FXR

FXR, or Farnesoid X receptor, is a bile acid–activated nuclear receptor that functions as a transcription factor to regulate bile acid, lipid, and glucose metabolism. The receptor is encoded by the NR1H4 gene and is most abundantly expressed in the liver and small intestine, with lower levels in kidney and other tissues. FXR forms a heterodimer with the retinoid X receptor (RXR) and binds to FXR response elements in the promoters of target genes to control their expression.

Endogenous ligands for FXR are primarily bile acids, with chenodeoxycholic acid (CDCA) being a potent activator. Activation of FXR leads to coordinated regulation of genes involved in bile acid synthesis, transport, and detoxification. Key targets include SHP (small heterodimer partner), which inhibits enzymes such as CYP7A1 and CYP8B1 to decrease bile acid synthesis, and transporters such as BSEP (ABCB11) and OSTα/β (SLC51A/B) to promote bile acid export. In the intestine, FXR activation induces FGF19 (FGF15 in mice), which travels to the liver to suppress bile acid synthesis, forming a feedback loop that helps maintain bile acid homeostasis.

Pharmacologically, synthetic FXR agonists have been developed, with obeticholic acid (OCA) being the most prominent. OCA is approved for primary biliary cholangitis and is under investigation for nonalcoholic steatohepatitis (NASH) and other metabolic disorders. FXR signaling has broader implications for lipid and glucose metabolism and for inflammatory processes, including the gut–liver axis. Therapeutic targeting of FXR can cause adverse effects such as pruritus and alterations in lipid profiles, necessitating careful safety considerations in clinical use.