Glycochenodeoxycholate (GCDC) Inhibits Cytokine Induced iNOS Expression in Rat Hepatocytes

Background

Although the accumulation of hydrophobic bile acid (e.g., glycine conjugated chenodeoxycholic acid, GCDC) is considered to be an important factor contributing to cholestatic liver dysfunction, its pathogenesis is poorly understood. The purpose of this study was to examine the effect of the bile salt GCDC on the regulation of iNOS expression, a key immune modulator during liver inflammation.

Materials and methods

GCDC significantly decreased cytokine-stimulated iNOS promoter activity, and both iNOS mRNA and protein expression. GCDC decreased iNOS promoter activity by preventing IκB degradation and inhibiting NF-κB DNA-binding activity. To explore the role of iNOS in bile salt induced apoptosis, we also examined the effect of NO on caspase-3 activity.

Results

GCDC strongly induced caspase-3 activity, and this increase was abrogated by both exogenous NO exposure and endogenous NO synthesis. Furthermore, adenoviral iNOS (AdiNOS) pre-treatment decreased acute cholestatic-induced liver injury in a rat bile duct ligation model.

Conclusions

These findings indicate a novel signaling pathway where potentially toxic bile salts down-regulate hepatic iNOS expression. This blockade of the iNOS mediated antiapoptotic phenotype may have important implications in certain liver disorders.

Key Words: bile acid, nitric oxide, cholestatic liver injury, apoptosis