Activated farnesoid X receptor attenuates apoptosis and liver injury in autoimmune hepatitis.

ABSTRACT

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease associated with interface hepatitis, the presence of autoantibodies, regulatory T­cell dysfunction and raised plasma liver enzyme levels. The present study assessed the hepatoprotective and antiapoptotic role of farnesoid X receptor (FXR) in AIH. a mouse model of AIH was induced by treatment with concanavalin A (ConA). The FXR agonist, chenodeoxycholic acid (CDCA), was administered to mice exhibiting ConA­induced liver injury and a normal control. Blood samples were obtained to detect the levels of aminotransferases and inflammatory cytokines. Liver specimens were collected, and hematoxylin­eosin staining was used for histopathological examination and detection. Apoptosis was evaluated using the terminal deoxynucleotidyl-transferase­mediated dUTP nick end labeling (TUNEL) method. The expression levels of apoptosis­associated genes and proteins were determined by reverse transcription­quantitative polymerase chain reaction and western blotting, respectively. The results demonstrated that FXR was downregulated at the mRNA and protein level in the liver specimens of mice induced with ConA­induced hepatitis. Increased levels of aminotransferases and inflammatory cytokines, including interferon­Î³, tumor necrosis factor­α, interleukin (IL)­4 and IL­2, were detected in ConA­treated mice. The mice pretreated with the FXR agonist, CDCA, were more resistant to ConA hepatitis, as indicated by reduced levels of alanine transaminase/aspartate aminotransferase and aminotransferases. The activation of FXR ameliorated hepatocyte apoptosis, as demonstrated by TUNEL analysis and downregulation of the Fas/Fas ligand, tumor necrosis factor­related apoptosis­inducing ligand and caspase­3. Taken together, FXR activation ameliorated liver injury and suppressed inflammatory cytokines in ConA­induced hepatitis. FXR, therefore, exerts a protective role against ConA-induced apoptosis.