Farnesoid X receptor

Function

FXR is expressed at high levels in the liver and intestine. Chenodeoxycholic acid and other bile acids are natural ligands for FXR. Similar to other nuclear receptors, when activated, FXR translocates to the cell nucleus, forms a dimer (in this case a heterodimer with RXR) and binds to hormone response elements on DNA, which up- or down-regulates the expression of certain genes.

One of the primary functions of FXR activation is the suppression of cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis from cholesterol. FXR does not directly bind to the CYP7A1 promoter. Rather, FXR induces expression of small heterodimer partner (SHP), which then functions to inhibit transcription of the CYP7A1 gene. FXR likewise stimulates the synthesis of fibroblast growth factor 19, which also inhibits expression of CYP7A1 and sterol 12-alpha-hydroxylase (CYP8B1) via fibroblast growth factor receptor 4. In this way, a negative feedback pathway is established in which synthesis of bile acids is inhibited when cellular levels are already high.

The absence of FXR in an FXR-/- mouse model led to increased bile acids in the liver, and the spontaneous development of liver tumors. Reducing the pool of bile acids in the FXR-/- mice by feeding the bile acid sequestering resin cholestyramine reduced the number and size of the malignant lesions.

FXR has also been found to be important in regulation of hepatic triglyceride levels. Specifically, FXR activation suppresses lipogenesis and promotes free fatty acid oxidation by PPARα activation. Studies have also shown the FXR to regulate the expression and activity of epithelial transport proteins involved in fluid homeostasis in the intestine, such as the cystic fibrosis transmembrane conductance regulator (CFTR).

Activation of FXR in diabetic mice reduces plasma glucose and improves insulin sensitivity, whereas inactivation of FXR has the opposite effect.

Gastroesophageal adenocarcinoma

FXR is an important modulator of bile acid homeostasis. Loss of FXR or bile-acid dependent inhibition of FXR in progenitor cells at the gastroesophageal junction drives gastroesophageal adenocarcinoma carcinogenesis.

Interactions

Farnesoid X receptor has been shown to interact with:

• Peroxisome proliferator-activated receptor gamma coactivator 1-alpha and
• Retinoid X receptor alpha.

Ligands

A number of ligands for FXR are known, of both natural and synthetic origin.

;Agonists

• Cafestol
• Chenodeoxycholic acid
• Fexaramine
• GW 4064
• Ivermectin
• Obeticholic acid
• Tropifexor ;Antagonists
• Guggulsterone

References

References

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4. Yang F, Huang X, Yi T, Yen Y, Moore DD, Huang W. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res. 2007 Feb 1;67(3):863-7. doi: 10.1158/0008-5472.CAN-06-1078. PMID 17283114
5. (January 2015). "Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis". Acta Pharmacologica Sinica.
6. (May 2014). "Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo". Gut.
7. (2025). "Loss of FXR or Bile Acid-dependent Inhibition Accelerate Carcinogenesis of Gastroesophageal Adenocarcinoma". Cellular and Molecular Gastroenterology and Hepatology.
8. (January 2004). "Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR". Genes & Development.
9. (January 1995). "Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors". Molecular Endocrinology.
10. (2012). "Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders". Current Topics in Medicinal Chemistry.
11. (May 2012). "Farnesoid X receptor: from medicinal chemistry to clinical applications". Future Medicinal Chemistry.
12. (November 2012). "Advances in drug design with RXR modulators". Expert Opinion on Drug Discovery.
13. (July 2007). "The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors". Molecular Endocrinology.
14. (May 2015). "GW4064, an agonist of farnesoid X receptor, represses CYP3A4 expression in human hepatocytes by inducing small heterodimer partner expression". Drug Metabolism and Disposition.
15. (2014). "Beyond bile acids: targeting Farnesoid X Receptor (FXR) with natural and synthetic ligands". Current Topics in Medicinal Chemistry.
16. (2013). "The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism". Nature Communications.