Metformin attenuates ischemia/reperfusion injury of fatty liver in rats through inhibition of the tlr4-nf-κb axis

Abstract

Background: Donor organs for liver transplantation may often have fatty liver disease, which confers a higher sensitivity to ischemia/reperfusion (I/R) injury. At present, there is no effective treatment for the condition. Evidence has suggested that metformin, a first-line medication for diabetes, has protective effects against many disorders. However, the potential role of metformin in I/R injury in fatty liver disease remains unclear. Aims: We examined the effect of metformin treatment during I/R injury in fatty liver, and determined the possible mechanisms. Methods: SD male rats were fed a high-fat diet (520 kcal/100 g) for 14 weeks and then were subjected to the orthotopic autologous liver transplantation (OALT) model. Sections of liver tissue were stained with hematoxylin and eosin to visualize the damage. Blood and liver samples were analyzed the related proteins and components involved in inflammatory signaling pathway. Results: We found that metformin significantly ameliorated the I/R injury of fatty liver through a reduction in ALT/AST concentrations in the serum and a decrease in dead cells, as shown by the TUNEL (TdT-mediated dUTP Nick-End Labeling) assay (p<0.05). In addition, metformin significantly attenuated IL-6, IL-1β, and TNF-α production and increased the expression of active caspase-3 and uncorrectBax in the liver (p<0.05). Mechanistically, metformin suppressed the activation of TLR4/NF-κB signaling (p<0.05), resulting in a decreased inflammatory response and apoptosis. Conclusions: Our findings demonstrated that metformin attenuated I/R injury in fatty liver disease via the TLR4/NF-κB axis, suggesting that metformin could have potential therapeutic applications in I/R injury associated with liver transplantation.