Metformin Attenuates Ischemia-reperfusion Injury of Fatty Liver in Rats Through Inhibition of the TLR4/NF-κB Axis

Background: Donor organs for liver transplantation may often have fatty liver disease, which confers a higher sensitivity to ischemia/reperfusion injury. At present, there is no effective treatment for the condition. Evidence has suggested that metformin, the first-line medication for diabetes, has protective effects against many disorders. However, the potential role of metformin in ischemia/reperfusion injury in fatty liver disease remains unclear. Aims: To examine the effect of metformin treatment during ischemia/reperfusion injury in fatty liver and determine the possible mechanisms. Study Design: Animal experimentation. Methods: Sprague-Dawley 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 model. Sections of liver tissue were stained with hematoxylin and eosin to visualize the damage. Blood and liver samples were used to analyze the related proteins and components involved in the inflammatory signaling pathway. Results: We found that metformin significantly ameliorated the ischemia/reperfusion injury of the fatty liver through a reduction in alanine aminotransferase/aspartate aminotransferase concentrations in the serum and a decrease in dead cells, as shown by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay (p<0.05). In addition, metformin significantly attenuated interleukin (IL)-6, IL-1β, and tumor necrosis factor-α production and increased the expression of active caspase-3 and Bax in the liver (p<0.05). Mechanistically, metformin suppressed the activation of toll-like receptor 4 (TLR4)/NF-κB signaling (p<0.05), resulting in a decreased inflammatory response and apoptosis. Conclusion: Our findings demonstrated that metformin attenuated ischemia/reperfusion injury in fatty liver disease via the TLR4/NF-κB axis, suggesting that metformin could have potential therapeutic applications in ischemia/reperfusion injury associated with liver transplantation.