Metformin Alleviates CCl 4 -Induced Acute Liver Injury in IL-33-Overexpressing Mice by Targeting Mitochondrial Pathway-Dependent Oxidative Stress and Inflammation

Abstract Background：The liver is the main organ that coordinates metabolic flexibility and participates in nutrient metabolism; and liver injury caused by alcoholic hepatitis, viral hepatitis or fatty liver has become increasingly more prevalent. Thus, it is urgent to explore the specific mechanisms that underlie the pathology of liver injury. Current research focuses on oxidative stress and inflammation as the major causes of acute liver injury, and interleukin-33 (IL-33) is thought to have an integral role, though its contributing mechanisms remain unclear. Methods：In the present study, we evaluated the coordinated roles of stress and inflammation in CCl4-induced acute liver injury in IL-33-overexpressing mice. Results：Our results demonstrate for the first time that concurrent treatment with the mitochondrial respiratory chain complex 1 inhibitor metformin enhances mitochondrial biosynthesis and alleviates acute liver injury in IL-33-overexpressing mice with CCl4-induced injury.These results were supported by the ability of metformin to reverse changes in liver tissue pathology, AST/ALT levels, inflammatory and stress related signaling pathways, oxidative response markers, and mitochondrial respiratory chain complex subunits. Conclusion： These results provide a mechanistic basis for the activity of metformin in alleviating acute liver injury. Metformin alleviates CCl4-Induced acute liver injury in IL-33-Overexpressing mice by targeting mitochondrial pathway-dependent oxidative stress and inflammation. When CCl4 was used as a strong stressor of liver injury, IL-33+ mice were more adaptive to the stress response, resulting in better effectiveness of metformin in ameliorating liver injury.