Bile acids are a large family of atypical steroids which exert their functions by binding to a family of ubiquitous cell membrane and nuclear receptors. There are two main bile acid activated receptors, FXR and GPBAR1, that are exclusively activated by bile acids, while other receptors CAR, LXRs, PXR, RORγT, S1PR2and VDR are activated by bile acids in addition to other more selective endogenous ligands. In the intestine, activation of FXR and GPBAR1 promotes the release of FGF15/19 and GLP1 which integrate their signaling with direct effects exerted by theother receptors in target tissues. This network is tuned in a time ordered manner by circadian rhythm and is critical for the regulation of metabolic process including autophagy, fast-to-feed transition, lipid and glucose metabolism, energy balance and immune responses. In the last decade FXR ligands have entered clinical trials but development of systemic FXR agonists has been proven challenging because their side effects including increased levels of cholesterol and Low Density Lipoproteins cholesterol (LDL-c) and reduced High-Density Lipoprotein cholesterol (HDL-c). In addition, pruritus has emerged as a common, dose related, side effect of FXR ligands. Intestinal-restricted FXR and GPBAR1 agonists and dual FXR/GPBAR1 agonists have been developed. Here we review the last decade in bile acids physiology and pharmacology.

胆汁酸是一大类非典型类固醇，它们通过与普遍存在的细胞膜和核受体家族结合来发挥其功能。有两种主要的胆汁酸激活受体 FXR 和 GPBAR1，它们仅被胆汁酸激活，而其他受体 CAR、LXR、PXR、RORγT、S1PR2 和 VDR 被胆汁酸以及其他更具选择性的内源性配体激活。在肠道中，FXR 和 GPBAR1 的激活促进了 FGF15/19 和 GLP1 的释放，它们将它们的信号传导与靶组织中其他受体发挥的直接作用相结合。该网络按昼夜节律及时调整，对调节代谢过程至关重要，包括自噬、快速进食过渡、脂质和葡萄糖代谢、能量平衡和免疫反应。在过去十年中，FXR 配体已进入临床试验，但已证明全身 FXR 激动剂的开发具有挑战性，因为它们的副作用包括胆固醇和低密度脂蛋白胆固醇 (LDL-c) 水平升高以及高密度脂蛋白胆固醇 (HDL-c) 降低）。此外，瘙痒已成为 FXR 配体常见的、剂量相关的副作用。已经开发了肠限制性 FXR 和 GPBAR1 激动剂和双重 FXR/GPBAR1 激动剂。在这里，我们回顾了过去十年胆汁酸生理学和药理学。瘙痒已成为 FXR 配体常见的、剂量相关的副作用。已经开发了肠限制性 FXR 和 GPBAR1 激动剂和双重 FXR/GPBAR1 激动剂。在这里，我们回顾了过去十年胆汁酸生理学和药理学。瘙痒已成为 FXR 配体常见的、剂量相关的副作用。已经开发了肠限制性 FXR 和 GPBAR1 激动剂和双重 FXR/GPBAR1 激动剂。在这里，我们回顾了过去十年胆汁酸生理学和药理学。