The farnesoid-X receptor (FXR) (image), also known as the chief regulator of bile acid metabolism, is thought to play a role in some hepatobiliary and gastrointestinal disorders. In a study published online on January 11, 2015 in The American Journal of Pathology, researchers demonstrated dysfunctional intestinal FXR-signaling in a rat model of cholestatic liver injury, accompanied by intestinal bacterial translocation (BTL) and increased permeability and inflammation. Notably, a highly potent, selective FXR agonist, obeticholic acid (INT-747), counteracted these effects, suggesting a potential new therapeutic avenue for liver disease. FXR has been recognized as a key transcription-regulator in hepatic and intestinal bile metabolism. “In experimental cholestasis, FXR-agonism improves ileal barrier function by attenuating intestinal inflammation leading to reduced bacterial translocation, demonstrating a crucial protective role for FXR in the gut-liver axis,” said lead investigator Len Verbeke, M.D., Ph.D., of the Division of Liver and Biliopancreatic Disorders at University Hospitals Leuven, KU Leuven-University of Leuven, Belgium. The experimental model used generated cholestatic liver injury in rats (cholestasis refers to a condition in which the flow of bile is blocked). In one experiment, 51 rats underwent ligation of the common bile duct (BDL) and were then treated with vehicle, 5 mg/kg ursodeoxycholic acid (UDCA), or 5 mg/kg of the FXR agonist INT-747 by gavage every two days for 10 days after surgery. UDCA is a bile acid similar in molecular structure to INT-747, which lacks FXR-agonizing properties. INT-747 is a semisynthetic bile acid derivative that is a first-in-class FXR agonist.
Login Or Register To Read Full Story