School of Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China.
School of Life Sciences, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China.
Biomed Pharmacother. 2022 Aug;152:113154. doi: 10.1016/j.biopha.2022.113154. Epub 2022 May 30.
Liver diseases and related complications have become one of the leading causes of morbidity and mortality worldwide, yet effective medicine or approved treatment approach is still limited. Thus, novel therapy is urgently required to prevent or at least slow down the growing burden of liver transplantation or even death caused by malignant liver diseases. As the irreplaceable modulator of hepatic and intestinal signaling cascades, bile acids (BAs) play complex physiological as well as pathological roles in regulating energy and immune homeostasis in various liver diseases, including but not limited to metabolic diseases and cholangiopathies, making them highly attractive therapeutic targets. In the current review, recent progress in the research of enterohepatic circulation of BAs and potential therapeutic targets of BAs signaling, especially the development of currently available treatments, including agonizts of FXR and TGR5, analogs of FGF19, inhibitors of ASBT, and the regulation of gut microbiome through fecal microbiota transplantation were extensively summarized. Their protective effects, molecular mechanisms, and outcomes of clinical trials were highlighted. The structural features of these candidates and perspectives for their future development were further discussed. In conclusion, we believe that pharmacological therapies targeting BAs signaling represent promising and efficient strategies for the treatment of complex and multifactorial liver disorders.
肝脏疾病及其相关并发症已成为全球发病率和死亡率的主要原因之一，但有效的药物或批准的治疗方法仍然有限。因此，迫切需要新的治疗方法来预防或至少减缓恶性肝脏疾病导致的肝移植或死亡负担的增长。作为肝脏和肠道信号级联的不可替代调节剂，胆汁酸（BAs）在调节各种肝脏疾病中的能量和免疫平衡方面发挥着复杂的生理和病理作用，包括但不限于代谢疾病和胆管疾病，使其成为极具吸引力的治疗靶点。在当前的综述中，广泛总结了胆汁酸肠肝循环及其信号通路的潜在治疗靶点的最新研究进展，特别是目前可用的治疗方法的发展，包括 FXR 和 TGR5 的激动剂、FGF19 的类似物、ASBT 的抑制剂以及通过粪便微生物移植调节肠道微生物组。强调了它们的保护作用、分子机制和临床试验结果。进一步讨论了这些候选药物的结构特征及其未来发展的前景。总之，我们相信靶向胆汁酸信号通路的药理学治疗方法代表了治疗复杂和多因素肝脏疾病的有前途和有效的策略。
