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Related Experiment Video

Updated: Apr 13, 2026

Bile Duct Ligation in Mice: Induction of Inflammatory Liver Injury and Fibrosis by Obstructive Cholestasis

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Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis.

Yaping Liu¹, Jane Binz, Mary Jo Numerick

¹Nuclear Receptor Functional Analysis, High Thruput Biology, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA.

The Journal of Clinical Investigation

|November 19, 2003

Summary

This summary is machine-generated.

Synthetic Farnesoid X receptor (FXR) agonist GW4064 protected rats from cholestatic liver damage by modulating bile acid pathways. This suggests FXR agonists may treat inherited cholestatic liver disorders.

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Area of Science:

Hepatology
Molecular Biology
Pharmacology

Background:

Farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids.
FXR regulates genes involved in bile acid metabolism and transport.
FXR deficiency in mice mimics Byler disease, a cholestatic liver disorder.

Purpose of the Study:

To investigate the protective effects of the synthetic FXR agonist GW4064 against cholestatic liver injury in rats.
To determine if GW4064 can modulate bile acid homeostasis in cholestatic conditions.

Main Methods:

Rats were subjected to bile duct ligation or alpha-naphthylisothiocyanate administration to induce cholestasis.
GW4064 was administered to cholestatic rats.
Liver injury markers (ALT, AST, LDH), liver histology, and gene expression were analyzed.

Main Results:

GW4064 treatment significantly reduced serum liver enzymes and markers of liver damage.
GW4064 decreased hepatic necrosis, inflammation, and bile duct proliferation.
Gene expression analysis showed decreased bile acid synthesis and increased bile acid transporter expression (e.g., MDR2).

Conclusions:

The synthetic FXR agonist GW4064 demonstrates significant hepatoprotective effects in rat models of cholestasis.
GW4064's mechanism involves restoring bile acid homeostasis by altering gene expression.
FXR agonists represent a potential therapeutic strategy for treating cholestatic liver diseases.