Farnesoid x receptor

The ligand activated transcription factor farnesoid X receptor (FXR) is a nuclear hormone receptor with high expression in the liver as well as in the intestine and kidney, which is activated by the primary bile acid chenodesoxycholic acid (CDCA) as well as by synthetic agonists.

The farnesoid receptor plays a central role in the metabolism and regeneration of the liver and in the integrity of the epithelial barrier of the gastrointestinal tract. Its activation leads to increased degradation and decreased biosynthesis of bile acids, thus contributing to the homeostasis of bile acids. FXR has been shown to be critically involved in the pathophysiology of liver regeneration and in lipoprotein and glucose metabolism.

Besides its function as a regulator of the bile acid balance, this receptor protein is involved in many other metabolic processes such as glucose and lipid homeostasis. It has anti-inflammatory properties. It therefore appears to be an interesting target structure for the treatment of metabolic diseases in hepatic, gastrointestinal and systemic diseases.

FXR-agonist: Based on the natural ligands of FXR, the bile acids, Obeticolic acid (OCA) as a semisynthetic derivative of the endogenous chenodesoxycholic acid has been developed to a potent FXR-agonist.

Progressive familial intrahepatic cholestasis type 5 (PFIC5) is caused by a mutation in the NR1H4 gene, which codes for the farnesoid X receptor (Vitale G et al. 2019).

1. Merk D et al (2012) Nuclear receptors as pharmaceutical targets: rise of FXR and rebirth of PPAR? Future Med Chem 4:587-588.
2. Choi JH et al (2011) Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation. Nature 477:477-81.
3. Merk D et al. (2012) Medicinal chemistry of farnesoid X receptor ligands: from agonists and antagonists to modulators. Future Med Chem 4:1015-1036.

4. Vitale G et al (2019) Familial intrahepatic cholestasis: New and wide perspectives. Dig Liver Dis 51:922-933.