AICAR-Induced AMPK Activation Inhibits the Noncanonical NF-κB Pathway to Attenuate Liver Injury and Fibrosis in BDL Rats

Background . To evaluate the AMP-activated protein kinase- (AMPK-) mediated signaling and NF- κ B-related inflammatory pathways that contribute to cholestatic diseases in the bile duct ligation (BDL) rat model of chronic cholestasis and verify the protective role of 5-Aminoimidazole-4-carboxamide1- β -D-ribofuranoside (AICAR) against hepatic injury and fibrosis triggered by cholestasis-related inflammation. Methods . Animals were randomly divided into three groups: sham-operated group, BDL group, and BDL+ AICAR group. Cholestatic liver injury was induced by common BDL. Two weeks later, rats in BDL+AICAR group started receiving AICAR treatment. Hepatic pathology was examined by haematoxylin and eosin (H&E) and sirius red staining and hydroxyproline assay was performed in evaluating the severity of hepatic cirrhosis. Real-time PCR and Western blot were performed for RNA gene expression of RNA and protein levels, respectively. Results . The BDL group showed liver injury as evidenced by histological changes and elevation in serum biochemicals, ductular reaction, fibrosis, and inflammation. The mRNA expression of canonical NF- κ B inflammatory cytokines such as TNF- α , IL-1 β , TGF- β , and the protein of noncanonical NF- κ B, P100, and P52 was upregulated in the livers of BDL rats. The BDL rats with the administration of AICAR could induce AMPK activation inhibiting the noncanonical NF- κ B pathway to attenuate liver injury and fibrosis in BDL rats. Conclusion . The BDL model of hepatic cholestatic injury resulting in activation of Kupffer cells and recruitment of immune cells might initiate an inflammatory response through activation of the NF- κ B pathway. The AMPK activator AICAR significantly alleviated BDL-induced inflammation in rats by mainly inhibiting the noncanonical NF- κ B pathway and thus protecting against hepatic injury and fibrosis triggered by BDL.