Dichloroacetate attenuates experimental acute liver injury and reduces hepatocyte apoptosis

Background Acute liver injury (ALI) is a severe clinical condition characterized by rapid hepatic dysfunction and may progress to acute liver failure. Hepatocyte apoptosis is a critical pathological event in ALI. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, has been reported to regulate cellular metabolism and apoptosis; however, its role in ALI remains unclear. This study investigated the protective effects and potential mechanisms of DCA in experimental ALI. Methods DCA was evaluated in mouse models of ALI induced by lipopolysaccharide (LPS)/d-galactosamine (D-GalN) or tumor necrosis factor-α (TNF-α)/D-GalN. Liver injury and hepatocyte apoptosis were assessed by serum transaminase activities, histopathology, and TUNEL staining. Hepatic immune cell profiles were analyzed by flow cytometry. Hepatic cytokine mRNA expression and serum cytokine levels were measured by RT-qPCR and ELISA, respectively. Apoptosis-related proteins were examined by Western blotting. Additional acetaminophen (APAP) and thioacetamide (TAA) models were used to assess DCA-mediated hepatoprotection. Results DCA pretreatment substantially attenuated LPS/D-GalN-induced ALI, as evidenced by reduced serum transaminase levels, less severe histopathological injury, and decreased hepatocyte apoptosis. This hepatoprotective effect was not accompanied by significant changes in surface TLR4 abundance on Kupffer cells, serum inflammatory cytokine levels, or hepatic immune cell composition at the examined time points. Notably, DCA treatment was associated with reduced cleaved caspase-3 expression and increased A20 protein levels in both LPS/D-GalN- and TNF-α/D-GalN-treated mice. Conclusion DCA attenuates experimental ALI and is associated with reduced hepatocyte apoptosis and increased A20 expression.