Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Nat Rev Gastroenterol Hepatol. 2021 May;18(5):335-347. doi: 10.1038/s41575-020-00404-2. Epub 2021 Feb 10.
Farnesoid X receptor (FXR) is a ligand-activated transcription factor involved in the control of bile acid (BA) synthesis and enterohepatic circulation. FXR can influence glucose and lipid homeostasis. Hepatic FXR activation by obeticholic acid is currently used to treat primary biliary cholangitis. Late-stage clinical trials investigating the use of obeticholic acid in the treatment of nonalcoholic steatohepatitis are underway. Mouse models of metabolic disease have demonstrated that inhibition of intestinal FXR signalling reduces obesity, insulin resistance and fatty liver disease by modulation of hepatic and gut bacteria-mediated BA metabolism, and intestinal ceramide synthesis. FXR also has a role in the pathogenesis of gastrointestinal and liver cancers. Studies using tissue-specific and global Fxr-null mice have revealed that FXR acts as a suppressor of hepatocellular carcinoma, mainly through regulating BA homeostasis. Loss of whole-body FXR potentiates progression of spontaneous colorectal cancer, and obesity-induced BA imbalance promotes intestinal stem cell proliferation by suppressing intestinal FXR in Apc mice. Owing to altered gut microbiota and FXR signalling, changes in overall BA levels and specific BA metabolites probably contribute to enterohepatic tumorigenesis. Modulating intestinal FXR signalling and altering BA metabolites are potential strategies for gastrointestinal and liver cancer prevention and treatment. In this Review, studies on the role of FXR in metabolic diseases and gastrointestinal and liver cancer are discussed, and the potential for development of targeted drugs are summarized.
法尼醇 X 受体 (FXR) 是一种配体激活的转录因子，参与胆汁酸 (BA) 合成和肠肝循环的调控。FXR 可以影响葡萄糖和脂质的稳态。目前，通过使用奥贝胆酸激活肝 FXR 来治疗原发性胆汁性胆管炎。正在进行晚期临床试验，以研究奥贝胆酸在治疗非酒精性脂肪性肝炎中的应用。代谢性疾病的小鼠模型表明，通过调节肝脏和肠道细菌介导的 BA 代谢以及肠道神经酰胺合成，抑制肠道 FXR 信号可减少肥胖、胰岛素抵抗和脂肪肝疾病。FXR 还在胃肠道和肝癌的发病机制中发挥作用。使用组织特异性和全局 Fxr 基因敲除小鼠的研究表明，FXR 作为肝细胞癌的抑制因子，主要通过调节 BA 稳态起作用。全身 FXR 缺失会促进自发性结直肠癌的进展，肥胖诱导的 BA 失衡通过抑制 Apc 小鼠的肠道 FXR 促进肠干细胞增殖。由于肠道微生物群和 FXR 信号的改变，总 BA 水平和特定 BA 代谢物的变化可能有助于肠肝肿瘤的发生。调节肠道 FXR 信号和改变 BA 代谢物可能是预防和治疗胃肠道和肝癌的潜在策略。在这篇综述中，讨论了 FXR 在代谢性疾病和胃肠道及肝癌中的作用，并总结了靶向药物开发的潜力。
