Fibrates suppress chenodeoxycholic acid-induced RANTES expression through inhibition of NF-kappaB activation

Abstract

Fibrates, hypolipidemic agents, are reported to be effective in treatment of primary biliary cirrhosis. However, the mechanism involved in therapeutic benefits of fibrates in primary biliary cirrhosis remains unknown. In contrast, hepatic regulated upon activation, normal T-cell expressed and secreted (RANTES) is increased in patients with primary biliary cirrhosis and bile acids up-regulate RANTES expression in hepatocytes. The role of fibrates in bile acid-induced RANTES expression was investigated in human hepatoma cells; 100 microM of bezafibrate and fenofibrate decreased expression of chenodeoxycholic acid-induced RANTES mRNA and protein. In addition, luciferase enzyme assay using RANTES promoter-luciferase reporter plasmid revealed that 100 microM of bezafibrate and fenofibrate transcriptionally reduced chenodeoxycholic acid-induced RANTES gene expression. Moreover, bezafibrate clearly repressed DNA-binding activity of nuclear factor-kappaB (NF-kappaB) induced by chenodeoxycholic acid. Therefore, fibrates might be inhibitory agents of inflammatory cell migration by RANTES to the liver in patients with primary biliary cirrhosis, possibly indicating that fibrates are therapeutic agents in primary biliary cirrhosis.