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 Apcmin/+ 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.
Farnesoid X receptor (FXR) signalling in liver and intestine modulates enterohepatic bile acid circulation and lipid and glucose metabolism.
Both activation of hepatic FXR and inhibition of intestinal FXR have beneficial effects on obesity-related metabolic diseases.
As a transcriptional factor, FXR directly regulates expression of tumour suppressors involved in gastrointestinal and liver cancers.
The protective role of FXR in hepatocellular carcinoma mainly depends on hepatic modulation of bile acid homeostasis.
Tissue-specific FXR agonists and antagonists should be explored as potentially clinical drugs for metabolic disease and cancer.
Gut microbiota-derived bile acid metabolism should be considered as a new drug target for development of therapeutic strategies.
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The authors are supported by the National Cancer Institute Intramural Research Program. J.C. was supported by a fellowship from the China Scholarship Council. We thank Y. Luo, S. Takahashi and T. Yan for reading the manuscript and providing feedback.
The authors declare no competing interests.
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Sun, L., Cai, J. & Gonzalez, F.J. The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat Rev Gastroenterol Hepatol 18, 335–347 (2021). https://doi.org/10.1038/s41575-020-00404-2
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