The nuclear bile acid receptor FXR as a novel therapeutic target in cholestatic liver diseases: Hype or hope?
✍ Scribed by Michael Trauner
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 216 KB
- Volume
- 40
- Category
- Article
- ISSN
- 0270-9139
No coin nor oath required. For personal study only.
✦ Synopsis
Farnesoid X receptor (FXR) is a bile acid-activated transcription factor that is a member of the nuclear hormone receptor superfamily. FXR-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestatic liver damage in rat models of extrahepatic and intrahepatic cholestasis. In the bile duct ligation and alpha-naphthylisothiocyanate models of cholestasis, GW4064 treatment resulted in significant reductions in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, as well as other markers of liver damage. Rats that received GW4064 treatment also had decreased incidence and extent of necrosis, decreased inflammatory cell infiltration, and decreased bile duct proliferation. Analysis of gene expression in livers from GW4064-treated cholestatic rats revealed decreased expression of bile acid biosynthetic genes and increased expression of genes involved in bile acid transport, including the phospholipid flippase MDR2. The hepatoprotection seen in these animal models by the synthetic FXR agonist suggests FXR agonists may be useful in the treatment of cholestatic liver disease.
Comments
The discovery of nuclear receptors for bile acids has revolutionized our understanding of bile secretion and its impairment under pathological conditions (for review, see Karpen 1 and Trauner and Boyer 2 ). Many alterations in bile acid transport and metabolism in cholestasis can now be understood as nuclear receptor-mediated action. 1,2 The farnesoid X receptor (FXR) was the first to be identified, and physiologically appears to be far the most relevant nuclear bile acid receptor. [3][4][5] This landmark discovery was soon followed by the insight that other nuclear receptors (e.g., pregnane X receptor [PXR] and vitamin D receptor [VDR]) are also activated by bile acids . 6 -8