FXR not required for inflammation during cholestasis

Abstract

Cholestasis is a condition that results when excretion of bile acids from the liver is interrupted. Liver injury occurs in both humans and animals as a result of cholestasis, and recent studies have shown that inflammation is required for injury. The mechanism by which cholestasis increases production of proinflammatory mediators is not completely understood. One recent study showed that farnesoid X receptor (FXR), a bile acid nuclear receptor, upregulates proinflammatory mediators in response to bile acids in vitro. This suggests that FXR is important for inflammation during cholestasis. To test this hypothesis in vivo, wild-type and FXR knockout mice were subjected to bile duct ligation (BDL), a commonly used model of cholestasis. Three days later, levels of intercellular adhesion molecule-1 (ICAM-1) and macrophage inflammatory protein-2 (MIP-2), both important for the recruitment of neutrophils to the liver, were measured. ICAM-1 levels were increased to a similar extent in wild-type and FXR knockouts subjected to BDL. MIP-2 levels increased after BDL, and induction of MIP-2 in FXR knockouts was three times greater than in wild-types. Neutrophil numbers in liver were quantified and found to be elevated to a similar extent in wild-types and FXR knockouts after BDL. Next, liver injury was evaluated by measuring serum levels of alanine aminotransferase (ALT), an indicator of hepatocyte injury. ALT levels were significantly elevated in wild-type mice subjected to BDL, and was further increased in FXR knockouts after BDL. Results from these studies suggest that inflammation in liver occurs independently of FXR during cholestasis.