State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Acta Pharmacol Sin. 2022 May;43(5):1103-1119. doi: 10.1038/s41401-022-00880-z. Epub 2022 Feb 25.
Nonalcoholic fatty liver disease (NAFLD), a series of liver metabolic disorders manifested by lipid accumulation within hepatocytes, has become the primary cause of chronic liver diseases worldwide. About 20%-30% of NAFLD patients advance to nonalcoholic steatohepatitis (NASH), along with cell death, inflammation response and fibrogenesis. The pathogenesis of NASH is complex and its development is strongly related to multiple metabolic disorders (e.g. obesity, type 2 diabetes and cardiovascular diseases). The clinical outcomes include liver failure and hepatocellular cancer. There is no FDA-approved NASH drug so far, and thus effective therapeutics are urgently needed. Bile acids are synthesized in hepatocytes, transported into the intestine, metabolized by gut bacteria and recirculated back to the liver by the enterohepatic system. They exert pleiotropic roles in the absorption of fats and regulation of metabolism. Studies on the relevance of bile acid disturbance with NASH render it as an etiological factor in NASH pathogenesis. Recent findings on the functional identification of bile acid receptors have led to a further understanding of the pathophysiology of NASH such as metabolic dysregulation and inflammation, and bile acid receptors are recognized as attractive targets for NASH treatment. In this review, we summarize the current knowledge on the role of bile acids and the receptors in the development of NAFLD and NASH, especially the functions of farnesoid X receptor (FXR) in different tissues including liver and intestine. The progress in the development of bile acid and its receptors-based drugs for the treatment of NASH including bile acid analogs and non-bile acid modulators on bile acid metabolism is also discussed.
非酒精性脂肪性肝病（NAFLD）是一种以肝细胞内脂质积聚为特征的一系列肝脏代谢紊乱，已成为全球慢性肝病的主要病因。约 20%-30%的 NAFLD 患者会进展为非酒精性脂肪性肝炎（NASH），伴有细胞死亡、炎症反应和纤维化。NASH 的发病机制复杂，其发展与多种代谢紊乱（如肥胖、2 型糖尿病和心血管疾病）密切相关。其临床结局包括肝功能衰竭和肝细胞癌。目前还没有获得 FDA 批准的 NASH 药物，因此迫切需要有效的治疗方法。胆汁酸在肝细胞内合成，被运入肠道，被肠道细菌代谢，然后通过肠肝循环系统重新回到肝脏。它们在脂肪吸收和代谢调节中发挥着多种作用。胆汁酸紊乱与 NASH 的相关性研究表明，它是 NASH 发病机制中的一个病因。最近关于胆汁酸受体功能鉴定的研究进一步了解了 NASH 的病理生理学，如代谢失调和炎症，胆汁酸受体被认为是 NASH 治疗的有吸引力的靶点。在这篇综述中，我们总结了胆汁酸及其受体在 NAFLD 和 NASH 发展中的作用的最新知识，特别是法尼醇 X 受体（FXR）在肝脏和肠道等不同组织中的功能。还讨论了基于胆汁酸及其受体的药物在 NASH 治疗中的进展，包括胆汁酸类似物和非胆汁酸调节剂在胆汁酸代谢方面的进展。
