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 T-cell 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 ConA-induced liver injury and a normal control. Blood samples were obtained to detect the levels of aminotransferases and inflammatory cytokines. Liver specimens were collected, and hematoxylin-eosin staining was used for histopathological examination and detection. Apoptosis was evaluated using the terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL) method. The expression levels of apoptosis-associated genes and proteins were determined by reverse transcription-quantitative 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 ConA-induced hepatitis. Increased levels of aminotransferases and inflammatory cytokines, including interferon-γ, tumor necrosis factor-α, interleukin (IL)-4 and IL-2, were detected in ConA-treated 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 factor-related apoptosis-inducing ligand and caspase-3. Taken together, FXR activation ameliorated liver injury and suppressed inflammatory cytokines in ConA-induced hepatitis. FXR, therefore, exerts a protective role against ConA-induced apoptosis.

Bacteroides acidifaciens in the gut plays a protective role against CD95-mediated liver injury

“…Previous studies showed that bile acids, SCFAs, and glutathione were involved in hepatocyte apoptosis. 34 , 39 , 40 The present study performed a metabonomic analysis of SCFAs and bile acids in the livers of Van- and Gen-treated mice (Supplementary Figures S7, S8). The levels of some SCFAs and bile acids in the livers of the Gen-treated mice were significantly higher than the Van-treated mice (Supplementary Figures S7c and S8).…”

Chenodeoxycholic Acid from Bile Inhibits Influenza A Virus Replication via Blocking Nuclear Export of Viral Ribonucleoprotein Complexes

“…The anti-apoptosis effect of CDCA has been well established by previous studies. For instance, Lian and coworkers demonstrated that CDCA, as a FXR agonist, exerts an anti-apoptotic role in a concanavalin A induced autoimmune hepatitis mouse model via downregulating Fas/Fas ligand, TRAIL, and caspase-3 [29]. Similarly, Hirano and coworkers showed that CDCA inhibited apoptosis through inducing cIAP-1 (cellular inhibitor of apoptosis protein-1) expression in hepatocytes [30].…”

Update on FXR Biology: Promising Therapeutic Target?

“…Both natural ligand CDCA and synthetic agonist GW4064 raised the expression of the suppressor of cytokine signaling 3, a negative regulator of cytokine-STAT3 signaling, contributing to the protection of hepatocellular inflammation [ 77 ]. In addition, the FXR activation also lessened apoptosis and liver injury in concanavalin A-induced autoimmune hepatitis in mice [ 78 ]. A recent study showed that FXR activation by OCA treatment ameliorated the HFD-induced hepatic inflammation through the reprogramming of arachidonate metabolism, by inducing a CYP450 epoxygenase expression [ 79 ].…”