FXR 介导肠道中的胆汁酸生物转化、肝脏再生、葡萄糖止血和脂质代谢。在这篇综述中,我们首先讨论了 FXR 激动剂不同的多效作用的机制。然后,我们深入探讨了第一类选择性、强效 FXR 激动剂奥贝胆酸 (OCA) 的药代动力学。我们还讨论了 OCA 在人类中的临床历程,它在各种人类疾病中的现有证据,以及它在未来可能发挥的作用。